Presence and dosing of HLA-DQ2 and HLA-DQ8 genotypes do not … · 2013-11-21 · Presence and dosing of HLA-DQ2 and HLA-DQ8 genotypes do not predict clinical or pathological severity

Presence and dosing of HLA-DQ2 and HLA-DQ8 genotypes do not predict clinical or pathological severity of

coeliac disease

NR Lewis1 J West1 RFA Logan1 DS Sanders2

1. Division of Epidemiology and Public Health, University of Nottingham2. Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield

HLAHLA--DQ and aetiology of DQ and aetiology of coeliac diseasecoeliac disease

Ivarsson Scand J Nutr 2001

Gliadin

Deamidated gliadin

tTG

HLAHLA--DQ and pathogenesis of DQ and pathogenesis of coeliac diseasecoeliac disease

APC

Molberg Nat Med 1998

CD4+T-cell

Deamidated gliadin bound to HLA-DQ2 (or DQ8) on antigen-presenting cell (APC) ispresented to T-cell

HLAHLA--DQ2 gene dose and magnitude DQ2 gene dose and magnitude of glutenof gluten--specific Tspecific T--cell responsecell response

2.5 M2.0 M

1.0 M1.5 M

0.5 M

DQ2.5homozygote

DQ2.5/non-DQ2heterozygote

DQ2.5/DQ2.2heterozygote

DQ2.2homozygote

IFN

-pr

oduc

tion

Vader PNAS 2003

Clinical relevance of HLAClinical relevance of HLA--DQ2?DQ2?StudyStudy Number of Number of

coeliacscoeliacsOutcomes associated with Outcomes associated with HLAHLA--DQ2 homozygosityDQ2 homozygosity

Zubillaga Zubillaga et alet al20022002

133 children133 children Female sexFemale sex Earlier mean age at diagnosisEarlier mean age at diagnosis

Johnson Johnson et alet al 20042004 110 adults110 adults No association with severity of VANo association with severity of VA

Karinen Karinen et alet al20062006

144 adults144 adults Lower mean Hb at diagnosisLower mean Hb at diagnosis Earlier mean age at diagnosisEarlier mean age at diagnosis Total villous atrophyTotal villous atrophy

Murray Murray et alet al20072007

84 mixed84 mixed No association with severity of VA or No association with severity of VA or age at diagnosisage at diagnosis

Jores Jores et al et al 20072007 187 children187 children Total villous atrophyTotal villous atrophy

Vermeulen Vermeulen et alet al20082008

113 children113 children No association with severity of VA or No association with severity of VA or age at diagnosisage at diagnosis

Thomas Thomas et alet al20092009

309 adults309 adults No association with age at diagnosis, No association with age at diagnosis, Hb nor bone mineral densityHb nor bone mineral density

Aims of studyAims of study

What is the association between HLAWhat is the association between HLA--DQ2DQ2genotype and:genotype and:

clinicalclinical

biochemicalbiochemical

pathological pathological

presentation of coeliac disease? presentation of coeliac disease?

Study populationStudy population

Coeliac ClinicCoeliac ClinicConsecutive incident andConsecutive incident andprevalent cases of coeliacprevalent cases of coeliacdisease attendingdisease attendingdedicated coeliac clinicdedicated coeliac clinicbetween 2004 between 2004 –– 2008 2008

Royal Hallamshire HospitalRoyal Hallamshire Hospital

Study population: HLA genotypeStudy population: HLA genotype

DQ2 homozygoteDQ2 homozygote

DRB1*03DRB1*03––DQA1*05DQA1*05––DQB1*02 (DR3) and DQB1*02 (DR3) and DRB1*07DRB1*07––DQA1*02DQA1*02––DQB1*02 (DR7) DQB1*02 (DR7) haplotypeshaplotypes

DQ2 heterozygoteDQ2 heterozygote

DR3/X, DR7/X, DR3/DR4 or DR4/DR7 DR3/X, DR7/X, DR3/DR4 or DR4/DR7 haplotypeshaplotypes

DQ2DQ2--negative DQ8negative DQ8

DQA1*03DQA1*03––DQB1*0302 (DR4) DQB1*0302 (DR4) haplotypehaplotype

DQ2DQ2--negative DQ8negative DQ8--negativenegative

Without DQ2 and DQ8Without DQ2 and DQ8

Study designStudy design

Measurement of variables:Measurement of variables:

