The InterAct Project

Dr Claudia Langenberg, MRC Epidemiology Unit, Cambridge

14th of February 2011,

Institute of Public Health

The InterAct Project

An Examination of the Interaction of Genetic and Lifestyle Factors on the Incidence of Type 2 Diabetes

Objectives• To discover how genetic and lifestyle behavioral factors,

particularly diet and physical activity, interact in their influence on the risk of developing type 2 diabetes.• EPIC nested case-cohort study

• To investigate how these discoveries may help to prevent the development of diabetes. • Lifestyle intervention studies

InterAct Research Lines

• RL1 Analysis of gene-lifestyle interaction in observational studies of diabetes incidence

• RL2 Analysis of nutritional factors and physical activity in observational studies of diabetes incidence

• RL3 Analysis of genetic factors in observational studies of diabetes incidence

• RL4 Analysis of gene-lifestyle interaction in intervention studies

InterAct Participants

• European, nested case-cohort study of 12,403 cases of incident type 2 diabetes and a subcohort of 15,376 participants conducted in 26 (21) centres in 8 European countries.

• Ascertainment and exclusion of all prevalent cases.

• Ascertainment and verification of T2D cases.

• Selection on a random subcohort (proportionate to T2D incidence and oversampled for prevalence).

InterAct Cases & Subcohort

EPIC Europe:5.42 million person-years

(n=455,680)

InterAct Denominator:3.99 million person-years

(340,234)

Random subcohort:16,835

Exclusions: 681Prevalent diabetes (548), post-

censoring diabetes (4), unknown status (129)

Exclusions:No stored buffy coat/ blood

(109,625) or no diabetes status reported (5,821)

Ascertained T2D cases: 17,928(17,407 from ascertainment, 521

identified in verification)

Random subcohort (post exclusions):

16,154

Verified incident T2D cases:12,403

Exclusions: 5,525Denmark (2,577), not diabetic

(838), prevalent diabetes (421), post-censoring diabetes (101),

unknown status (1,588)

Overlap: 778 verified incident T2D cases

HRs for T2D per 1 SD difference in waist and BMI

Overall

Centre

Potsdam

Netherlands

Turin

Navarra

Granada

Bilthoven

Sweden

Subtotal

Subtotal

Asturias

Subtotal

Oxford

Umea

Subtotal

Malmo

Cambridge

UK

Italy

Spain

Denmark

Subtotal

Florence

Copenhagen

Subtotal

Germany

San Sebastian

Subtotal

Murcia

Aarhus

Varese

Heidelberg

Ragusa

1.93 (1.82, 2.05)

Ratio (95% CI)

2.05 (1.69, 2.50)

Hazard

2.02 (1.62, 2.51)

1.57 (1.34, 1.85)

1.86 (1.33, 2.61)

1.81 (1.40, 2.35)

1.92 (1.48, 2.49)

1.89 (1.70, 2.10)

2.15 (1.77, 2.63)

2.22 (1.93, 2.57)

2.25 (1.72, 2.95)

1.68 (1.47, 1.93)

2.18 (1.89, 2.52)

2.19 (1.92, 2.51)

2.21 (1.87, 2.62)

1.76 (1.56, 1.99)

1.91 (1.41, 2.61)

1.87 (1.65, 2.12)

1.81 (1.40, 2.35)

1.83 (1.48, 2.25)

1.98 (1.73, 2.28)

1.59 (1.35, 1.89)

1.93 (1.59, 2.36)

1.74 (1.24, 2.44)

2.33 (1.89, 2.88)

2.17 (1.63, 2.89)

1.93 (1.82, 2.05)

Ratio (95% CI)

2.05 (1.69, 2.50)

Hazard

2.02 (1.62, 2.51)

1.57 (1.34, 1.85)

1.86 (1.33, 2.61)

1.81 (1.40, 2.35)

1.92 (1.48, 2.49)

1.89 (1.70, 2.10)

2.15 (1.77, 2.63)

2.22 (1.93, 2.57)

2.25 (1.72, 2.95)

1.68 (1.47, 1.93)

2.18 (1.89, 2.52)

2.19 (1.92, 2.51)

2.21 (1.87, 2.62)

1.76 (1.56, 1.99)

1.91 (1.41, 2.61)

1.87 (1.65, 2.12)

1.81 (1.40, 2.35)

1.83 (1.48, 2.25)

1.98 (1.73, 2.28)

1.59 (1.35, 1.89)

1.93 (1.59, 2.36)

1.74 (1.24, 2.44)

2.33 (1.89, 2.88)

2.17 (1.63, 2.89)

11 2 5

BMI (z scores)

Overall

Copenhagen

Denmark

Centre

Asturias

Subtotal

Granada

Sweden

Subtotal

Varese

Subtotal

Cambridge

Netherlands

Subtotal

Ragusa

UK

Florence

Oxford

Spain

Aarhus

Malmo

Turin

San Sebastian

Murcia

Bilthoven

Subtotal

Navarra

Germany

Potsdam

Subtotal

Heidelberg

Subtotal

Italy

1.95 (1.83, 2.08)

1.97 (1.74, 2.22)

Ratio (95% CI)

2.21 (1.80, 2.73)

1.95 (1.76, 2.17)

1.98 (1.34, 2.94)

2.11 (1.84, 2.42)

1.78 (1.22, 2.59)

1.80 (1.57, 2.07)

2.25 (1.84, 2.76)

2.28 (1.99, 2.61)

2.38 (1.72, 3.29)

2.04 (1.47, 2.83)

