686
Views
62
CrossRef citations to date
0
Altmetric
Review

Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility

&
Pages 1091-1107 | Received 06 Feb 2016, Accepted 28 Apr 2016, Published online: 15 Jun 2016

References

  • Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathologic and clinical entity. JAMA. 1932;99:1323–1329.
  • Cho JH. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol. 2008;8:458–466.
  • Yang H, McElree C, Roth MP, et al. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut. 1993;34:517–524.
  • Ek WE, D’Amato M, Halfvarson J. The history of genetics in inflammatory bowel disease. Ann Gastroenterol. 2014;27:294–303.
  • Brant SR. Update on the heritability of inflammatory bowel disease: the importance of twin studies. Inflamm Bowel Dis. 2011;17:1–5.
  • Roth MP, Petersen GM, McElree C, et al. Familial empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews. Gastroenterology. 1989;96:1016–1020.
  • Peeters M, Nevens H, Baert F, et al. Familial aggregation in Crohn’s disease: increased age-adjusted risk and concordance in clinical characteristics. Gastroenterology. 1996;111:597–603.
  • de Lange KM, Barrett JC. Understanding inflammatory bowel disease via immunogenetics. J Autoimmun. 2015;64:91–100.
  • Hugot JP, Laurent-Puig P, Gower-Rousseau C, et al. Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature. 1996;379:821–823.
  • Ohmen JD, Yang HY, Yamamoto KK, et al. Susceptibility locus for inflammatory bowel disease on chromosome 16 has a role in Crohn’s disease, but not in ulcerative colitis. Hum Mol Genet. 1996;5:1679–1683.
  • Parkes M, Satsangi J, Lathrop GM, et al. Susceptibility loci in inflammatory bowel disease. Lancet. 1996;348:1588.
  • Curran ME, Lau KF, Hampe J, et al. Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16. Gastroenterology. 1998;115:1066–1071.
  • Brant SR, Fu Y, Fields CT, et al. American families with Crohn’s disease have strong evidence for linkage to chromosome 16 but not chromosome 12. Gastroenterology. 1998;115:1056–1061.
  • Cavanaugh JA, Callen DF, Wilson SR, et al. Analysis of Australian Crohn’s disease pedigrees refines the localization for susceptibility to inflammatory bowel disease on chromosome 16. Ann Hum Genet. 1998;62:291–298.
  • Cavanaugh J. International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. Am J Hum Genet. 2001;68:1165–1171.
  • Cooney R, Jewell D. The genetic basis of inflammatory bowel disease. Dig Dis. 2009;27:428–442.
  • Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599–603.
  • Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411:603–606.
  • Lesage S, Zouali H, Cézard J-P, et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet. 2002;70:845–857.
  • Cuthbert AP, Fisher SA, Mirza MM, et al. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology. 2002;122:867–874.
  • Hampe J, Grebe J, Nikolaus S, et al. Association of NOD2 (CARD 15) genotype with clinical course of Crohn’s disease: a cohort study. Lancet. 2002;359:1661–1665.
  • Vermeire S, Wild G, Kocher K, et al. CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. Am J Hum Genet. 2002;71:74–83.
  • Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273:1516–1517.
  • Sachidanandam R, Weissman D, Schmidt SC, et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature. 2001;409:928–933.
  • The International HapMap Consortium. A haplotype map of the human genome. Nature. 2005;437:1299–1320.
  • McVean GAT, Myers SR, Hunt S, et al. The fine-scale structure of recombination rate variation in the human genome. Science. 2004;304:581–584.
  • McGovern DP, Kugathasan S, Cho JH. Genetics of inflammatory bowel diseases. Gastroenterology. 2015;149:1163–1176.
  • Kitsios GD, Zintzaras E. Genome-wide association studies: hypothesis-“free” or “engaged”? Transl Res. 2009;154:161–164.
  • Yamazaki K, McGovern D, Ragoussis J, et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet. 2005;14:3499–3506.
  • Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461–1463.
  • Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207–211.
  • Libioulle C, Louis E, Hansoul S, et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 2007;3:e58.
  • Rioux JD, Xavier RJ, Taylor KD, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39:596–604.
  • Van Limbergen J, Wilson DC, Satsangi J. The genetics of Crohn’s disease. Annu Rev Genomics Hum Genet. 2009;10:89–116.
  • Zhernakova A, Van Diemen CC, Wijmenga C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet. 2009;10:43–55.