Clinical features Clinical features age at diagnosis,age at diagnosis, symptomssymptoms

BiochemicalBiochemical full blood count, haematinic profile, full blood count, haematinic profile,

liver profile (ALP, ALT, liver profile (ALP, ALT, bilirubinbilirubin, GGT), GGT)lipid profile (total and HDL cholesterol)lipid profile (total and HDL cholesterol)EMA status, EMA status, tTGtTG titretitre

HistologyHistology Marsh grading of duodenal biopsiesMarsh grading of duodenal biopsies

at diagnosis of coeliac diseaseat diagnosis of coeliac disease

Statistical analysisStatistical analysisOneOne--way analysis of varianceway analysis of varianceAssociations between HLAAssociations between HLA--DQ genotype with continuousDQ genotype with continuousvariablesvariablese.g. mean age at diagnosis of coeliac diseasee.g. mean age at diagnosis of coeliac disease

Logistic regression Logistic regression Associations between HLAAssociations between HLA--DQ genotype with categoricalDQ genotype with categoricalvariables variables e.g. Marsh grading of duodenal biopsye.g. Marsh grading of duodenal biopsy

HLA genotype of cohortHLA genotype of cohort

020406080

100120140160180200220240260280300320

DQ2homozygote

DQ2heterozygote

DQ2-negativeDQ8

DQ2-negativeDQ8-negative

Num

ber o

f coe

liacs n = 447

Demography of cohortDemography of cohortAll All

coeliacs coeliacs (n = 447)(n = 447)

DQ2 DQ2 homozygotes homozygotes

(n = 113)(n = 113)

DQ2 DQ2 heterozygotes heterozygotes

(n = 308)(n = 308)

DQ2DQ2--negative negative DQ8 DQ8

(n = 24)(n = 24)

Female Female (%)(%)

318 318 (71.1)(71.1)

82 82 (73.2)(73.2)

220 220 (71.4)(71.4)

15 15 (62.5)(62.5)

Mean age at Mean age at diagnosis diagnosis (SD)(SD)

45.9 45.9 (17.8)(17.8)

46.3 46.3 (17.5)(17.5)

45.5 45.5 (18.1)(18.1)

48.1 48.1 (16.8)(16.8)

Childhood Childhood diagnosis (%)diagnosis (%)

27 27 (6.0)(6.0)

7 7 (6.2)(6.2)

18 18 (5.8)(5.8)

2 2 (8.3)(8.3)

p > 0.05 p > 0.05

p > 0.05

Presenting featuresPresenting featuresAll All



(n = 113)(n = 113)


(n = 308)(n = 308)


(n = 24)(n = 24)

Iron deficiency Iron deficiency anaemia (%)anaemia (%)

174174(39)(39)

5252(46)(46)

113113(37)(37)

99(38)(38)

Diarrhoea Diarrhoea (%)(%)

161161(36)(36)

3535(31)(31)

114114(37)(37)

1010(42)(42)

Weight loss Weight loss (%)(%)

6060(13)(13)

1010(9)(9)

4747(15)(15)

22(8)(8)

Malabsorption Malabsorption (%)(%)

1313(3)(3)

22(2)(2)

1111(4)(4)

00(0)(0)

p > 0.05 p > 0.05

p > 0.05

Presenting biochemical testsPresenting biochemical testsAll All



(n = 113)(n = 113)


(n = 308)(n = 308)


(n = 24)(n = 24)

Mean Hb Mean Hb (SD) g/L(SD) g/L

12.812.8(2.0)(2.0)

12.412.4(1.8)(1.8)

12.912.9(2.1)(2.1)

12.412.4(2.4)(2.4)

Mean ALT Mean ALT (SD) U/L(SD) U/L

34.334.3(77.0)(77.0)

31.631.6(32.4)(32.4)

33.833.8(85.7)(85.7)

49.849.8(104.8)(104.8)

Mean ALP Mean ALP (SD) U/L(SD) U/L

84.384.3(58.5)(58.5)

78.678.6(47.9)(47.9)

83.583.5(49.9)(49.9)

