Skaaby, T., Kilpeläinen, T. O. , Taylor, A. E., Mahendran ... · Skaaby, T., Kilpeläinen, T. O., Taylor, A. E., Mahendran, Y., Wong, A., Ahluwalia, T. S., Paternoster, L., Trompet,

Skaaby, T., Kilpeläinen, T. O., Taylor, A. E., Mahendran, Y., Wong, A.,Ahluwalia, T. S., Paternoster, L., Trompet, S., Stott, D. J., Flexeder,C., Zhou, A., Brusselle, G., Sajjad, A., Lahousse, L., Tiemeier, H.,Have, C. T., Thuesen, B. H., Kårhus, L. L., Møllehave, L. T., ...Linneberg, A. (2019). Association of alcohol consumption with allergicdisease and asthma: a multi-centre Mendelian randomizationanalysis. Addiction, 114(2), 216-225.https://doi.org/10.1111/add.14438

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1

Supplementary Material

CONTENTS

STUDY DESCRIPTIONS ...................................................................................................................................... 3

The Allergy98 Cohort ........................................................................................................................................ 3

British 1958 Birth Cohort .................................................................................................................................. 4

The Dan-Monica10 study .................................................................................................................................. 5

GOYA Males ..................................................................................................................................................... 6

Health2006 ......................................................................................................................................................... 7

Inter99 ................................................................................................................................................................ 8

DanFunD............................................................................................................................................................ 9

KORA .............................................................................................................................................................. 11

NSHD .............................................................................................................................................................. 12

The 1936 Cohort .............................................................................................................................................. 13

Prosper ............................................................................................................................................................. 14

The Rotterdam Study ....................................................................................................................................... 14

SHIP ................................................................................................................................................................. 15

SHIP TREND .................................................................................................................................................. 16

The Copenhagen City Heart Study .................................................................................................................. 17

The NEO study ................................................................................................................................................ 18

UK Biobank ..................................................................................................................................................... 19

SUPPLEMENTARY TABLES ............................................................................................................................ 22

Table S1 ........................................................................................................................................................... 22

Table S2 ........................................................................................................................................................... 25

Table S4 ........................................................................................................................................................... 27

MAIN SUPPLEMENTARY FIGURES ............................................................................................................... 29

Figure S1 .......................................................................................................................................................... 29

Figure S2 .......................................................................................................................................................... 30

Figure S3 .......................................................................................................................................................... 31

Figure S4 .......................................................................................................................................................... 33

Figure S5 .......................................................................................................................................................... 34

Figure S6 .......................................................................................................................................................... 35

Figure S7 .......................................................................................................................................................... 36

Figure S8 .......................................................................................................................................................... 37

Figure S9 .......................................................................................................................................................... 38

Figure S10 ........................................................................................................................................................ 39

2

Figure S11 ........................................................................................................................................................ 40

Figure S12 ........................................................................................................................................................ 41

Figure S13 ........................................................................................................................................................ 42

REFERENCES ..................................................................................................................................................... 43

3

Study descriptions

The Allergy98 Cohort

The Copenhagen Allergy study began in 1990 that included two groups of persons living in

the Western part of the Copenhagen Region (1). The first group was randomly selected from

the general population, and the other group included persons with allergic respiratory

symptoms that were chosen by a screening questionnaire from a random sample of the

general population. In the present study, we used data from the follow-up study in 1997–1998

(referred to as ‘Allergy98’). In the Allergy98 study, 1,966 persons aged 15–77 years with

Danish nationality were invited, and 1,216 (participation rate 61.9%) participated. The study

included comprehensive questionnaire, interview, clinical, and biochemical data.

Genotyping

Genotyping of the rs1229984 SNP was performed by TaqMan Chemistry (Applied

Biosystems, Foster City, CA) or PCR amplification followed by restriction cleavage

analysis(2).

Hay fever, asthma, allergic sensitization and total IgE

Hay fever was defined as a positive answer to the question: “Have you had hay fever in the

last 12 months?” Asthma was defined as a positive answer to the question: “Have you had

asthma in the last 12 months?” We used the ADVIA Centaur sIgE assay (Bayer Corporation,

New York, NY) to test serum specific IgE to mite (Dermatophagoides pteronyssinus), grass,

cat, and birch, dog and mugwort(3). The specific IgE analysis was positive if the

measurement was ≥0.35 kU/l. Specific IgE positivity, atopy, was defined as one or more

positive tests for specific IgE against the tested allergens. Serum total IgE was measured with

Immulite (Siemens, Erlangen, Germany).

Alcohol status and intake

Participants were classified as non-drinkers and ever-drinkers, respectively, depending on

their answers to the following questions: “On average, how much of the following have you

drunk each week in the last 12 months? Number of beers/glasses of wine/glasses of liquor?”

Alcohol intake per week was calculated as the sum of the number of each alcoholic beverage

consumed according to the question above.

Ethics

The Allergy98 Cohort was approved by the Ethics Committee of Copenhagen and the Danish

Data Protection Agency. We followed the recommendations of the Declaration of Helsinki,

and each participant gave informed written consent.

Funding and acknowledgements

We thank the staff at the Centre for Preventive Medicine for their assistance. The

Copenhagen Allergy Study is supported by grants from the Danish Medical Research

Council, the Danish Health Insurance Fund, the Danish Ministry of Health (the National

Health Fund for Research and Development), the Danish Medical Research Council and the

Danish Ministry of Health (Research Centre for Environmental Health: Environmental Health

Research Programme 1997), and ALK Abelló A/S, Denmark.

Additional information

The analyses are not adjusted for principal component. The alcohol and rs1229984 SNP data

was previously published by Linneberg et al(4) and Husemoen et al(2).

4

British 1958 Birth Cohort

The British 1958 birth cohort (1958BC) is a longitudinal population based study and includes

all births during one week in March in 1958 in England, Scotland and Wales (5).

Approximately 17,000 participants were recruited at birth and were subsequently followed up

at ages 7, 11, 16, 23, 33, 42 and 45 years. At each follow-up, information on socioeconomic

status, health and development, and familial and education factors were obtained. Information

on asthma and hay fever is based on information collected at the age of 42. At 45 years of

age, 11,971 participants currently living in Britain were invited to take part in a biomedical

survey, of whom 9,377 (78%) filled in a questionnaire, in which information on alcohol

intake were obtained and 8,302 (89%) also provided a blood sample, in which serum IgE

concentration were measured and DNA were extracted for genotyping.

Genotyping

Genetic information was obtained from 3000 randomly selected blood samples collected at

45 years, through the Wellcome Trust Case Control Consortium(6) in which the 1958BC was

used as a source for population controls. The samples were genotyped on the Affymetrix 6.0

platform. The SNP rs1229984 was directly genotyped with a call rate of 96%.


At age 42, participants were asked whether they had ever had asthma. 3.25% missing data

(percentage of participants with missing information on the outcome among those with

genetic data). Allergic sensitization was defined as specific IgE ≥0.30 kU/l in blood serum for

any of the following 3 inhalant allergens including dust, cat and grass. Note: specific IgE

were only measured if total IgE was greater than 30 kU/l. 2.98% missing data (percentage of

participants with missing information on the outcome among those with genetic data). Total

IgE was assayed using the HYTEC-automated enzyme immunoassay (7).

2.86% missing data (percentage of participants with missing information on the outcome

among those with genetic data). Serum total IgE were measured at the age of 45. Information

on hayfever and asthma were collected at the age of 42.


The information on alcohol intake was obtained at the age of 45. The alcohol intake data in

1958BC are intervals and we take the median value of each interval (1-7 units/week = 4

units/week; 7-14 units/week = 10.5 units/week; 14-21 units/week = 17.5 units/week; >21

units/week = 21 units/week).

Ethics

Written consent was obtained from participants for the use of information in medical studies.

The 45-year biomedical survey and genetic studies were approved by the South-East Multi-

Centre Research Ethics Committee (ref: 01/1/44) and the joint UCL/UCLH Committees on

the Ethics of Human Research (Ref: 08/H0714/40).


This work made use of data and samples generated by the 1958 Birth Cohort (NCDS) , which

is managed by the Centre for Longitudinal Studies at the UCL Institute of Education, The

authors are deeply grateful to the 1958 birth cohort participants for their longstanding

commitment and support, and to all staff for cohort coordination and data collection.

5

The management of the 1958 Birth Cohort is funded by the Economic and

Social Research Council (grant number ES/M001660/1). Access to these resources was

enabled via the 58READIE Project funded by Wellcome Trust and Medical Research Council

(grant numbers WT095219MA and G1001799). DNA collection was funded by MRC grant

G0000934 and cell-line creation by Wellcome Trust grant 068545/Z/02. This study makes

use of data generated by the Wellcome Trust Case-Control Consortium. A full list of

investigators who contributed to generation of the data is available from the Wellcome Trust

Case-Control Consortium website. Funding for the project was provided by the Wellcome

Trust under the award 076113. This research used resources provided by the Type 1 Diabetes

Genetics Consortium, a collaborative clinical study sponsored by the National Institute of

Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and

Infectious Diseases, National Human Genome Research Institute, National Institute of Child

Health and Human Development, and Juvenile Diabetes Research Foundation International

(JDRF) and supported by U01 DK062418. Great Ormond Street Hospital/University College

London, Institute of Child Health receives a proportion of funding from the Department of

Health's National Institute for Health Research (NIHR) ('Biomedical Research Centres'

funding).


The analyses are adjusted for principal component. The observational or genetic data have

previously been published.

The Dan-Monica10 study

In 1982–1984, a random sample of 4807 persons from the referral area of Glostrup County

Hospital, Copenhagen, was invited to participate in the Danish MONICA I health survey (8).

The study was a part of an international World Health Organization (WHO) co-ordinated

study, MONItoring of trends and determinants in CArdiovascular Diseases (MONICA). The

sample was selected to represent an equal number of men and women born in 1922, 1932,

1942 or 1952 (age 30, 40, 50 and 60 years). A total of 226 Individuals, who were not of

Danish nationality, were excluded. Of the remaining 4581 Danes, 3608 participated (79%).

We used data from a follow-up examination performed in 1993-1994, called Dan-

MONICA10. Since the first examination, 428 subjects had died and 23 had moved and could

not be reached. The remaining 4130 Danes were invited to a new examination, when the

participants were aged 41, 51, 61, or 71 years old. A total of 2656 (64%) participated in the

Dan-MONICA10 follow-up study. The health examinations took place a Research Centre for

Prevention and Health, Glostrup. Participants completed a self-administered questionnaire on

cardiovascular risk factors, medical history and lifestyle habits, including smoking and

physical activity. A physical examination was performed by trained staff.