  • Liu JZ, Anderson CA. Genetic studies of Crohn’s disease: past, present and future. Best Pract Res Clin Gastroenterol. 2014;28:373–386.
  • Fisher SA, Tremelling M, Anderson CA, et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease. Nat Genet. 2008;40:710–712.
  • Franke A, Balschun T, Karlsen TH, et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet. 2008;40:1319–1323.
  • Barrett JC, Lee JC, Lees CW, et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet. 2009;41:1330–1334.
  • Silverberg MS, Cho JH, Rioux JD, et al. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet. 2009;41:216–220.
  • Satsangl J, Farrant JM, Jewell DP, et al. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet. 1996;347:1212–1217.
  • Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–124.
  • Maher B. Personal genomes: the case of the missing heritability. Nature. 2008;456:18–21.
  • Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–753.
  • Cortes A, Brown MA. Promise and pitfalls of the Immunochip. Arthritis Res Ther. 2010;13:101.
  • Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40:955–962.
  • Franke A, Dpb M, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42:1118–1125.
  • McGovern DP, Gardet A, Torkvist L, et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet. 2010;42:332–337.
  • Anderson CA, Boucher G, Lees CW, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43:246–252.
  • Yamazaki K, Takazoe M, Tanaka T, et al. Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn’s disease. J Hum Genet. 2002;47:469–472.
  • Inoue N, Tamura K, Kinouchi Y, et al. Lack of common NOD2 variants in Japanese patients with Crohn’s disease. Gastroenterology. 2002;123:86–91.
  • Croucher PJ, Mascheretti S, Hampe J, et al. Haplotype structure and association to Crohn’s disease of CARD15 mutations in two ethnically divergent populations. Eur J Hum Genet. 2003;11:6–16.
  • Lee GH, Kim CG, Kim JS, et al. Frequency analysis of NOD2 gene mutations in Korean patients with Crohn’s disease. Korean J Gastroenterol. 2005;45:162–168.
  • Yamazaki K, Onouchi Y, Takazoe M, et al. Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn’s disease in Japanese patients. J Hum Genet. 2007;52:575–583.
  • Yang S-K, Park M, Lim J, et al. Contribution of IL23R but not ATG16L1 to Crohn’s disease susceptibility in Koreans. Inflamm Bowel Dis. 2009;15:1385–1390.
  • Bin C, Zhirong Z, Xiaoqin W, et al. Contribution of rs11465788 in IL23R gene to Crohn’s disease susceptibility and phenotype in Chinese population. J Genet. 2009;88:191–196.
  • Kim SW, Kim ES, Moon CM, et al. Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease. Gut. 2011;60:1527–1536.
  • Yamazaki K, Umeno J, Takahashi A, et al. A genome-wide association study identifies 2 susceptibility loci for Crohn’s disease in a Japanese population. Gastroenterology. 2013;144:781–788.
  • Yang S-K, Hong M, Zhao W, et al. Genome-wide association study of Crohn’s disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations. Gut. 2014;63:80–87.
  • Asano K, Matsushita T, Umeno J, et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet. 2009;41:1325–1329.
  • Yang S-K, Hong M, Zhao W, et al. Genome-wide association study of ulcerative colitis in Koreans suggests extensive overlapping of genetic susceptibility with Caucasians. Inflamm Bowel Dis. 2013;19:954–966.
  • Juyal G, Negi S, Sood A, et al. Genome-wide association scan in north Indians reveals three novel HLA-independent risk loci for ulcerative colitis. Gut. 2015;64:571–579.
  • Yang S-K, Hong M, Choi H, et al. Immunochip analysis identification of 6 additional susceptibility loci for Crohn’s disease in Koreans. Inflamm Bowel Dis. 2015;21:1–7.
  • Ye BD, Choi H, Hong M, et al. Identification of ten additional susceptibility loci for ulcerative colitis through Immunochip analysis in Koreans. Inflamm Bowel Dis. 2016;22:13–19.
  • Huang C, Haritunians T, Okou DT, et al. Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans. Gastroenterology. 2015;149:1575–1586.
  • Okada Y, Yamazaki K, Umeno J, et al. HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases risk for ulcerative colitis but reduces risk for Crohn’s disease. Gastroenterology. 2011;141:864–871.
  • Liu JZ, Van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47:979–986.
