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The Role of Twin Studies in IBD Research

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1 The Role of Twin Studies in IBD Research
Dr Hannah Gordon Clinical Research Fellow Chelsea and Westminster Hospital

2 Introduction Review History of twin studies Twin studies in IBD
New molecular techniques in IBD UK IBD Nixon Twin and Multiplex Registry and Biobank MH’s research fellow. Job setting up IBD TAM registry and biobank……250 twin pairs from existing database, advertising new twin pairs.

3 History of Twin Studies
1st recorded 1875 Francis Galton (1) Description of twin pairs Personal traits Physical and mental health “Nature is far stronger than nurture” Monozygotic vs dizygotic distinguished 1914 (2) Subsequent multiple phenotypes studied

4 Twin Studies – study design
Classical Monozygotic vs dizygotic (nature vs nurture) Adoption Genetically identical individuals reared apart Longitudinal Correlation between environment and discordance over time Exercise and depression Offspring of twins Birth weight of children of MZ female twins more similar than birth weight of children of MZ male twins Bouchard – twins reared apart – striking similar lifestyle choices

5 Twin Studies in IBD – Inheritance
Twin study showed CD MZ concordance 55% DZ concordance 3.8% (3) Figure 1: Range of Concordance of Crohn’s and UC between Twin Pairs (from Swedish, UK, Danish, Dutch and German Twin Populations (4)) Variation CC defined 1960s Genetic differences between populations Crohn’s has stronger genetic basis Strong environmental component Crohn’s Disease Ulcerative Colitis Monozygotic 20-55% 6.3-17% Dizygotic 0-3.6% 0-6.3% Swedish twins – compelling evidence for genetic component. Not replicated ?1960s recognition of Crohn’s colitis (earlier studies crohn’s bias towards ileal disease which does have stronger genetic basis). ?population.

6 Twin studies: UC altered mucosal glycosylation presented in discordant MZ pairs (9) MZ concordance CD location and behaviour UC extent (5,6) monozygotic twin pairs x1CD x1 UC (7) X2 concordance DZ twins compared with other siblings (8) Shared uterus More similar childhood environment Altered mucousal glycolsylation in UC>healthy controls. Interestingly also increased in healthy discordant twin - ?precursor to disease development.

7 Genome Wide Association Studies
163 SNPs associated with IBD (10,11) Following GWAS 163 SNPs identified. It can be seen that some overlap, perhaps explaining twin x1UC x1 Crohn’s. There are genes distinct for both and even associated with location. However only accounts for approx. 30% heritability. In addition high discordance rates support large environmental role. One area implicated = microbiota.

8 The Microbiome – a living active ecosystem
Trillions of microbes (10x number of human cells) (12) >1000 species level phylotypes Microbial genome 150x larger than human host (13) Changes during life Interactions with host (and each other) Obesity DM IBD CV disease Previously thought to be commensal organisms; now much widely recognised as an ecosystem essential for health and disease development.

9 Study of Microbiota Megagenomics
16srRNA PCR sequencing and amplification (14) Metaproteomics Expressed gene products Metabolomics Metabolites of host-microbiota interactions High res NMR spect Multivariate statistical analysis “Metabolic fingerprint” Initially very difficult to study as unable to culture. However over past decade techniques involving to gradually piece together what is there and what it is doing and how it impacts development of IBD in susceptible individuals.

10 Microbiota of MZ twins:
Healthy MZ twins have similar microbiota (15) Twins with CD have differing microbiota (concordant or discordant) (16) Microbiota tends towards phenotype rather than genotype (17) Inactive UC microbiota no different from healthy twin (18) Metagenomic studies do not show clear differences between discordant twin pairs; however studied when disease inactive.

11 Metabolomics – “Fingerprints” in IBD
Metabolomic profile of faecal water of A) CD (n=10), B) UC (n=10), C) Healthy control (n=13) (19) Key: 1, butyrate; 2, leucine; 3, propionate; 4, valine; 5, isoleucine; 6, threonine; 7, alanine; 8, lysine; 9, acetate; 10, glutamate; 11, succinate; 12, aspartic acid; 13, asparagine; 14, trimethylamine; 15, cysteine; 16, proline; 17, glycerol; 18, methylamine; 19, 5-aminosalicylic acid; 20, N -acetyl-5-aminosalicylic acid; 21, tyrosine; and 22, uracil Metabolomic studies allow snap shot of inter-reactions between bacteria and host. Distinct patterns in crohn’s, uc and healthy controls

12 Metabolomic profiles IBD:
CD Depletion of short chain fatty acids Decreased methylamine and trimethylamine UC Increased amino acids

13 Metabolomic profiles of Twins
Difference between discordant MZ pairs (ICD and CCD) (20) Similarity between healthy MZ Differentiation between ICD and CCD ?Metabolites associated with SNPs higher in affected twin Studies of MZ twins with CD have demonstrated different profiles between concordant and discordant. Striking similarity between healthy twins supporting evidence of genetic or early environment component to microbiome development.

14 Epigenetics – Blurring the distinction between nature and nurture
“Heritable changes in gene expression that occur without alterations in DNA sequence” (11) Methylation gene silencing Histone modification Changes persist after mitosis ?persist after meiosis (transgenerational)

15 Epigenetics IBD – 50 genes with different methylation between patients with CD and controls (21) Twin studies – different methylation patterns SLE MZ discordant Role of twin studies ?timing of methylation ?Inheritance of methylation in offspring Methylation patterns differ between CD and controls. Twin studies of epigenetics in other disease, namely SLE, showed varying methylation in discordant MZ twins. ?timing ?inheritance to offspring.

