UK IBD twin and multiplex registry: Concordance and environmental risk factors of twins with IBD Dr Hannah Gordon, Prof Timothy Orchard, Dr Alan Steel, Dr Marcus Harbord ECCO 2015 Barcelona

Declarations: The authors have no competing interests Funded by an unrestricted grant from the Jesse and Thomas Tam Family Foundation

Introduction: Background IBD twin studies Methods UK IBD Twin and Multiplex Registry Concordance and environmental risk factors Results Conclusion

Background: First twin study 1876: ”Nature is far stronger than nurture” (Galton 1876) Classical twin design Compares MZ and DZ concordance CD and UC both heritable (Tysk 1988, Halfvarson 2007, Brant 2011, Chen 2014) Rate of increase in IBD incidence outweighs genetic drift (Molodecky 2012) Twin studies provide control for genetic factors Environmental factors Microbiota and epigenome (Dongen 2012)

Method 1: Recruitment into UK IBD Twin and Multiplex Registry UK research registry Twins Multiplex (at least 3 first degree) Recruitment IBD charities (including Royal Free cohort) Clinician referral

Method 2: Inclusion into this analysis Twins Monozygotic and Dizygotic Concordant and Discordant Crohn’s Disease and Ulcerative Colitis

Method 3: Collecting Information QUESTIONNAIRE Demographics Zygosity Concordance Disease history (IBD sufferers only) Environmental factors Smoking (including cannabis) Diet Stress Early Environment MEDICAL RECORDS Primary care physicians Gastroenterologist Disease history Montreal (CD) Disease extent (UC) Medication Surgical History

Method 4: Data Analysis Pair concordance of MZ and DZ pairs Analysis of environmental factors After adjusting for correlated data due to comparisons of twins, multivariable mixed-effects logistic regression analysis was performed invoking the GEE method using PROC GENMOD using the repeated statement for twins with logit link

Results 1: Demographics and pair concordance Mean age 57 years (range 21-83) 31 MZ:69 DZ UC 52: CD 48 Pair Concordance: Crohn’s DiseaseUlcerative Colitis Monozygotic53.3% (8:7)25% (4:12) Dizygotic9.1% (3:30)19.4% (7:29)

Results 2: Concordance compared with other twin cohorts Pair concordance (UK IBD TAM 2014) Previous twin cohorts (Tysk et al 1988, Halfvarson 2007, Brant 2011) Crohn’s DiseaseUlcerative Colitis Monozygotic20-55%3.6-17% Dizygotic0-3.6%0-6.3%

Results 3: Environmental Factors – smoking history In line with the literature, multivariate analysis suggests VariableNo.% CD N=58 % Non CD N=38 Odds Ratio 95% CIP Value Smoking history before diagnosis - CD No Yes Not Known /58 (58.6%) 22/24 (91.7%) 2/14 (14.3%) 24/58 (41.4%) 2/24 (8.3%) 12/14 (85.7%) Ref 4.11(1.60 to 10.54) VariableNo.% UC N=62 % Non UC N=42 Odds Ratio 95% CIP Value Smoking history before diagnosis - UC No Yes Not Known /84 (63.1%) 7/10 (70%) 3/10 (30%) 31/84 (36.9%) 3/10 (30%) 7/10 (70%) Ref 0.39(0.14 to 1.07) 0.067

Results 4: Environmental Factors – Childhood Illness Variable N%IBD % Non IBD Odds ratio 95% CI p- value Childhood illness Equal to peers More than peers Less than peers Not Known (65.2%) 16(94.1%) 26(59.1%) 5(20.8%) 40(34.7%) 1 (5.89%) 18(40.9%) 19(79.2%) Ref (1.34 to 39.5) (0.47 to 1.35) Gastroenteritis prior to diagnosis Equal to peers More than peers Less than peers Not Known (66.9%) 10(90.0%) 24(58.5%) 5(20.8%) 41(33.1%) 1(10%) 15(41.5%) 19(79.2%) Ref (0.92 to 7.05) (0.49 to 1.43) More self reports of frequent childhood illness amongst IBD cohort Non significant increase in childhood gastroenteritis

Results 5: Environmental Factors - Diet Variable Odds ratio95% CIp-value CD “ready made meals” at least weekly Yes4.23 (1.58 to 11.34) Univariate analysis significant for CD Significance lost with correction for multiple comparisons

Results 6: Environmental Factors – Infant Feeding

Limitations: Recall bias Pair not proband concordance Sample size

Conclusion: Support heritability CD UC less heritable than other cohorts (Bengtson 2010) Smoking Childhood health

Future Direction: Resource to study interface between genes and environment Epigenome Microbiota and metabolome Biobank International Collaboration Denmark Scotland

Questions?

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