Hay fever was defined as a positive answer to the question: “Has a doctor ever told you that

you had allergic hay fever?” Asthma was defined as a positive answer to the question: “Has a

doctor ever told you that you had asthma?”Allergic sensitisation, atopy, was defined by

determination of serum specific IgE as described in previous studies (9-12). In the Monica1

study, serum specific IgE positivity was tested using the ADVIA Centaur Allergy Screen

assay (Bayer HealthCare Diagnostics division, Tarrytown, N.Y., USA) (13) that is a multi-

allergen assay to detect specific serum IgE antibodies to 19 common inhalant allergens.

6

Atopy was defined as one or more positive results according to the manufacturer’s

instructions. Total IgE was not measured.




drunk each week in the last 12 months? Number of beers/glasses of wine/glasses of liquor?”



Genotyping

Genotyping of the rs1229984 SNP was performed using KBiosciences allele-specific PCR

(KASPar) (KBioscience, Hoddesdon, UK).

Ethics

Ethics approval was given by the local research ethics committee. All participants in the Dan-

Monica10 study gave written consent and the study was conducted in accordance with the

Second Helsinki Declaration.


The Dan-MONICA10 was sponsored by The Danish Heart Foundation; the Danish Medical

Research Council; The Danish Hospital Foundation of Medical Research, region of

Copenhagen, the Faroe Islands and Greenland; The Danish Health Insurance Foundation; The

Foundation of E. & M. Wedel-Wedellsborg; Landsforeningen til Bekæmpelse af

Kredsløbssygdomme; The Augustinus Foundation; The Becket Foundation; and The

Foundation of senior registrar J. & L. Boserup.


The analyses are not adjusted for principal component. The associations assessed in this study

have not previously been published.

GOYA Males

Genomics of Overweight Young Adults (GOYA) males is a longitudinal case-cohort (obese,

non-obese) study comprising a randomly (1%) selected control group and all extremely

overweight men identified among 362,200 Caucasian men examined at the mean age of 20

years at the draft boards in Copenhagen and its surrounding areas during 1943–1977. Obesity

was defined as 35% overweight relative to a local standard in use at the time (mid 1970’s),

corresponding to a BMI ≥31.0 kg/m2, which proved to be above the 99th percentile. All of

the obese and 50% of the random sampled controls, who were still living in the region, were

invited to a follow-up survey in 1992–94 at the mean age of 46 years, at which time the blood

samples were taken and genotyping were performed for a total of 673 extremely overweight

and 792 controls. With a sampling fraction of 0.5% (50% of 1%), the controls represent about

158,000 men among whom the case group was the most obese. In the current study,

information from cohort part comprising 790 individuals with non-missing data was utilized.

Genotype

Genome-wide genotyping on the Illumina 610 k quad chip was carried out at the Centre

National de Ge´notypage (CNG), Evry, France. We excluded SNPs with minor allele

7

frequency, 1%, 0.5% missing genotypes or which failed an exact test of Hardy-Weinberg

equilibrium (HWE) in the controls. We also excluded any individual who did not cluster with

the CEU individuals (Utah residents with ancestry from northern and western Europe) in a

multidimensional scaling analysis seeded with individuals from the International HapMap

release 22.


Participants were classified as non-drinkers if they reported to drink alcohol “never/almost

never” and ever-drinkers if they reported to drink alcohol “Monthly”, “Weekly” or “Daily”.

Alcohol intake per week was calculated as the sum of the number of self-reported

consumption of beers, glasses of wine, and glasses of liquor per week.


Asthma was evaluated by questionnaire with the question: ”Do you suffer from Asthma?”

Hay fever was evaluated by the question: “Does food, medicine or grass give you hay fever?”

Allergic sensitization and serum total IgE were not determined.

Ethics

The study was approved by the regional scientific ethics committee and the Danish Data

Protection Board with consent from the participants.


The GOYA study was conducted as part of the activities of the Danish Obesity Research

Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in

Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the

Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth

Cohort which was established with major funding from the Danish National Research

Foundation. Additional support for this cohort has been obtained from the Pharmacy

Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the

Augustinus Foundation, and the Health Foundation. TSA was supported by the Gene Diet

Interactions in Obesity (GENDINOB, www.gendinob.dk ) postdoctoral fellowship grant. LP

is funded by an MRC Population Health Scientist Fellowship (MR/J012165/1).


The analyses are not adjusted for principal components, but ethnic outliers and related

individuals were already excluded during post genotyping quality control. Some data were

previously published (14).

Health2006

The Health2006 study took place from 2006 to 2008 and consisted of a random sample of

7,931 Danish (Danish nationality and born in Denmark) men and women aged 18-69 years

invited to participate in a health examination(15). A total of 3,471 (43.8%) persons

participated. Potential participants living in the Copenhagen area were identified in the

central Danish Civil Registration System, and then recruited by invitation. The aim was to

investigate the prevalence and risk factors of chronic diseases such as asthma, allergies,

cardiovascular disease, and diabetes.

Genotyping

8

Blood samples were taken from all participants as part of their health examination. The buffy

coat was frozen for DNA extraction, and later genomic DNA was extracted using a Qiagen

AutoPure LS system. Genotyping was performed using KBiosciences allele-specific PCR

(KASPar) (KBiosciences, Hoddesdon, UK).


We used the ADVIA Centaur sIgE assay (Bayer Corporation, New York, NY) to test serum

specific IgE to mite (Dermatophagoides [D.] pteronyssinus), grass, cat, and birch (3). The

specific IgE analysis was positive if the measurement was ≥0.35 kU/l. Allergic sensitization,

atopy, was defined as one or more positive tests for specific IgE against the allergens.

Classification of hay fever and asthma was done by the questions: ”Has a doctor ever told

you that you had/have hay fever?” and ”Has a doctor ever told you that you had/have

asthma”. Serum total IgE was not determined.




drunk each week in the last 12 months? Number of beers/number of strong beers/glasses of

wine/ glasses of fortified wine/glasses of liquor. Alcohol intake per week was calculated as

the sum of the number of each alcoholic beverage consumed (strong beers count for 1.5 units

of alcohol) according to the question above.

Ethics

The Health2006 study was approved by the Ethical Committee of Copenhagen (KA-

20060011) and the Danish Data Protection Agency. Informed written consent was obtained

from all participants.


The Health2006 study was financially supported by grants from the Velux Foundation; the

Danish Medical Research Council, Danish Agency for Science, Technology and Innovation;

the Aase and Ejner Danielsens Foundation; ALK-Abello´ A/S (Hørsholm, Denmark), Timber

Merchant Vilhelm Bangs Foundation, MEKOS Laboratories (Denmark) and Research Centre

for Prevention and Health, the Capital Region of Denmark.


The analyses are not adjusted for principal component. The data concerning the alcohol-

associated SNP and allergy have not been published previously.

Inter99

The Inter99 study is a randomised controlled trial (CT00289237, ClinicalTrials.gov)

investigating the effects of lifestyle intervention on CVD (N=61,301) (16). We used baseline

data from a random subsample of 12,934 men and women aged approximately 30, 35, 40, 45,

50, 55, or 65 years invited to participate in a health examination during 1999-2001.

Participants were living in the Copenhagen area and were identified in the central Danish

Civil Registration System, and recruited by invitation. Only participants with a Northern

European origin (Denmark, Norway, Sweden, Iceland, and Faeroe Islands) were included in

the present study.

9

Genotyping

DNA was extracted from blood samples taken from all participants as part of their health

examination. Genotyping was performed using KBiosciences allele-specific PCR (KASPar)

(KBiosciences, Hoddesdon, UK).


Asthma was defined as a positive answer to the question: “Has a doctor ever told you that

you had asthma?” Serum samples were analyzed for specific IgE to mite (D. pteronyssinus),

grass, cat, and birch by the IMMULITE 2000 Allergy Immunoassay System (17). The

specific IgE analysis was positive if the measurement was ≥0.35 kU/l. Allergic sensitization

was defined as a positive test for specific IgE against any of the allergens. Serum total IgE

was measured with IMMULITE_ 2000 Allergy Immunoassay System in 2008(17). Hay fever

was not determined.


Alcohol intake was defined as the number of self-reported units of alcohol consumed each

week. Strong beers contributed 1.5 units of alcohol. Participants were classified as non-

drinkers and ever-drinkers, respectively, depending on their reported consumption of alcohol.

Ethics

Informed written consent was obtained from all participants. The study was approved by the

Ethical Committee of Copenhagen.


Data collection in the Inter99 study was supported economically by The Danish Medical

Research Council, The Danish Centre for Evaluation and Health Technology Assessment,

Novo Nordisk, Copenhagen County, The Danish Heart Foundation, The Danish

Pharmaceutical Association, Augustinus foundation, Ib Henriksen foundation and Becket

foundation. LLNH was supported by the Health Insurance Foundation (grant No. 2010 B

131).


The analyses are not adjusted for principal component. The data concerning the alcohol-

associated SNP (rs1229984) and allergy have not been published previously.

DanFunD

The DanFunD study (18) was initiated at the Research Centre for Prevention and Health,

Glostrup, Denmark, as a random sample of the general adult population. The cohort

comprises a total of 9,656 individuals aged 18–76 years, born in Denmark and living in the

Western part of the greater Copenhagen. The cohort consist of DanFunD part one and

DanFunD part two. In the current study, we use the DanFunD part two data. The DanFunD

part two was carried out from 2012 to 2015. A total of 7,493 individuals aged 18–72 years

participated.

Genotyping

Genotyping was conducted applying Human OmniExpress Bead array on human leukocyte

DNA, covering ~800,000 single nucleotides. The genotyping data was imputed from national

and international genotype panels.

10


Classification of hay fever and asthma was done by the questions: ”Has a doctor ever told

you that you had/have hay fever?” and ”Has a doctor ever told you that you had/have

asthma”. Serum samples were analyzed for IgE sensitization to inhalant allergens on a Phadia

250 system at Thermo Scientific ImmunoDiagnostics, Allerød, Denmark. Measurements

were performed in March-July 2016. Samples were screened for specific IgE to the most

common inhalant allergens by using the Phadiatop. Phadiatop-positive (>0.35 kUA/L)

samples were further analyzed for specific IgE to the four most clinical relevant inhalant

allergens in Denmark: grass, birch, Dermatophagoides pteronyssinus, and cat. The specific

IgE analysis was positive if the measurement was ≥0.35 kU/l. Allergic sensitization was

defined as a positive test for specific IgE against any of the allergens. Total IgE was not

measured.

Lung function

Forced expiratory volume in 1-second (FEV1) and forced vital capacity (FVC) were

measures at baseline by spirometry and expressed in litres.



their answers to the following questions: “Did you drink alcohol in the last 12 months?


consumed.

Ethics

Written informed consent was obtained from all participants, and the study was approved by

the Ethical Committee of Copenhagen County (Ethics Committee: KA-2006-0011, H-3-

2011-081, and H-3-2012- 0015) and the Danish Data Protection Agency.