16 MicroRNA Small non coding RNA molecule Transported from nucleus
Forms protein complex Binds with mRNA mRNA degraded sooner and translated less How does it change in IBD? Distinct miRNA signatures in peripheral blood in CD vs UC vs Control (11) MiRNA NOD2 controls miRNA expression (24) MiRNA 29 deficient mice – worse colitis Increasing microRNA involved in pathophysiology of IBD.

17 Limitations of twin studies
Sample size MZ twins 3/1000 births DZ twins 13/1000 births IBD prevalence UK 400/100,000 One of the major limitations of twin studies is the sample size. Despite increase in IBD and twin pregnancies both are still relatively rare

18 IBD Nixon TAM Registry and Biobank
History Royal Free Dataset 250 twin pairs Study of MZ vs DZ concordance 1996 (23) Database revisited and reanalysed 2011 (6) Concordance of disease location and extent Childhood infection Current Contacting Twins from previous dataset Recruiting new Twin pairs Biobank Biobank to be stored within SMH biobank.

19 Conclusion Continuing relevance to twin studies in omics era(2)
Microbiome Epigenetics Twin studies to date Evidence of genetic component Development Disease pattern Galton wrong – environmental factors predominate

20 References: Galton, F. The history of twins, as a criterion of the relative powers of nature and nurture. J. Anthropol. Institute Great Britain Ireland 5, 391–406 (1876) Dongen J, Slagboom P, Draisma H, Martin N, Boomsana DL. The continuing value of twin studies in the omics era. Nat Rev Genet Sep;13(9):640-53 Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut. 1988; 29: 990–996 Brant S. Update on the heritability of IBD: The importance of twin studies. Inflammatory Bowel Disease Vol 17, Issue 1, Pg 1-5 Jan 2011 Halfvarson J, Jess T, Bodin L, et al. Longitudinal concordance for clinical characteristics in a Swedish-Danish twin population with inflammatory bowel disease. Inflamm Bowel Dis. 2007; 13: 1536–1544. Ng SC, Woodrow S, Patel N, Subhani J, Harbord M. Role of genetic and environmental factors in British twins with Inflamatory Bowel disease. Inflamm Bowel Dis Apr;18(4): doi: /ibd.2174 Halfvarson J. Genetics in twins with Crohn's disease: less pronounced than previously believed? Inflamm Bowel Dis. Epub ahead of print: 2010; June Bengtson MB, Aamodt G, Vatn MH, Harris JR. Concordance for IBD among twins compared to ordinary siblings – a Nowegian population based study. J Crohns Colitis Sep;4(3):312-8 Bodger K, Halfvarson J, Dodson AR, Campbell F, Wilson S, Lee R, Lindberg E, Järnerot G, Tysk C, Rhodes JM. Altered colonic glycoprotein expression in unaffected monozygotic twins of inflammatory bowel disease patients. Gut Jul;55(7): Epub 2006 Feb 4 Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;490:119–124 Ventham NT, Kennedy NA, Nimmo ER, Satsangi J. Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics. Gastroenterology.2013 Aug;145(2): Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S. Host-gut microbiota metabolic interatctions. Science Jun 8;336(6086):1262-7 Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K.S., Manichanh, C., Nielsen, T., Pons, N., Levenez, F., and Yamada, T., et al A human gut microbial gene catalogue established by metagemonic sequencing .MetaHIT Consortium Nature 464, 59-65(2010) Holmes E, Li JV, Marchesi JR, Nicholson JK. Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk. Cell Metab. 2012;16(5): Dicksved J, Halfvarson J, Rosenquist M, Jarnerot G, Tysk C, et al. (2008) Molecular analysis of the gut microbiota of identical twins with Crohn's disease. ISME Journal 2: 716–727 Erickson AR, Cantarel BL, Lamdela R, Darzi Y, Mongeodin EF, Pan C, Shah M, Halvarson J, Tysk C, Henrissat B, Rees J, Verberkmoes NC, Fraser CM, Hettich RL, Jannson JK. Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn’s disease. 2012;7(11):e doi: /journal.pone Epub 2012 Nov 28. Willing B, Halfvarson J, Dicksved J, et al. Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn's disease. Inflamm Bowel Dis. 2009; 15: 653–660 Willing BP, Dicksved J, Halfvarson J, Andersson AF, Lucio M, et al. (2010) A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 139: 1844–1854 Marchesi RJ, Holmes E, Khan F, Kochhar S, Scanlan P, Shanahan F, Willson ID, Wang Y. Rapid and noninvesive metabolomics characterization of inflammatory bowel disease. J. Proteome Res 2007 Feb;6(2): Jansson J, Willing B, Lucio M, Fekete A, Dicksved J, et al. (2009) Metabolomics Reveals Metabolic Biomarkers of Crohn's Disease. PLoS One 4: e3686 Nimmo ER, Prendergast JG, Aldhous MC, et al. Genome-wide methylation profiling in Crohn’s disease identifies altered epigenetic regulation of key host defense mechanisms including the Th17 pathway. Inflamm Bowel Dis. 2012;18:889–899 Wu F, Guo NJ, Tian H, et al. Peripheral blood microRNAs distinguish active ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis. 2012;17:241–250 Thompson N, Driscoll R, Pounder R E, Wakefield A J. Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ January 13; 312(7023): 95–96 Brain O, Owen B et al. The intracellular sensor NOD2 Induces MicroRNA-29 Expression In Human Dendritic Cells to limit IL23 release. Immunity –536, September 19, 2013

21 Inflammatory Bowel Diseases 2014
Bella Center Copenhagen, Denmark EACCME applied Register online at

22 CALLING ALL TWINS!!!!! If you know of any IBD patients who are part of a twin pair please contact me: Tel: +44 (0)

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