  • De Cruz P, Prideaux L, Wagner J, et al. Characterization of the gastrointestinal microbiota in health and inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:372–390.
  • Tong M, McHardy I, Ruegger P, et al. Reprograming of gut microbiome energy metabolism by the FUT2 Crohn’s disease risk polymorphism. ISME J. 2014;8:2193–2206.
  • Chen GB, Lee SH, Brion MJ, et al. Estimation and partitioning of (co)heritability of inflammatory bowel disease from GWAS and immunochip data. Hum Mol Genet. 2014;23:4710–4720.
  • Rigaud S, Fondaneche MC, Lambert N, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006;444:110–114.
  • Worthey EA, Mayer AN, Syverson GD, et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med. 2011;13:255–262.
  • Pachlopnik Schmid J, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011;117:1522–1529.
  • Chang D, Gao F, Slavney A, et al. Accounting for eXentricities: analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases. PLoS One. 2014;9:e113684.
  • Zeissig Y, Petersen B-S, Milutinovic S, et al. XIAP variants in male Crohn’s disease. Gut. 2015;64:66–76.
  • Li B, Liu DJ, Leal SM. Identifying rare variants associated with complex traits via sequencing. Curr Protoc Hum Genet. 2013;Chapter 1:Unit1.26.
  • Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361:2033–2045.
  • Blaydon DC, Biancheri P, Di WL, et al. Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med. 2011;365:1502–1508.
  • Rivas MA, Beaudoin M, Gardet A, et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet. 2011;43:1066–1073.
  • Beaudoin M, Goyette P, Boucher G, et al. Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. PLoS Genet. 2013;9:e1003723.
  • Ng SB, Turner EH, Robertson PD, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009;461:272–276.
  • Okou DT, Mondal K, Faubion WA, et al. Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2014;58:561–568.
  • Hasler R, Feng Z, Backdahl L, et al. A functional methylome map of ulcerative colitis. Genome Res. 2012;22:2130–2137.
  • Chen Y, Wang C, Liu Y, et al. miR-122 targets NOD2 to decrease intestinal epithelial cell injury in Crohn’s disease. Biochem Biophys Res Commun. 2013;438:133–139.
  • Brain O, Owens Benjamin MJ, Pichulik T, et al. The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. Immunity. 2013;39:521–536.
  • Lu C, Chen J, Xu H-G, et al. MIR106B and MIR93 prevent removal of bacteria from epithelial cells by disrupting ATG16L1-mediated autophagy. Gastroenterology. 2014;146:188–199.
  • Li Y, Sidore C, Kang HM, et al. Low-coverage sequencing: implications for design of complex trait association studies. Genome Res. 2011;21:940–951.
  • Kichaev G, Yang WY, Lindstrom S, et al. Integrating functional data to prioritize causal variants in statistical fine-mapping studies. PLoS Genet. 2014;10:e1004722.
  • Farh KK, Marson A, Zhu J, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518:337–343.
  • Inohara N, Ogura Y, Fontalba A, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem. 2003;278:5509–5512.
  • Arnott ID, Nimmo ER, Drummond HE, et al. NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn’s disease patients: evidence for genetic heterogeneity within Europe? Genes Immun. 2004;5:417–425.
  • Economou M, Trikalinos TA, Loizou KT, et al. Differential effects of NOD2 variants on Crohn’s disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol. 2004;99:2393–2404.
  • Ng SC, Tsoi KK, Kamm MA, et al. Genetics of inflammatory bowel disease in Asia: systematic review and meta-analysis. Inflamm Bowel Dis. 2012;18:1164–1176.
  • Bonen DK, Ogura Y, Nicolae DL, et al. Crohn’s disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan. Gastroenterology. 2003;124:140–146.
  • Mathew CG, Lewis CM. Genetics of inflammatory bowel disease: progress and prospects. Hum Mol Genet. 2004;13 Spec No 1:R161–R168.
  • Hirano A, Yamazaki K, Umeno J, et al. Association study of 71 European Crohn’s disease susceptibility loci in a Japanese population. Inflamm Bowel Dis. 2013;19:526–533.
  • Hisamatsu T, Suzuki M, Reinecker H-C, et al. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology. 2003;124:993–1000.
  • Kobayashi KS, Chamaillard M, Ogura Y, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307:731–734.
  • Maeda S, Hsu LC, Liu H, et al. Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1β processing. Science. 2005;307:734–738.