This study was supported by TrygFonden (7-11-0213), the Lundbeck Foundation (R155-

2013-14070), and Novo Nordisk Foundation (NNF15OC0015896). The measurements of

serum specific IgE were funded by the Lundbeck Foundation (Grant number R165-2013-

15410), the A.P. Møller Foundation for the Advancement of Medical Science (Grant number

15-363), and Aase and Einar Danielson’s Foundation (Grant number 10-001490). The Novo

Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center

at the University of Copenhagen partially funded by an unrestricted donation from the Novo

Nordisk Foundation (www.metabol.ku.dk).


The principal investigator of the DanFunD, Torben Jørgensen, from RCPH leads the

coordination of projects and activities and is responsible for the operation of DanFunD,

including scientific, administrative, financial, ethics, and communication tasks. The steering

committee consists of Professor Torben Jørgensen, Professor Per Fink, senior scientist Sine

Skovbjerg, chief physician Jesper Mehlsen, and chief physician Lene Falgaard Eplov. The

steering committee reviews the scientific progress and oversees the direction and progress of

the scientific objectives. For more information, please contact DanFunD administrative and

scientific officer Thomas Dantoft or visit our webpage at http://www.danfund.org.

http://www.metabol.ku.dk/

11

KORA

The Cooperative Health Research in the Region of Augsburg (KORA) study is a population

based study. The study participants were recruited from the third MONICA survey (S3)

which was conducted in 1994–1995 in Augsburg, Germany. The objective and protocols of

the MONICA surveys have been previously described (19). Briefly, four cross-sectional

health surveys (MONICA S1 to S4) were performed in the population aged 25-74 years of

the city of Augsburg and two surrounding counties. In total, 4856 participants were recruited

in the S3 survey in 1994/1995. The study used for these analyses is a nested case-control

study comprising 1537 participants, which was performed between September 1997 and

December 1998 and in which cases were defined by sensitization status (SPT/RAST). Details

of the sampling frame and study design have been published earlier (20).

Genotyping

The study participants underwent a standardized medical examination including blood draw.

Genotyping was performed on the Illumina Omni 2.5 and the Illumina Omni Express

platform. Genotypes were called with Genome Studio and annotated to NCBI build 37.

(Before imputation, SNPs with call rates <98% were excluded. Imputation was performed

with IMPUTE v2.3.0 using the 1000G phase 1 (v3) reference panel.) (21).


Information on hay fever was requested using a self-administered questionnaire. The

participants were asked whether hay fever was ever diagnosed by a doctor. Information on

asthma was requested using a self-administered questionnaire. The participants were asked

whether asthma was ever diagnosed by a doctor. Allergen specific IgE antibodies to common

aeroallergens (grass and birch pollen, housedust mite, cat and Cladosporium) were

determined by the fluorescence enzyme immunoassay technique (CAP-FEIA, Pharmacia,

Uppsala, Sweden). Allergic sensitization was defined as serum specific IgE sensitivity (≥

0.35 kU/l) against at least one inhalant allergen.


Information on self-reported alcohol status and alcohol intake was not available.

Ethics

The study was approved by the ethics committee of the Bavarian Medical Association, and

written informed consent was obtained from each participant.

Funding

The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) and

the MONICA Augsburg studies were initiated and financed by the Helmholtz Zentrum

München – German Research Center for Environmental Health, which is funded by the

German Federal Ministry of Education and Research and by the State of Bavaria.

Furthermore, KORA research was supported within the Munich Center of Health Sciences

(MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ.


The analyses were not adjusted for principal components. The current associations have not

been previously published.

12

NSHD

The Medical Research Council National Survey of Health and Development (NSHD) is an

on-going prospective population based birth cohort study consisting of all births in England,

Scotland and Wales in one week in March 1946 (22). The sample includes single, legitimate

births whose fathers were in non-manual or agricultural occupations and a randomly selected

one in four of all others, whose fathers were in manual labor. The original cohort comprising

2,547 women and 2,815 men have been followed-up over 24 times since their birth. The data

collected to date include repeat cognitive function, physical, lifestyle and anthropomorphic

measures, as well as blood analytes and other measures. The cohort recently completed a

particularly intensive phase of clinical assessment and biological sampling with blood and

urine sampling and analysis, and cardiac and vascular imaging (23).

Genotyping

DNA was extracted from blood samples collected in 1999 (24). Genotyping was carried out

by LGC Genomics (Hoddesdon, UK; www.lgcgenomics.com) using fluorescence-based

competitive allele-specific PCR (KASPar).


The study has data on self-reported hay fever and self-reported asthma. The outcome hay

fever variable was derived from responses to questions about hay fever asked by the research

nurses at home visits in 1989 and 1999. In 1989, cohort members were asked whether they

had ever had hay fever, and in 1999 they were asked whether they had had it in the last 10

years. The asthma variable was derived from responses to questions about asthma asked by

the research nurses at home visits in 1989 and 1999. In 1989, cohort members were asked

whether they had ever had asthma, and in 1999 they were asked whether they had had it in

the last 10 years. Allergic sensitization and serum total IgE were not determined.


Alcohol status and intake were derived from responses to questions about drinking asked by

research nurses at home visits in 1999. The alcohol status variable was derived from

responses to whether cohort members had drunk alcohol in the last year. The alcohol intake

variable was derived from responses to questions asked about number of alcoholic drinks in

the last 7 days.


The analyses are not adjusted for principal component. Some of the observational or genetic

data have previously been published in CARTA papers or elsewhere (25).

Ethics

Ethical approval was given by the Central Manchester Research Ethics Committee, and the

participants gave informed written consent.


We are very grateful to the members of this birth cohort for their continuing interest and

participation in the study. We would like to acknowledge the Swallow group at University

College London, who performed the DNA extractions. This work was funded by the Medical

Research Council [MC_UU_12019/1].

13

The 1936 Cohort

The 1936 Cohort is a longitudinal population-based study based on a sample of 1,200

randomly selected persons living in 1976 (aged 40 years at the time of the study) in 4

municipalities (Broendby, Glostrup, Herlev, and Ledoeje-Smoerum) of Copenhagen drawn

from the Danish Civil Registration. They were invited by letter for a health examination that

focused on cardiovascular risk factors. The letter contained a questionnaire regarding medical

history, health and lifestyle that they were asked to complete in advance. Between 1976 and

1977, a total of 1,052 persons were examined (participation rate=87.7%). In 1995–1996 all

participants (now aged 60 years) were invited for a re-examination where a total of 695 were

examined (participation rate=66%). We use the re-examination data in the current study.

Genotyping

DNA was extracted and purified from leukocytes (LGC Genomics, Hoddlesdon, UK). All

participants were genotyped with the Illumina Infinium HumanCoreExome-12 BeadChip

(CoreExomeChip) using HiScan system (Illumina) at the Novo Nordisk Foundation Centre

for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. The

standard pipeline in Illumina Genome Studio software was used for the genotype calling.

A total of 538,448 markers on 684 individuals entered the Quality Control (QC) pipeline,

where 9886 markers were removed due to a call-rate below 95% before QC on individuals

could begin. 28 individuals were excluded due to: 1) a call-rate below 95%, 2) extreme

positive or negative inbreeding coefficients 3) ethnic outliers using Principal Component

Analysis (PCA) on ancestral markers, 4) unknown pedigree relation found by Identical By

Descent (IBD) analysis, where the individual with the lowest call rate for each pedigree-pair

was removed, 5) sample duplicates, and finally 6) sex discrepancy.

We used a combination of scripts written in Python (v2.7.3) and R (v3.0.1)

together with the PLINK (v1.07) software in our QC pipeline. After QC, 656 individuals with

528,562 markers were ready for imputation.

Additional genotypes were imputed with 1,000 Genomes haplotypes Phase I

integrated variant set release (SHAPE2) in NCBI build 37 (hg19) coordinates, using

IMPUTE2 (26) on all markers that passed a Hardy-Weinberg Equilibrium (HWE) filter

(pHWE<0.005), into the 1000 genomes phase 1 panel(27).


The questionnaire used in 1995–1996 (at 60 years of age) included the following questions on

atopic diseases: “Has a doctor ever told you that you had hay fever?” (self-reported hay fever

if they answered “yes”)” and “Has a doctor ever told you that you had asthma?” (self-

reported asthma if they answered “yes”).

Measurements of aeroallergen sensitization were performed using the ADVIA

Centaur® Allergy Screen assay (Bayer HealthCare Diagnostics division, Tarrytown, N.Y.,

USA) that is a multi-allergen assay for the qualitative detection of specific serum IgE

antibodies specific to serum levels of common inhalant allergens. The test includes a total of

19 common inhalant allergens. Allergic sensitization was defined as a positive result of the

binary assay output. Serum total IgE was not determined.



their self-reported consumption of beers, glasses of wine, and glasses of liquor each week.



14

Ethics

The study was conducted according to the principles of the Declaration of Helsinki. It was

approved by the Local Ethics Committee, and participants gave written informed consent.


The current analyses are not adjusted for principal component. The current associations have

not been previously published.

Prosper

All data come from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER)

that is a population-based randomized controlled trial. A detailed description of the study has

been published elsewhere (28). PROSPER was a prospective multicenter randomized

placebo-controlled trial to assess whether treatment with pravastatin diminishes the risk of

major vascular events in elderly. Between December 1997 and May 1999, we screened and

enrolled subjects in Scotland (Glasgow), Ireland (Cork), and the Netherlands (Leiden). Men

and women aged 70-82 years were recruited if they had pre-existing vascular disease or

increased risk of such disease because of smoking, hypertension, or diabetes. A total number

of 5,804 subjects were randomly assigned to pravastatin or placebo. A large number of

prospective tests were performed including Biobank tests and cognitive function

measurements.

Genotyping

A total of 5,763 subjects’ DNA was available for genotyping. Genotyping was performed

with a Taqman assay.


Asthma was defined as a self-reported diagnosis of asthma in the adverse events database.

Hay fever, allergic sensitization and total IgE were not assessed.


Alcohol status was self-reported and requested as units per week during the last month at

baseline of the study (mean age 75.3yr).

Ethics

Local hospital ethics committees in Scotland, Ireland, and the Netherlands approved the

PROSPER study, and all participants provided informed consent.


The current associations have not been previously published.

The Rotterdam Study

This study was embedded in the Rotterdam Study, a prospective population-based cohort that

started in 1990 among inhabitants aged ≥55 years residing in a suburb of Rotterdam, the

Netherlands (29). Initially 7983 persons living in the well-defined Ommoord district in the

15

city of Rotterdam in The Netherlands (78 % of 10,215 invitees) participated in the study.