1.63 (1.27, 2.08)

1.92 (1.58, 2.34)

1.69 (1.42, 2.02)

2.14 (1.76, 2.59)

1.81 (1.42, 2.30)

1.52 (1.20, 1.92)

1.87 (1.50, 2.33)

1.69 (1.42, 2.02)

1.65 (1.37, 1.97)

2.29 (1.87, 2.80)

1.87 (1.50, 2.33)

2.27 (1.88, 2.73)

1.93 (1.41, 2.66)

Hazard

1.95 (1.83, 2.08)

1.97 (1.74, 2.22)

Ratio (95% CI)

2.21 (1.80, 2.73)

1.95 (1.76, 2.17)

1.98 (1.34, 2.94)

2.11 (1.84, 2.42)

1.78 (1.22, 2.59)

1.80 (1.57, 2.07)

2.25 (1.84, 2.76)

2.28 (1.99, 2.61)

2.38 (1.72, 3.29)

2.04 (1.47, 2.83)

1.63 (1.27, 2.08)

1.92 (1.58, 2.34)

1.69 (1.42, 2.02)

2.14 (1.76, 2.59)

1.81 (1.42, 2.30)

1.52 (1.20, 1.92)

1.87 (1.50, 2.33)

1.69 (1.42, 2.02)

1.65 (1.37, 1.97)

2.29 (1.87, 2.80)

1.87 (1.50, 2.33)

2.27 (1.88, 2.73)

1.93 (1.41, 2.66)

Hazard

11 2 5

Waist (z scores)

Men

Cumulative risk of T2D in the subcohort by sex, BMI and waist groups

0.00

0.05

0.10

0.15

0.20

0.25

0 5 10 15

BMI < 25 kg/m2

0 5 10 15

BMI 25-29.9 kg/m2

0 5 10 15

BMI >=30 kg/m2

Cu

mu

lativ

e r

isk

of

dia

bete

s

Time since study entry (years)

Men

___ Waist <94cm in men/ 80cm in women ___ Waist ≥94-101.9cm in men/ 80-87.9cm in women ___ Waist ≥102cm in men/ 88cm in women

Main effects iPLEX1 (n=21,178; 9,233 cases/ 11,945 random controls)

Adjusted for sex, centre Adjusted for sex, latitude and longitude of the centre

Adjusted for sex, centre and BMI

Gene SNP HR T2D 95% CI p-value HR T2D* 95% CI* p-value* HR T2D* 95% CI* p-value* SLC30A8 rs13266634 1.13 1.07-1.20 1.06E-05 1.13 1.07-1.20 6.67E-06 1.13 1.04-1.22 0.002 KCNJ11 proxy rs757110 1.06 1.01-1.10 0.008 1.06 1.01-1.10 0.008 1.09 1.03-1.14 0.001 TSPAN8 rs7961581 1.05 1.00-1.10 0.035 1.05 1.00-1.10 0.036 1.08 1.02-1.14 0.007 CDKN2A/B rs564398 1.02 0.94-1.11 0.612 1.02 0.94-1.10 0.625 1.05 0.95-1.16 0.319 INS1 rs689 1.03 0.97-1.08 0.340 1.03 0.97-1.08 0.329 1.04 0.97-1.12 0.219 PPARg rs1801282 1.05 0.94-1.17 0.362 1.05 0.94-1.17 0.358 1.09 0.98-1.20 0.102 HHEX rs1111875 1.11 1.01-1.21 0.030 1.11 1.01-1.21 0.028 1.13 1.02-1.25 0.018 KCNQ1 rs2237892 1.07 0.90-1.27 0.455 1.07 0.90-1.26 0.458 1.06 0.87-1.28 0.582 NOTCH2 rs10923931 1.09 0.94-1.28 0.263 1.09 0.94-1.27 0.266 1.15 0.96-1.37 0.123 THADA rs7578597 1.11 0.98-1.26 0.103 1.11 0.98-1.26 0.101 1.16 1.03-1.32 0.016 MTNR1B rs10830963 1.07 1.01-1.13 0.021 1.07 1.01-1.13 0.020 1.06 0.98-1.15 0.161 CDC123 rs12779790 1.05 1.00-1.11 0.049 1.05 1.00-1.11 0.050 1.03 0.95-1.12 0.516 CDKN2A/B rs10811661 1.13 1.07-1.19 4.50E-06 1.13 1.07-1.19 3.50E-06 1.19 1.11-1.28 6.59E-07 JAZF1 rs864745 1.08 1.03-1.12 3.16E-04 1.08 1.03-1.12 3.43E-04 1.12 1.07-1.18 3.57E-06 ADAMTS9 rs4607103 0.97 0.92-1.02 0.275 0.97 0.92-1.02 0.276 0.99 0.92-1.06 0.687 CDKAL1 rs10946398 1.12 1.07-1.17 6.03E-07 1.12 1.07-1.17 7.03E-07 1.14 1.06-1.22 0.001 Genetic score 1.08 1.06-1.09 4.01E-31 1.08 1.06-1.09 3.52E-31 1.10 1.08-1.12 2.91E-30 G6PC2 rs563694 0.99 0.95-1.03 0.712 0.99 0.95-1.04 0.718 0.99 0.94-1.04 0.624 ETV5 rs7647305 1.00 0.96-1.06 0.849 1.00 0.96-1.06 0.850 0.97 0.92-1.04 0.396 MC4R rs17782313 1.04 0.97-1.10 0.266 1.04 0.98-1.10 0.249 1.00 0.91-1.11 0.966

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Acknowledgements