113.2113.2(133.6)(133.6)

Mean Mean cholesterol (SD) cholesterol (SD) mmol/Lmmol/L

4.84.8(1.1)(1.1)

4.74.7(0.9)(0.9)

4.84.8(1.2)(1.2)

4.44.4(1.4)(1.4)

p > 0.05 p > 0.05p > 0.05

Presenting histologyPresenting histologyAll All



(n = 113)(n = 113)


(n = 308)(n = 308)


(n = 24)(n = 24)

Marsh grade(%)Marsh grade(%)3a, 2 or 13a, 2 or 13b or 3c3b or 3c

162 (40)162 (40)247 (60)247 (60)

37 (36)37 (36)65 (64)65 (64)

110 (39)110 (39)175 (61)175 (61)

16 (68)16 (68)8 (32)8 (32)

p > 0.05

p = 0.008

p = 0.005

Presenting histologyPresenting histologyAll All



(n = 113)(n = 113)


(n = 308)(n = 308)


(n = 24)(n = 24)

Marsh grade(%)Marsh grade(%)1 or 21 or 23a, 3b or 3c3a, 3b or 3c

33 (8)33 (8)439 (92)439 (92)

7 (7)7 (7)106 (93)106 (93)

23 (8)23 (8)285 (92)285 (92)

3 (14)3 (14)21 (86)21 (86)

p > 0.05 p > 0.05

p > 0.05

Presenting serologyPresenting serologyAll All



(n = 113)(n = 113)


(n = 308)(n = 308)


(n = 24)(n = 24)

EMA positivity EMA positivity (%)(%)

341 341 (88)(88)

8686(91)(91)

243243(90)(90)

1111(52)(52)

Mean tTG Mean tTG (SD) iu(SD) iu

176.4176.4(123.2)(123.2)

193.5193.5(125.9)(125.9)

175.0175.0(121.4)(121.4)

130.1130.1(123.6)(123.6)

p > 0.05 p = 0.0001

p = 0.0001

ConclusionsConclusions

DQ2 heterozygosity is the most prevalent DQ2 heterozygosity is the most prevalent HLAHLA--DQ genotype in contemporary DQ genotype in contemporary coeliac disease with 94% coeliacs coeliac disease with 94% coeliacs carrying at least one DQ2 heterodimercarrying at least one DQ2 heterodimer


Presence, heterozygosity nor homozygosity for Presence, heterozygosity nor homozygosity for HLAHLA--DQ2 genotype was not associated with: DQ2 genotype was not associated with:

-- age at diagnosisage at diagnosis-- clinical severityclinical severity-- biochemical severitybiochemical severity-- histological severityhistological severity

of coeliac diseaseof coeliac disease


HLAHLA--DQ2 and HLADQ2 and HLA--DQ8 genotyping DQ8 genotyping should be reserved for assessing risk of should be reserved for assessing risk of coeliac disease in equivocal cases rather coeliac disease in equivocal cases rather than predicting presentation and severity than predicting presentation and severity of coeliac diseaseof coeliac disease


DQ2 heterozygosity is the most prevalent HLADQ2 heterozygosity is the most prevalent HLA--DQ DQ genotype in contemporary coeliac disease with 94% genotype in contemporary coeliac disease with 94% coeliacs carrying at least one DQ2 heterodimercoeliacs carrying at least one DQ2 heterodimer

Presence, heterozygosity nor homozygosity for HLAPresence, heterozygosity nor homozygosity for HLA-- DQ2 genotype was not associated with presentation; DQ2 genotype was not associated with presentation; clinical, biochemical or histological severity of clinical, biochemical or histological severity of coeliac diseasecoeliac disease

HLAHLA--DQ2 and HLADQ2 and HLA--DQ8 genotyping should be DQ8 genotyping should be reserved for assessing risk of coeliac disease in reserved for assessing risk of coeliac disease in equivocal cases rather than predicting presentation equivocal cases rather than predicting presentation and severity of coeliac diseaseand severity of coeliac disease

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Presence and dosing of HLA-DQ2 and HLA-DQ8 genotypes do not … · 2013-11-21 · Presence and dosing of HLA-DQ2 and HLA-DQ8 genotypes do not predict clinical or pathological severity