From January 1990 onwards, participants were recruited for the Rotterdam Study. In 2000,

3011 participants (out of 4472 invitees) who had become 55 years of age or moved into the

study district since the start of the study were added to the cohort. In 2006 a further extension

of the cohort was initiated in which 3932 subjects were included, aged 45–54 years, out of

6057 invited, living in the Ommoord district. For the present study, after exclusion of

participants with missing data on one of the exposures and outcome (alcohol status (n=2608);

alcohol quantity (n=2321); rs1229984 genotype (n=1511); and asthma (n=509) information

on each determinant was available from 7977 participants for analyses.

Genotyping

All persons attending the baseline examination in 1990-1993 consented to genotyping, and

had DNA extracted from blood leucocytes. Genotyping of autosomal SNPs was performed in

persons with high-quality extracted DNA using the Illumina Infinium II HumanHap550chip

v3.0® array according to the manufacturer’s protocols. In the second cohort (baseline

examination in 2000), the majority of the DNA samples were genotyped using the

HumanHap 550 Duo Arrays; 5% were genotyped using the Human 610 Quad Arrays

(Illumina). In the third cohort (baseline examination in 2006), all DNA samples were

genotyped using the Illumina Infinium II HumanHap550chip v3.0®array. Regarding

imputation, the set of genotyped input SNPs used for imputation in each study was selected

based on highest quality GWA data. The call rate was set at >98% in Rotterdam Study; the

minor allele frequency at >0.01; and the Hardy-Weinberg P >10-6.


The study has information of both alcohol status and alcohol quantity.


Asthma was defined as a physician-diagnosed asthma at cohort entry (or within 1 year after

cohort entry). The number of missing data relative to asthma was 6% (n=509). Hay fever,

allergic sensitization and serum total IgE were not measured at baseline.

Ethics

A written informed consent was obtained from all participants. The Rotterdam Study has

been approved by the medical ethics committee according to the Population Study Act

Rotterdam Study, executed by the Ministry of Health, Welfare and Sports of the Netherlands.

SHIP

The Study of Health in Pomerania (SHIP) is a population-based epidemiological study in the

region of Western Pomerania. SHIP was at first planned as a cross-sectional study (30).

Examinations were held in centers stationed at Stralsund and Greifswald between the 16th of

October 1997 and the 19th of May 2001. SHIP-0 concluded with a participant proportion of

68,8%. The participation proportion of women was slightly higher (69.4%) than the men’s

(68.2%). Participation in the different age groups for women ranged from 76.6% (participants

aged between 50 and 60) to 49.5% (participants aged between 70 and 80) and for men from

74.3% (participants aged between 50 and 60) to 63.2% (participants aged between 70 and

80). More information incl. the above can be found at: http://www.medizin.uni-

greifswald.de/cm/fv/ship/stud_desc_en.html

http://www.medizin.uni-greifswald.de/cm/fv/ship/stud_desc_en.html


16

Genotyping

Genotyping was performed using the Human SNP 6.0 Array (Affymetrix, Santa Clara, CA,

USA). Hybridization of genomic DNA was genotyped according to the manufacturer’s

standard recommendations. Genotypes were determined using the Birdseed2 clustering

algorithm. All remaining arrays had a sample call rate > 92 %.


Participants were classified as having hay fever if they answered confirmatory to the

question: “Do you sometimes or all the time suffer from hay fever?” The participants were

defined as having allergic asthma or not according to self-reported questionnaire information.

Serum total IgE levels were measured by the Latex IgE test on the BN II Nephelometer

(Dade Behring Marburg GmbH, Marburg, Germany) and expressed in IU/ml (31). Serum

specific IgE was not measured.


Alcohol intake was defined as the amount of self-reported alcohol consumption last week.


their reported consumption of alcohol.


The analyses are not adjusted for principal components.

Ethics

SHIP was planned and accompanied with support and advice from an external Data Safety

and Monitoring Committee (DSMC). Each participant gave written informed consent. The

study conformed to the principles of the Declaration of Helsinki and was approved by the

Ethics Committee of the University of Greifswald.


SHIP is part of the Community Medicine Research Network of the University Medicine

Greifswald, which is supported by the German Federal State of Mecklenburg – West

Pomerania.

SHIP TREND

The Study of Health in Pomerania (SHIP) is a population-based epidemiological study in the

region of Western Pomerania. In SHIP TREND baseline, a new sample has been drawn for a

new cohort, to be examined from September 2008. More information can be found at:


Genotyping

Genotyping was performed using the Illumina Human Omni 2.5 array. Hybridisation of

genomic DNA was done in accordance with the manufacturer’s standard recommendations at

the Helmholtz Zentrum München. The genetic data analysis workflow was created using the

Software InforSense. Genetic data were stored using the database Caché (InterSystems).

Genotypes were determined using the GenomeStudio Genotyping Module v1.0 (GenCall

algorithm). All arrays included had a genotyping rate of at least 94%. The overall genotyping

efficiency of the GWA was 99.67 %.


17


In interview, participants were asked whether a doctor had ever diagnosed them with allergy,

and if so, which type of allergy. Participants who answered “allergy to house dust mite” or

“pollen allergy” were defined as having hay fever in the current study. A diagnosis of lung

asthma was defined as the participants that reported to have bronchial asthma. Allergic

sensitization and serum total IgE were not measured.


Alcohol intake per week was defined according to the amount of self-reported alcohol

consumption in the last 30 days. Participants were classified as non-drinkers and ever-

drinkers, respectively, depending on their reported consumption of alcohol.


The analyses are not adjusted for principal components.

Ethics

SHIP was planned and accompanied with support and advice from an external Data safety

and Monitoring Committee (DSMC). Each participant gave written informed consent. The

study conformed to the principles of the Declaration of Helsinki and was approved by the

Ethics Committee of the University of Greifswald.


SHIP-Trend is part of the Community Medicine Research Network of the University

Medicine Greifswald, which is supported by the German Federal State of Mecklenburg –

West Pomerania.

The Copenhagen City Heart Study

Data originates from The Copenhagen City Heart Study which consists of four consecutive

studies conducted in Denmark in 1976-78, 1981-83, 1991-94, and in 2001-03. Participants

were randomly chosen from the general population above 20 years living in the Copenhagen

area. Before visiting the study clinic, participants completed a questionnaire including

questions on alcohol intake and other lifestyle factors. At the clinic visit, physical

examinations were performed and questionnaires were checked for missing information and

any uncertainties were clarified. Also, blood samples were obtained for the purpose of

measurement of different biochemical and DNA markers at the 1991-94 examination. Hence,

participants attending this examination were included in the present study. Of 10,135

individuals who participated in this examination (response rate=61%), 91% gave blood for

biochemical and DNA analyses. Participants of Asian or Black descent (n=142) or with

missing questionnaire data (n=14) were excluded from further study. In all, 9080 Whites of

Danish ethnicity were eligible for this study, some of whom also participated in the

examinations in 1976-78 (n=6408), 1981-83 (n=6615), and in 2001-03 (n=4684). All

participants gave informed consent and the ethics committee for Copenhagen and

Frederiksberg approved the study (#100.2039/91). Enrolment and examination procedures

have been described in more detail elsewhere (32;33).

18

Genotyping

The ADH1B·2 allele (rs1229984, Arg47His in exon 3) and ADH1C·2 allele (rs698,

Ile349Val in exon 8) were identified by means of duplex polymerase chain reaction (PCR)

followed by Nanogen microelectronic chip technology (Nanogen NMW 1000 NanochipTM

Molecular Biology Workstation (34) using standard conditions (details available from

authors). In a validation study, the accuracy of the Nanogen method was found to be

comparable to restriction fragment length polymorphism (35).


A diagnosis of hay fever was defined as a positive answer to the question: “Does food,

medicine, grass animals etc. give you, hay fever?” A diagnosis of asthma was defined as a

positive answer to the question: “Do you have asthma?" Allergic sensitization and serum total

IgE were not measured.


Amount of usual alcohol intake was reported as weekly consumption of beer (in bottles),

wine (in glasses), and spirits (in units). Assuming one drink to be equal to 12 grams of pure

alcohol, a measure of total weekly alcohol intake was calculated. Participants were classified

as non-drinkers or ever-drinkers, respectively, if they had answered 0 or >0 drinks/week.


The analyses are not adjusted for principal components. The analyses have not been

published previously.

Ethics

Each participant gave written informed consent. The study conformed to the principles of the

Declaration of Helsinki and was approved by the Ethics Committee.

The NEO study

The NEO study is a population-based cohort with oversampling of individuals with BMI > 27

kg/m2. It was designed for extensive phenotyping to investigate pathways that lead to obesity-

related diseases. The NEO study is a population-based, prospective cohort study that includes

6,671 individuals aged 45–65 years, with an oversampling of individuals with overweight or

obesity. At baseline, information on demography, lifestyle, and medical history have been

collected by questionnaires. In addition, samples of 24-h urine, fasting and postprandial blood

plasma and serum, and DNA were collected. Participants underwent an extensive physical

examination, including anthropometry, electrocardiography, spirometry, and measurement of

the carotid artery intima-media thickness by ultrasonography. In random subsamples of

participants, magnetic resonance imaging of abdominal fat, pulse wave velocity of the aorta,

heart, and brain, magnetic resonance spectroscopy of the liver, indirect calorimetry, dual

energy X-ray absorptiometry, or accelerometry measurements were performed. The

collection of data started in September 2008 and completed at the end of September 2012.

Participants are currently being followed for the incidence of obesity-related diseases and

mortality. More information: http://www.ncbi.nlm.nih.gov/pubmed/23576214

Genotyping

http://www.ncbi.nlm.nih.gov/pubmed/23576214

19

Genotyping was performed using the Illumina HumanCoreExome chip, which was

subsequently imputed to the 1000 genome reference panel. Genotyping calling algorithm is

GenCall. Genotyping and SNP call rates >98%.


Participants were defined as having asthma if they had the general practitioner record code

R96 (asthma) according to the International Classification of Primary Care. Hay fever,

allergic sensitization and serum total IgE were not assessed.


Alcohol intake was calculated from total dietary intake. Dietary intake was assessed using a

semi-quantitative food frequency questionnaire (FFQ), originally validated in the Dutch

general population. For calibration purposes in our study population, two 24-h dietary recalls

have been performed by telephone in a random subsample of 110 men and 119 women.

Ethics

The Medical Ethical Committee of the Leiden University Medical Center (LUMC) approved

the design of the study. All participants gave their written informed consent.


The authors of the NEO study thank all individuals who participated in the Netherlands

Epidemiology in Obesity study, all participating general practitioners for inviting eligible

participants and all research nurses for collection of the data. We thank the NEO study group,

Pat van Beelen, Petra Noordijk and Ingeborg de Jonge for the coordination, lab and data

management of the NEO study. The genotyping in the NEO study was supported by the

Centre National de Génotypage (Paris, France), headed by Jean-Francois Deleuze. The NEO

study is supported by the participating Departments, the Division and the Board of Directors

of the Leiden University Medical Center, and by the Leiden University, Research Profile

Area Vascular and Regenerative Medicine. Dennis Mook-Kanamori is supported by Dutch

Science Organization (ZonMW-VENI Grant 916.14.023).


The analyses are adjusted for principal components (4). The data has not been published

previously.

UK Biobank

The UK Biobank is a large prospective study with over 500,000 participants from across the

United Kingdom and aged 40–69 years at recruitment in 2006–2010 (36). The study has both

data from questionnaires, physical measures, sample assays, accelerometry, multimodal

imaging, genome-wide genotyping and longitudinal follow-up for a large number of health-

related outcomes. We included participants of Caucasian descent assessed by self-report and

genetic ethnic grouping.

The UK Biobank Lung Exome Variant Evaluation (UK BiLEVE) study is a

subsample of the UK Biobank study selected on the basis of lung function (37). In additional

analyses, we performed MR-analyses in the UKB Biobank without the BiLEVE sample.

Genotyping

20

Approximately 450,000 of the participants have been/are being genotyped using the UK

Biobank Axiom array from Affymetrix. There are approximately 800,000 markers on this

array. The other approximately 50,000 samples were genotyped on the closely related UK

BiLEVE array. These are two very similar arrays with more than 95% common marker

content.


Hay fever was defined as a positive answer to the question: ”Has a doctor ever told you that

you have had any of the following conditions? Hayfever, allergic rhinitis, or eczema”.

Asthma was defined as a positive answer to the question: “Has a doctor ever told you that

you have had any of the following conditions? Asthma” Allergic sensitization and total IgE

were not determined.

Due to the non-specific hay fever variable (i.e. including eczema), we assessed two different

variables concerning hay fever in additional analyses:

1) Self-reported medication for hay fever. This was assessed in the initial assessment visit

2006-2010 (N=364,071). First, from the complete list of >6000 recorded types of medication,

we manually excluded the medication that <100 persons were taking or which we knew was

not used in the treatment of hay fever. Second, for each of the remaining medication, we

assessed the general indication and excluded those not related to or too non-specific to

treatment of hay fever. We ended up with 31 entries. Persons reporting taking one or more of

the medication on the list were defined as having hay fever according to this definition, and

persons who did not were defined as not having hay fever.

2) Doctor diagnosed serious illness: hay fever. If the participants stated in the touch screen

questionnaire that they had other serious illnesses or disabilities, they were later asked by an

interviewer: “In the touch screen you selected that you have been told by a doctor that you

have other serious illnesses or disabilities, could you now tell me what they are?” If the

participant answered “hay fever” the participant was defined as having hay fever according to

this definition. Otherwise, the participants were defined as not having hay fever. This was

assessed in the initial assessment visit 2006-2010 (N=379,887).

Lung function

Forced expiratory volume in 1-second (FEV1) and forced vital capacity (FVC) were

measures at baseline by spirometry by a Vitalograph Pneumotrac 6800 (Vitalograph, UK)

operated via a PC for data capture and in order to visualise flow graphs from each test. The

spirometer was calibrated in the beginning of each day by the Spirotrac software supplied

with the Pneumotrac 6800. FEV1 and FVC were expressed in litres.


Participants were classified as non-drinkers or ever-drinkers (previous and current drinkers)

according to self-report. Alcohol intake of units of alcohol per week among those who

indicated drinking alcohol more often than once or twice a week was calculated as the sum of

the answers to the questions: Average weekly champagne plus white wine intake/fortified

wine intake/intake of other alcoholic drinks/red wine intake/spirits intake.

Ethics

Each participant has given informed consent. An independent Ethics and Governance Council

oversees adherence to the Ethics and Governance Framework (36).

21


UK Biobank has received funding from the UK Medical Research Council, Wellcome Trust,

Department of Health, British Heart Foundation, Diabetes UK, Northwest Regional

Development Agency, Scottish Government, and Welsh Assembly Government. As

described in the manuscript, the MRC and Wellcome Trust played a key role in the decision

to establish UK Biobank, a large, population-based, prospective, open access resource that

would allow detailed investigations of the genetic and environmental determinants of the

diseases of middle and old age. The MRC, Wellcome Trust, Department of Health, and

Scottish Chief Scientist Office each have a representative on the UK Biobank Board. The

MRC and Wellcome Trust fund the independent Ethics and Governance Council (36).


The genetic analyses are adjusted for principal components.

22

Supplementary tables Table S1. Descriptive statistics of study populations.

23

Male sex Age Serum total IgE, (IU/m) Hay fever Asthma Allergic sensitization

Study Alcohol status N % (N) Median P25 P75 Median P25 P75 % (N) % (N) % (N)

The 1936 Cohort Non-drinkers 94 18.1 (17) 60.4 60.1 60.7 NA NA NA 11.7 (11) 8.51 (8) 10.6 (10)

Ever-drinkers 498 52.8 (263) 60.5 60.2 60.8 NA NA NA 9.4 (47) 6.4 (32) 14.9 (74)

All 592 47.3 (280) 60.5 60.2 60.8 NA NA NA 9.8 (58) 6.8 (40) 14.2 (84)

Allergy98 Non-drinkers 221 20.4 (45) 33.1 24.8 44.7 35.7 10.5 99.6 25.8 (57) 13.1 (29) 36.2 (80)

Ever-drinkers 927 51.6 (478) 39.0 30.0 51.7 37.7 13.1 109.0 27.1 (251) 10.5 (97) 38.7 (359)

All 1148 45.6 (523) 38.0 28.7 51.3 37.3 12.4 107.5 26.8 (308) 11.0 (126) 38.2 (439)

CCHS Non-drinkers 1944 24.6 (479) 66.1 56.1 73.8 NA NA NA 9.2 (179) 7.3 (141) NA

Ever-drinkers 7041 49.8 (3504) 58.7 45.5 69.0 NA NA NA 11.6 (820) 5.8 (406) NA

All 8985 44.3 (3983) 60.5 47.8 70.3 NA NA NA 11.1 (999) 6.1 (547) NA

Health2006 Non-drinkers 151 37.8 (57) 50.0 34.0 60.0 NA NA NA 15.9 (24) 14.6 (22) 19.9 (30)


All 2818 45.0 (1269) 50.0 40.0 60.0 NA NA NA 18.1 (509) 10.7 (301) 23.2 (655)

Inter99 Non-drinkers 448 31.0 (139) 44.8 39.7 50.0 25.6 10.4 70.7 NA 12.0 (54) 35.0 (157)

Ever-drinkers 4432 50.8 (2252) 45.1 40.0 50.3 28.3 10.6 75.9 NA 8.3 (368) 33.6 (1491)

All 4880 49.0 (2391) 45.1 40.0 50.2 28.2 10.6 75.6 NA 8.6 (422) 33.8 (1648)

DanFunD Non-drinkers 329 31.9 (105) 54 44 63 NA NA NA 19.1 (63) 13.1 (43) 22.5 (74)

Ever-drinkers 6764 47.0 (3178) 54 44 63 NA NA NA 18.8 (1272) 9.8 (662) 25.9 (1752)

All 7093 46.3 (3283) 54 44 63 NA NA NA 18.8 (1335) 9.9 (705) 25.7 (1826)

KORA Non-drinkers NA NA NA NA NA NA NA NA NA NA NA

Ever-drinkers NA NA NA NA NA NA NA NA NA NA NA

All 1255 46.3 (581) 49.0 39.0 59.0 53.0 20.0 145.0 18.2 (229) 7.0 (88) 46.4 (581)

NEO Non-drinkers 842 29.7 (250) 56.0 50.0 61.0 NA NA NA NA 13.9 (117) NA

Ever-drinkers 4713 51.7 (2435) 57.0 51.0 61.0 NA NA NA NA 10.0 (473) NA

All 5557 48.3 (2685) 57.0 51.0 61.0 NA NA NA NA 10.6 (590) NA

NSHD Non-drinkers 162 36.4 (59) 53 53 53 NA NA NA 22.0 (33) 13.9 (21) NA

Ever-drinkers 2513 50.7 (1275) 53 53 53 NA NA NA 23.8 (564) 9.8 (232) NA

24

All 2675 49.9 (1334) 53 53 53 NA NA NA 23.7 (597) 10.0 (253) NA

Prosper Non-drinkers 2439 32.1 (784) 75.2 72.7 78.1 NA NA NA NA 2.8 (69) NA


All 5504 48.3 (2657) 75.0 72.4 77.9 NA NA NA NA 2.8 (153) NA

Rotterdam Non-drinkers 1123 24.4 (274) 67.1 60.0 74.0 NA NA NA NA 2.7 (30) NA


All 7977 43.0 (3434) 62.5 58.2 70.5 NA NA NA NA 2.6 (206) NA

SHIP Non-drinkers 1364 33.4 (456) 54.0 36.0 67.0 33.8 14.5 93.7 7.3 (100) 1.1 (15) NA

Ever-drinkers 2361 57.5 (1357) 48.0 36.0 60.0 37.6 17.6 112.0 8.7 (206) 0.8 (19) NA

All 3725 48.7 (1813) 50.0 36.0 62.0 36.2 16.4 104.0 8.2 (306) 0.9 (34) NA

SHIP TREND Non-drinkers 116 35.3 (41) 54.0 42.0 65.0 NA NA NA 14.7 (17) 6.0 (7) NA

Ever-drinkers 870 44.9 (391) 50.0 40.0 60.0 NA NA NA 14.3 (124) 3.9 (34) NA

All 986 43.8 (432) 50.0 40.0 61.0 NA NA NA 14.3 (141) 4.2 (41) NA

1958 BC Non-drinkers 124 31.4 (39) 42 42 42 21.0 8.5 65.0 13.7 (17) 5.7 (7) 13.7 (17)

Ever-drinkers 2296 53.3 (1223) 42 42 42 27.0 11.0 67.0 19.2 (441) 5.8 (133) 17.2 (394)

All 2420 52.1 (1262) 42 42 42 27.0 11.0 67.0 18.9 (458) 5.8 (140) 17.0 (411)

Dan-Monica10 Non-drinkers 313 24.0 (75) 61.4 51.4 71.1 NA NA NA 9.9 (31) 8.6 (27) 13.7 (43)


All 2262 49.7 (1125) 52.0 42.1 61.9 NA NA NA 14.2 (321) 6.6 (150) 18.1 (409)

GOYA Males Non-drinkers 52 100 (52) 46 40.5 55.5 NA NA NA 11.5 (6) 0 (0) NA

Ever-drinkers 738 100 (738) 46 41 53 NA NA NA 13.1 (97) 4.9 (36) NA

All 790 100 (790) 46 41 53 NA NA NA 13.0 (103) 4.6 (36) NA

UK Biobank Non-drinkers 12884 24.8 (3191) 61 54 66 NA NA NA 20.4 (2631) 13.1 (1686) NA

Ever-drinkers 394883 46.6 (184188) 58 51 63 NA NA NA 23.0 (90791) 11.5 (45297) NA

All 407767 46.0 (187379) 58 51 63 NA NA NA 22.9 (93422) 11.5 (46983) NA

Abbreviations: 1958 BC, British 1958 Birth Cohort; Allergy98, Copenhagen Allergy study; CCHS, Copenhagen City Heart Study; GOYA, Genomics of extremely

Overweight Young Adults; HUNT, Nord-Trøndelag Health Study; IgE, immunoglobulin E; Inter99, Intervention 1999; IQR, interquartile range; HW, Hardy Weinberg

Equilibrium; KORA, The Cooperative Health Research in the Region of Augsburg; MAF, minor allele frequency; Monica, Monitoring of trends and determinants in

Cardiovascular Diseases; NA, not available; NEO, Netherlands Epidemiology of Obesity; NSHD, National Survey of Health and Development; PROSPER, PROspective

Study of Pravastatin in the Elderly at Risk; SHIP, Study of Health in Pomerania; UK Biobank, United Kingdom Biobank.

25

Table S2. Serum total IgE-levels according to study group, alcohol status and the rs1229984 genotype.

Study Alcohol status Genotype* Number Median P25 P75

Allergy Non-drinkers Wild type 215 36.9 10.5 100.0

Variant 6 17.5 8.4 29.9

Ever-drinkers Wild type 914 37.7 13.1 109.0

Variant 13 38.3 23.9 153.0

Inter99 Non-drinkers Wild type 422 25.1 10.5 68.7

Variant 26 40.3 9.6 132.0


Variant 160 20.8 10.2 71.5

SHIP Non-drinkers Wild type 990 34.0 14.5 97.2

Variant 86 28.9 14.2 83.2


Variant 145 33.1 15.0 104.0

1958 BC Non-drinkers Wild type 117 23.0 9.0 66.0

Variant 7 5.0 3.0 33.0


Variant 124 31.0 12.0 72.5

KORA** Non-drinkers Wild type NA NA NA NA

Variant NA NA NA NA

Ever-drinkers Wild type NA NA NA NA

Variant NA NA NA NA

* ‘Wild type’ refers to major allele homozygotes, and ‘Variant’ refers to heterozygotes and minor allele

homozygotes. ** Alcohol status is not available.

Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; IgE,

immunoglobulin E; Inter99, Intervention 1999; SHIP, Study of Health in Pomerania.

26

Table S3. Allele frequencies for the rs1229984 SNP in the participating studies

Study Major

homozygotes Heterozygotes

Minor

homozygotes MAF

HW, p-

value Total

Allergy98 1129 19 0 0.008 0.777 1148

1958 BC 2289 131 0 0.027 0.171 2420

CCHS 8583 396 6 0.023 0.515 8985

Dan-Monica10 2173 89 0 0.020 0.340 2262

GOYA Males 752 38 0 0.025 0.489 790

Health2006 2718 97 3 0.018 0.031 2818

Inter99 4694 181 5 0.020 0.051 4880

DanFunD 6846 245 2 0.018 0.899 7093

KORA 1099 149 7 0.070 0.358 1255

NEO 5192 362 3 0.033 0.195 5557

NSHD 2550 125 0 0.023 0.216 2675

The 1936 Cohort 559 33 0 0.028 0.485 592

Prosper 5319 185 0 0.017 0.205 5504

Rotterdam 7471 504 2 0.032 0.027 7977

SHIP 3447 276 2 0.038 0.140 3725

SHIP TREND 915 70 1 0.036 0.776 986

UK Biobank 389674 17869 224 0.022 0.192 407767

Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British, 1958 Birth Cohort; CCHS, Copenhagen City

Heart Study; GOYA, Genomics of extremely Overweight Young Adults; Inter99, Intervention 1999; HW, Hardy

Weinberg Equilibrium; KORA, The Cooperative Health Research in the Region of Augsburg; MAF, minor allele

frequency; Monica, Monitoring of trends and determinants in Cardiovascular Diseases; NEO, Netherlands

Epidemiology of Obesity; NSHD, National Survey of Health and Development; PROSPER, PROspective Study of

Pravastatin in the Elderly at Risk; SHIP, Study of Health in Pomerania; UK Biobank, United Kingdom Biobank.

27

Table S4. Study-specific measures of hay fever, asthma, allergic sensitization, and serum total IgE.

Study Hay fever Asthma Allergic

sensitization

Serum total

IgE

1958 BC

A positive answer to the

question: “Have you ever

had hay fever?”


question: “Have you ever had

hay asthma?”

Serum specific

IgE positivity

against inhalant

allergens

HYTEC-

automated

enzyme

immunoassay

Dan-

Monica10


question: “Has a doctor ever

told you that you had

allergic hay fever?”



told you that you had asthma?”

Serum specific

IgE positivity

against inhalant

allergens

NA

GOYA Males


question: “Does food,

medicine or grass give you

hay fever?”


question: “Do you suffer from

Asthma?”

NA NA

Health2006



told you that you had hay

fever?”




Serum specific

IgE positivity

against inhalant

allergens

NA

HUNT2


question: “Do you have hay

fever or nasal allergies?”


question: “Do you have or

have you had asthma?”

NA NA

Inter99 NA




Serum specific

IgE positivity

against inhalant

allergens

IMMULITE_

2000 Allergy

Immunoassay

System

DanFunD


question: ”Has a doctor ever

told you that you had/have

hay fever?”



told you that you had/have

asthma ?”

Serum specific

IgE positivity

against inhalant

allergens

NA

KORA




fever?”




Serum specific

IgE positivity

against inhalant

allergens

NA

NSHD


question: “Have you ever

had hay fever?” or “Have

you had hay fever in the

last 10 years?”


question: “Have you ever had

asthma?” or “Have you had

asthma in the last 10 years?”

NA NA

The 1936

Cohort




fever?”




Serum specific

IgE positivity

against inhalant

allergens

NA

SHIP

A confirmative answer to

the question: “Do you

sometimes or all the time

suffer from hay fever?”

The participants were defined

as having allergic asthma or

not according to self-reported

questionnaire information.

NA

Latex IgE test

on the BN II

Nephelometer

(Dade Behring

Marburg

GmbH,

Marburg,

Germany)

SHIP TREND

Self-reported doctor-

diagnosed “allergy to house

dust mite” or “pollen

allergy”

Participants who reported to

have bronchial asthma NA

NA

CCHS


question: “Does food,

medicine, grass animals etc.

give you, hay fever?”


question: “Do you have

asthma?"

NA NA

28

NEO NA General practitioner record

code R96 (asthma) NA NA

Allergy98


question: “Have you had

hay fever in the last 12

months?”


question: “Have you had

asthma in the last 12 months?”

Serum specific

IgE positivity

against inhalant

allergens

Immulite

(Siemens,

Erlangen,

Germany)

Prosper NA

A self-reported diagnosis of

asthma in the adverse events

database

NA NA

Rotterdam NA Physician-diagnosed asthma NA NA

UK Biobank



told you that you have had

any of the following

conditions? Hayfever,

allergic rhinitis, or eczema”



told you that you have had any

of the following conditions?

Asthma”

NA NA

Abbreviations: 1958 BC, Allergy98, Copenhagen Allergy study; British 1958 Birth Cohort; CCHS, Copenhagen City

Heart Study; GOYA, Genomics of extremely Overweight Young Adults; HUNT, Nord-Trøndelag Health Study; IgE,

immunoglobulin E; Inter99, Intervention 1999; KORA, The Cooperative Health Research in the Region of Augsburg;

Monica, Monitoring of trends and determinants in Cardiovascular Diseases; NA, not available; NEO, Netherlands

Epidemiology of Obesity; NSHD, National Survey of Health and Development; PROSPER, PROspective Study of

Pravastatin in the Elderly at Risk; SHIP, Study of Health in Pomerania; UK Biobank, United Kingdom Biobank.

Main supplementary figures

Figure S1. Random effects meta-analysis of the associations between the rs1229984 genotype (major homozygotes vs.

minor homozygotes and heterozygotes) and the logarithm transformed alcohol intake. Abbreviations: Allergy98,

Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City Heart Study; Inter99,

Intervention 1999; NEO, Netherlands Epidemiology of Obesity; NSHD, National Survey of Health and Development;

SHIP, Study of Health in Pomerania.

NOTE: Weights are from random effects analysis

Overall (I-squared = 45.8%, p = 0.024)

NSHD

The 1936 Cohort

CCH

SHIP TREND

GOYA Males

Monica10

Prosper

UK Biobank

Rotterdam

NEO

study

SHIP

Allergy98

Inter99

Health2006

1958 BC

DanFunD

0.17 (0.12, 0.22)

0.23 (0.05, 0.42)

0.02 (-0.35, 0.38)

0.27 (0.17, 0.38)

0.21 (-0.08, 0.49)

0.20 (-0.11, 0.51)

0.11 (-0.10, 0.33)

-0.00 (-0.19, 0.19)

0.15 (0.13, 0.16)

-0.02 (-0.19, 0.16)

0.23 (0.10, 0.35)

ES (95% CI)

0.13 (-0.02, 0.28)

0.10 (-0.38, 0.58)

0.32 (0.17, 0.47)

0.33 (0.11, 0.54)

0.06 (-0.06, 0.17)

0.27 (0.14, 0.39)

0.17 (0.12, 0.22)

0.23 (0.05, 0.42)

0.02 (-0.35, 0.38)

0.27 (0.17, 0.38)

0.21 (-0.08, 0.49)

0.20 (-0.11, 0.51)

0.11 (-0.10, 0.33)

-0.00 (-0.19, 0.19)

0.15 (0.13, 0.16)

-0.02 (-0.19, 0.16)

0.23 (0.10, 0.35)

ES (95% CI)

0.13 (-0.02, 0.28)

0.10 (-0.38, 0.58)

0.32 (0.17, 0.47)

0.33 (0.11, 0.54)

0.06 (-0.06, 0.17)

0.27 (0.14, 0.39)

0-.576 0 .576

Estimate for alcohol-increasing genotype

Log(alcohol intake)

30


minor homozygotes and heterozygotes) and hay fever in all and by alcohol status. Abbreviations: Allergy98,

Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City Heart Study; KORA,

Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of Obesity; NSHD, National

Survey of Health and Development; SHIP, Study of Health in Pomerania.


.

.

.

All

Monica10

Health2006

Allergy98

1958 BC

Kora

The 1936 Cohort

SHIP

SHIP TREND

CCH

NSHD

DanFunD

UK Biobank

GOYA Males

Subtotal (I-squared = 19.6%, p = 0.245)

Non-drinkers

Monica10

Health2006

SHIP

SHIP TREND

CCH

NSHD

DanFunD

UK Biobank


Ever-drinkers

Monica10

Health2006

Allergy98

1958 BC

The 1936 Cohort

SHIP

SHIP TREND

CCH

NSHD

DanFunD

UK Biobank

GOYA Males


study

0.99 (0.51, 1.94)

0.74 (0.46, 1.19)

0.63 (0.25, 1.63)

1.05 (0.66, 1.65)

0.72 (0.48, 1.10)

0.57 (0.21, 1.56)

0.85 (0.56, 1.31)

1.15 (0.56, 2.40)

1.04 (0.75, 1.45)

0.73 (0.49, 1.09)

0.73 (0.54, 0.99)

0.99 (0.95, 1.02)

5.53 (0.75, 40.85)

0.90 (0.81, 1.01)

0.47 (0.10, 2.30)

0.42 (0.10, 1.76)

0.75 (0.38, 1.50)

0.60 (0.06, 6.14)

1.26 (0.62, 2.56)

1.70 (0.20, 14.69)

0.91 (0.25, 3.35)

0.99 (0.83, 1.19)

0.97 (0.82, 1.14)

1.14 (0.54, 2.40)

0.78 (0.47, 1.30)

0.32 (0.11, 0.98)

0.99 (0.63, 1.57)

0.40 (0.14, 1.14)

0.91 (0.53, 1.57)

1.21 (0.56, 2.63)

0.98 (0.68, 1.42)

0.70 (0.46, 1.06)

0.72 (0.53, 0.98)

0.99 (0.95, 1.02)

5.14 (0.69, 38.05)

0.88 (0.75, 1.03)

ratio (95% CI)

Odds

0.99 (0.51, 1.94)

0.74 (0.46, 1.19)

0.63 (0.25, 1.63)

1.05 (0.66, 1.65)

0.72 (0.48, 1.10)

0.57 (0.21, 1.56)

0.85 (0.56, 1.31)

1.15 (0.56, 2.40)

1.04 (0.75, 1.45)

0.73 (0.49, 1.09)

0.73 (0.54, 0.99)

0.99 (0.95, 1.02)

5.53 (0.75, 40.85)

0.90 (0.81, 1.01)

0.47 (0.10, 2.30)

0.42 (0.10, 1.76)

0.75 (0.38, 1.50)

0.60 (0.06, 6.14)

1.26 (0.62, 2.56)

1.70 (0.20, 14.69)

0.91 (0.25, 3.35)

0.99 (0.83, 1.19)

0.97 (0.82, 1.14)

1.14 (0.54, 2.40)

0.78 (0.47, 1.30)

0.32 (0.11, 0.98)

0.99 (0.63, 1.57)

0.40 (0.14, 1.14)

0.91 (0.53, 1.57)

1.21 (0.56, 2.63)

0.98 (0.68, 1.42)

0.70 (0.46, 1.06)

0.72 (0.53, 0.98)

0.99 (0.95, 1.02)

5.14 (0.69, 38.05)

0.88 (0.75, 1.03)

ratio (95% CI)

Odds

1.0245 1 40.9

Odds ratio for alcohol-increasing genotype

Hay fever

31


minor homozygotes and heterozygotes) and asthma in all and by alcohol status. Abbreviations: Allergy98, Copenhagen

Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City Heart Study; Inter99, Intervention 1999;

KORA, Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of Obesity; NSHD,

National Survey of Health and Development; SHIP, Study of Health in Pomerania.

32


.

.

.

AllMonica10Health2006Inter99Allergy98ProsperRotterdam1958 BCKoraThe 1936 CohortSHIPSHIP TRENDNEOCCHNSHDDanFunDUK BiobankGOYA MalesSubtotal (I-squared = 13.6%, p = 0.295)

Non-drinkersMonica10Health2006Inter99Allergy98ProsperRotterdamSHIPSHIP TRENDNEOCCHDanFunDUK BiobankSubtotal (I-squared = 0.0%, p = 0.844)

Ever-drinkersMonica10Health2006Inter99Allergy98ProsperRotterdam1958 BCThe 1936 CohortSHIP TRENDNEOCCHNSHDDanFunDUK BiobankGOYA MalesSubtotal (I-squared = 30.7%, p = 0.124)

study

0.82 (0.37, 1.82)0.67 (0.38, 1.19)0.94 (0.56, 1.56)0.47 (0.15, 1.44)0.83 (0.36, 1.90)1.68 (0.82, 3.42)0.54 (0.30, 0.98)0.88 (0.47, 1.68)2.39 (0.31, 18.17)2.71 (0.37, 19.86)1.59 (0.38, 6.75)1.04 (0.74, 1.47)0.82 (0.56, 1.22)0.75 (0.43, 1.31)0.66 (0.46, 0.96)0.99 (0.94, 1.04)1.81 (0.24, 13.63)0.91 (0.80, 1.02)

0.90 (0.11, 7.33)0.64 (0.12, 3.29)0.55 (0.20, 1.54)0.75 (0.08, 6.77)1.03 (0.25, 4.30)0.87 (0.26, 2.97)1.22 (0.16, 9.35)0.28 (0.02, 3.34)2.23 (0.88, 5.67)0.68 (0.36, 1.30)0.94 (0.20, 4.34)0.91 (0.74, 1.13)0.90 (0.75, 1.08)

0.80 (0.34, 1.87)0.69 (0.38, 1.26)1.12 (0.61, 2.03)0.40 (0.11, 1.49)0.74 (0.26, 2.05)2.20 (0.90, 5.39)0.51 (0.28, 0.93)1.85 (0.24, 14.44)2.93 (0.39, 21.83)0.92 (0.63, 1.36)0.93 (0.57, 1.52)0.68 (0.39, 1.19)0.64 (0.44, 0.94)1.00 (0.95, 1.04)1.79 (0.24, 13.48)0.87 (0.73, 1.03)

ratio (95% CI)Odds

0.82 (0.37, 1.82)0.67 (0.38, 1.19)0.94 (0.56, 1.56)0.47 (0.15, 1.44)0.83 (0.36, 1.90)1.68 (0.82, 3.42)0.54 (0.30, 0.98)0.88 (0.47, 1.68)2.39 (0.31, 18.17)2.71 (0.37, 19.86)1.59 (0.38, 6.75)1.04 (0.74, 1.47)0.82 (0.56, 1.22)0.75 (0.43, 1.31)0.66 (0.46, 0.96)0.99 (0.94, 1.04)1.81 (0.24, 13.63)0.91 (0.80, 1.02)

0.90 (0.11, 7.33)0.64 (0.12, 3.29)0.55 (0.20, 1.54)0.75 (0.08, 6.77)1.03 (0.25, 4.30)0.87 (0.26, 2.97)1.22 (0.16, 9.35)0.28 (0.02, 3.34)2.23 (0.88, 5.67)0.68 (0.36, 1.30)0.94 (0.20, 4.34)0.91 (0.74, 1.13)0.90 (0.75, 1.08)

0.80 (0.34, 1.87)0.69 (0.38, 1.26)1.12 (0.61, 2.03)0.40 (0.11, 1.49)0.74 (0.26, 2.05)2.20 (0.90, 5.39)0.51 (0.28, 0.93)1.85 (0.24, 14.44)2.93 (0.39, 21.83)0.92 (0.63, 1.36)0.93 (0.57, 1.52)0.68 (0.39, 1.19)0.64 (0.44, 0.94)1.00 (0.95, 1.04)1.79 (0.24, 13.48)0.87 (0.73, 1.03)

ratio (95% CI)Odds

1.0241 1 41.5


Asthma

33


minor homozygotes and heterozygotes) and allergic sensitization in all and by alcohol status. Abbreviations: Allergy98,

Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; Inter99, Intervention 1999; KORA, Cooperative

Health Research in the Region of Augsburg.


.

.

.

AllMonica10Health2006Inter99Allergy981958 BCKoraThe 1936 CohortDanFunDSubtotal (I-squared = 29.6%, p = 0.192)

Non-drinkersMonica10Health2006Inter99Allergy98The 1936 CohortDanFunDSubtotal (I-squared = 12.6%, p = 0.335)

Ever-drinkersMonica10Health2006Inter99Allergy981958 BCThe 1936 CohortDanFunDSubtotal (I-squared = 40.5%, p = 0.121)

study

0.93 (0.54, 1.61)0.72 (0.46, 1.12)1.55 (1.10, 2.17)1.40 (0.54, 3.65)0.95 (0.60, 1.50)0.90 (0.64, 1.27)0.72 (0.29, 1.81)1.00 (0.74, 1.34)1.00 (0.83, 1.21)

1.47 (0.18, 11.91)0.22 (0.06, 0.83)0.74 (0.33, 1.68)3.59 (0.40, 31.93)0.91 (0.09, 9.02)0.85 (0.26, 2.79)0.74 (0.40, 1.36)

0.90 (0.51, 1.58)0.81 (0.50, 1.31)1.79 (1.23, 2.62)1.00 (0.33, 3.06)0.90 (0.57, 1.43)0.73 (0.27, 2.02)1.00 (0.74, 1.36)1.04 (0.81, 1.33)

ratio (95% CI)Odds

0.93 (0.54, 1.61)0.72 (0.46, 1.12)1.55 (1.10, 2.17)1.40 (0.54, 3.65)0.95 (0.60, 1.50)0.90 (0.64, 1.27)0.72 (0.29, 1.81)1.00 (0.74, 1.34)1.00 (0.83, 1.21)

1.47 (0.18, 11.91)0.22 (0.06, 0.83)0.74 (0.33, 1.68)3.59 (0.40, 31.93)0.91 (0.09, 9.02)0.85 (0.26, 2.79)0.74 (0.40, 1.36)

0.90 (0.51, 1.58)0.81 (0.50, 1.31)1.79 (1.23, 2.62)1.00 (0.33, 3.06)0.90 (0.57, 1.43)0.73 (0.27, 2.02)1.00 (0.74, 1.36)1.04 (0.81, 1.33)

ratio (95% CI)Odds

1.0313 1 31.9


Allergic sensitization


minor homozygotes and heterozygotes) and the logarithm transformed serum total IgE in all and by alcohol status.

Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; IgE, immunoglobulin E;

Inter99, Intervention 1999; KORA, Cooperative Health Research in the Region of Augsburg.


.

.

.

All

Inter99

Allergy98

1958 BC

Kora

SHIP


Non-drinkers

Inter99

Allergy98

1958 BC

SHIP


Ever-drinkers

Inter99

Allergy98

1958 BC

SHIP


study

0.12 (-0.10, 0.33)

0.03 (-0.66, 0.72)

0.03 (-0.22, 0.27)

0.05 (-0.19, 0.28)

0.05 (-0.13, 0.24)

0.06 (-0.05, 0.17)

-0.30 (-0.87, 0.28)

0.83 (-0.46, 2.12)

1.04 (-0.07, 2.16)

0.04 (-0.26, 0.34)

0.16 (-0.31, 0.63)

0.18 (-0.05, 0.41)

-0.32 (-1.15, 0.51)

-0.03 (-0.28, 0.22)

0.05 (-0.18, 0.29)

0.06 (-0.07, 0.20)

ES (95% CI)

0.12 (-0.10, 0.33)

0.03 (-0.66, 0.72)

0.03 (-0.22, 0.27)

0.05 (-0.19, 0.28)

0.05 (-0.13, 0.24)

0.06 (-0.05, 0.17)

-0.30 (-0.87, 0.28)

0.83 (-0.46, 2.12)

1.04 (-0.07, 2.16)

0.04 (-0.26, 0.34)

0.16 (-0.31, 0.63)

0.18 (-0.05, 0.41)

-0.32 (-1.15, 0.51)

-0.03 (-0.28, 0.22)

0.05 (-0.18, 0.29)

0.06 (-0.07, 0.20)

ES (95% CI)

0-2.16 0 2.16

Estimate for alcohol-increasing genotype

Log(total IgE)

35

Figure S6. Random effects meta-analysis of the associations between alcohol status and hay fever in all. Abbreviations:

Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City Heart Study;





Monica10

DanFunD

UK Biobank

The 1936 Cohort

SHIP

study

Allergy98

SHIP TREND

Health2006

NSHD

CCH

1958 BC

GOYA Males

1.13 (1.08, 1.17)

1.20 (0.80, 1.80)

0.98 (0.74, 1.29)

1.13 (1.08, 1.18)

1.09 (0.53, 2.23)

1.16 (0.90, 1.50)

ratio (95% CI)

1.01 (0.71, 1.43)

0.91 (0.52, 1.59)

1.22 (0.78, 1.91)

1.09 (0.73, 1.62)

1.14 (0.95, 1.36)

1.49 (0.88, 2.52)

1.15 (0.48, 2.78)

Odds

1.13 (1.08, 1.17)

1.20 (0.80, 1.80)

0.98 (0.74, 1.29)

1.13 (1.08, 1.18)

1.09 (0.53, 2.23)

1.16 (0.90, 1.50)

ratio (95% CI)

1.01 (0.71, 1.43)

0.91 (0.52, 1.59)

1.22 (0.78, 1.91)

1.09 (0.73, 1.62)

1.14 (0.95, 1.36)

1.49 (0.88, 2.52)

1.15 (0.48, 2.78)

Odds

1.36 1 2.78

Ever-drinkers vs. non-drinkers

Hay fever

36

Figure S7. Random effects meta-analysis of the associations between alcohol status and asthma in all. Abbreviations:






1958 BC

DanFunD

Health2006

UK Biobank

NEO

Inter99

study

Rotterdam

SHIP

Prosper

NSHD

Allergy98

Monica10

SHIP TREND

CCH

0.85 (0.81, 0.89)

0.99 (0.45, 2.18)

0.73 (0.52, 1.02)

0.73 (0.46, 1.17)

0.86 (0.82, 0.91)

0.76 (0.61, 0.95)

0.70 (0.51, 0.95)

ratio (95% CI)

0.91 (0.61, 1.36)

0.83 (0.41, 1.67)

1.00 (0.72, 1.41)

0.68 (0.42, 1.10)

0.81 (0.51, 1.28)

0.76 (0.48, 1.19)

0.67 (0.29, 1.57)

Odds

0.84 (0.69, 1.04)

0.85 (0.81, 0.89)

0.99 (0.45, 2.18)

0.73 (0.52, 1.02)

0.73 (0.46, 1.17)

0.86 (0.82, 0.91)

0.76 (0.61, 0.95)

0.70 (0.51, 0.95)

ratio (95% CI)

0.91 (0.61, 1.36)

0.83 (0.41, 1.67)

1.00 (0.72, 1.41)

0.68 (0.42, 1.10)

0.81 (0.51, 1.28)

0.76 (0.48, 1.19)

0.67 (0.29, 1.57)

Odds

0.84 (0.69, 1.04)

1.29 1 3.45


Asthma

37

Figure S8. Random effects meta-analysis of the associations between alcohol status and allergic sensitization in all.

Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City

Heart Study; KORA, Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of

Obesity; NSHD, National Survey of Health and Development; SHIP, Study of Health in Pomerania.



Allergy98

The 1936 Cohort

DanFunD

Health2006

study

Inter99

Monica10

1958 BC

1.059 (0.936, 1.197)

0.955 (0.691, 1.320)

1.413 (0.687, 2.907)

1.119 (0.856, 1.463)

1.277 (0.841, 1.938)

Odds ratio (95% CI)

0.935 (0.760, 1.150)

1.222 (0.860, 1.738)

1.155 (0.681, 1.957)

1.059 (0.936, 1.197)

0.955 (0.691, 1.320)

1.413 (0.687, 2.907)

1.119 (0.856, 1.463)

1.277 (0.841, 1.938)

Odds ratio (95% CI)

0.935 (0.760, 1.150)

1.222 (0.860, 1.738)

1.155 (0.681, 1.957)

1.344 1 2.91



38

Figure S9. Random effects meta-analysis of the associations between alcohol status and the logarithm transformed

serum total IgE. Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; IgE,

immunoglobulin E; Inter99, Intervention 1999; KORA, Cooperative Health Research in the Region of Augsburg.



Inter99

study

Allergy98

SHIP

1958 BC

0.01 (-0.06, 0.09)

0.02 (-0.13, 0.16)

ES (95% CI)

-0.01 (-0.24, 0.22)

0.01 (-0.10, 0.11)

0.07 (-0.19, 0.32)

0.01 (-0.06, 0.09)

0.02 (-0.13, 0.16)

ES (95% CI)

-0.01 (-0.24, 0.22)

0.01 (-0.10, 0.11)

0.07 (-0.19, 0.32)

0-.319 0 .319


Log(total IgE)

39

Figure S10. Random effects meta-analysis of the associations between alcohol intake and hay fever. Abbreviations:






SHIP TREND

study

Monica10

NSHD

Health2006

UK Biobank

GOYA Males

The 1936 Cohort

CCH

Allergy98

SHIP

DanFunD

1958 BC

0.999 (0.995, 1.002)

1.001 (0.985, 1.018)

Odds ratio (95% CI)

1.007 (0.996, 1.018)

0.993 (0.982, 1.004)

0.985 (0.973, 0.997)

1.003 (1.002, 1.004)

0.986 (0.968, 1.005)

1.002 (0.973, 1.031)

0.999 (0.995, 1.003)

0.999 (0.980, 1.017)

0.989 (0.929, 1.053)

0.995 (0.988, 1.003)

1.006 (0.989, 1.024)

0.999 (0.995, 1.002)

1.001 (0.985, 1.018)

Odds ratio (95% CI)

1.007 (0.996, 1.018)

0.993 (0.982, 1.004)

0.985 (0.973, 0.997)

1.003 (1.002, 1.004)

0.986 (0.968, 1.005)

1.002 (0.973, 1.031)

0.999 (0.995, 1.003)

0.999 (0.980, 1.017)

0.989 (0.929, 1.053)

0.995 (0.988, 1.003)

1.006 (0.989, 1.024)

1.929 1 1.08

Per unit of alcohol

Hay fever

40

Figure S11. Random effects meta-analysis of the associations between alcohol intake and asthma. Abbreviations:






1958 BC

Inter99

CCH

GOYA Males

SHIP TREND

NEO

Prosper

DanFunD

The 1936 Cohort

Health2006

SHIP

Rotterdam

Monica10

UK Biobank

NSHD

Allergy98

study

0.9999 (0.9961, 1.0037)

0.9842 (0.9548, 1.0145)

0.9957 (0.9865, 1.0051)

1.0040 (0.9992, 1.0089)

1.0082 (0.9864, 1.0305)

1.0048 (0.9739, 1.0366)

0.9971 (0.9902, 1.0040)

1.0163 (1.0000, 1.0329)

0.9917 (0.9810, 1.0025)

1.0083 (0.9751, 1.0427)

0.9963 (0.9816, 1.0112)

0.9215 (0.7148, 1.1881)

1.1002 (1.0292, 1.1761)

0.9966 (0.9797, 1.0138)

1.0026 (1.0013, 1.0039)

0.9856 (0.9682, 1.0033)

0.9878 (0.9584, 1.0182)

Odds ratio (95% CI)

0.9999 (0.9961, 1.0037)

0.9842 (0.9548, 1.0145)

0.9957 (0.9865, 1.0051)

1.0040 (0.9992, 1.0089)

1.0082 (0.9864, 1.0305)

1.0048 (0.9739, 1.0366)

0.9971 (0.9902, 1.0040)

1.0163 (1.0000, 1.0329)

0.9917 (0.9810, 1.0025)

1.0083 (0.9751, 1.0427)

0.9963 (0.9816, 1.0112)

0.9215 (0.7148, 1.1881)

1.1002 (1.0292, 1.1761)

0.9966 (0.9797, 1.0138)

1.0026 (1.0013, 1.0039)

0.9856 (0.9682, 1.0033)

0.9878 (0.9584, 1.0182)

Odds ratio (95% CI)

1.715 1 1.4

Per unit of alcohol

Asthma

41

Figure S12. Random effects meta-analysis of the associations between alcohol intake and allergic sensitization.

Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City

Heart Study; KORA, Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of

Obesity; NSHD, National Survey of Health and Development; SHIP, Study of Health in Pomerania.



DanFunD

Monica10

Inter99

study

1958 BC

Health2006

The 1936 Cohort

Allergy98

1.00 (1.00, 1.01)

1.00 (1.00, 1.01)

1.01 (1.00, 1.02)

1.00 (1.00, 1.01)

ratio (95% CI)

1.01 (0.99, 1.02)

1.00 (0.99, 1.01)

1.01 (0.99, 1.03)

0.99 (0.97, 1.01)

odds

1.00 (1.00, 1.01)

1.00 (1.00, 1.01)

1.01 (1.00, 1.02)

1.00 (1.00, 1.01)

ratio (95% CI)

1.01 (0.99, 1.02)

1.00 (0.99, 1.01)

1.01 (0.99, 1.03)

0.99 (0.97, 1.01)

odds

1.97 1 1.03

Per unit of alcohol


42

Figure S13. Random effects meta-analysis of the associations between alcohol intake and the logarithm transformed

serum total IgE. Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; IgE,

immunoglobulin E; Inter99, Intervention 1999; KORA, Cooperative Health Research in the Region of Augsburg.



1958 BC

study

Allergy98

Inter99

SHIP

0.01 (0.01, 0.02)

0.01 (0.00, 0.02)

ES (95% CI)

0.02 (0.01, 0.03)

0.01 (0.01, 0.01)

0.04 (0.01, 0.07)

0.01 (0.01, 0.02)

0.01 (0.00, 0.02)

ES (95% CI)

0.02 (0.01, 0.03)

0.01 (0.01, 0.01)

0.04 (0.01, 0.07)

0-.0653 0 .0653

Per unit of alcohol

Log(total IgE)

43

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