  • Travassos LH, Carneiro LAM, Ramjeet M, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol. 2010;11:55–62.
  • Homer CR, Richmond AL, Rebert NA, et al. ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn’s disease pathogenesis. Gastroenterology. 2010;139:1630–1641.
  • Cooney R, Baker J, Brain O, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010;16:90–97.
  • Wehkamp J, Harder J, Weichenthal M, et al. NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal alpha-defensin expression. Gut. 2004;53:1658–1664.
  • Hampe J, Cuthbert A, Croucher PJ, et al. Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet. 2001;357:1925–1928.
  • Baxt LA, Xavier RJ. Role of autophagy in the maintenance of intestinal homeostasis. Gastroenterology. 2015;149:553–562.
  • Burton PR, Clayton DG, Cardon LR, et al. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678.
  • Parkes M, Barrett JC, Prescott NJ, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet. 2007;39:830–832.
  • Prescott NJ, Fisher SA, Franke A, et al. A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn’s disease and is independent of CARD15 and IBD5. Gastroenterology. 2007;132:1665–1671.
  • Glas J, Konrad A, Schmechel S, et al. The ATG16L1 gene variants rs2241879 and rs2241880 (T300A) are strongly associated with susceptibility to Crohn’s disease in the German population. Am J Gastroenterol. 2008;103:682–691.
  • Van Limbergen J, Russell RK, Nimmo ER, et al. Autophagy gene ATG16L1 influences susceptibility and disease location but not childhood-onset in Crohn’s disease in Northern Europe. Inflamm Bowel Dis. 2008;14:338–346.
  • Weersma RK, Zhernakova A, Nolte IM, et al. ATG16L1 and IL23R are associated with inflammatory bowel diseases but not with celiac disease in the Netherlands. Am J Gastroenterol. 2008;103:621–627.
  • Yang S-K, Ye BD, Song K. ATG16L1 contributes to Crohn’s disease susceptibility in Koreans: overmuch concern for ethnic difference? Gut. 2015;64:687–688.
  • Ishibashi K, Fujita N, Kanno E, et al. ATG16L2, a novel isoform of mammalian ATG16L that is not essential for canonical autophagy despite forming an ATG12-5-16L2 complex. Autophagy. 2011;7:1500–1513.
  • Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40:955–962.
  • Prescott NJ, Dominy KM, Kubo M, et al. Independent and population-specific association of risk variants at the IRGM locus with Crohn’s disease. Hum Mol Genet. 2010;19:1828–1839.
  • Moon CM, Shin D-J, Kim SW, et al. Associations between genetic variants in the IRGM gene and inflammatory bowel diseases in the Korean population. Inflamm Bowel Dis. 2013;19:106–114.
  • Fuyuno Y, Yamazaki K, Takahashi A, et al. Genetic characteristics of inflammatory bowel disease in a Japanese population. J Gastroenterol. 2015 Oct 28. [Epub ahead of print].
  • Baskaran K, Pugazhendhi S, Ramakrishna BS. Association of IRGM gene mutations with inflammatory bowel disease in the Indian population. PLoS One. 2014;9:e106863.
  • Lassen KG, Kuballa P, Conway KL, et al. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc Natl Acad Sci USA. 2014;111:7741–7746.
  • VanDussen KL, Liu TC, Li D, et al. Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of Crohn’s disease. Gastroenterology. 2014;146:200–209.
  • Levine B, Packer M, Codogno P. Development of autophagy inducers in clinical medicine. J Clin Invest. 2015;125:14–24.
  • Raelson JV, Little RD, Ruether A, et al. Genome-wide association study for Crohn’s disease in the Quebec Founder Population identifies multiple validated disease loci. Proc Natl Acad Sci USA. 2007;104:14747–14752.
  • Di Meglio P, Di Cesare A, Laggner U, et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS One. 2011;6:e17160.
  • Sarin R, Wu X, Abraham C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc Natl Acad Sci USA. 2011;108:9560–9565.
  • Pidasheva S, Trifari S, Phillips A, et al. Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLoS One. 2011;6:e25038.
  • Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008;135:1130–1141.
  • Sands B, Chen J, Penney M, et al. A randomized, double-blind placebo-controlled phase 2a induction study of MEDI2070 (anti-p19 antibody) in patients with active Crohn’s disease who have failed anti-TNF antibody therapy. J Crohns Colitis. 2015;9:S15–S16.
  • Kakuta Y, Kinouchi Y, Negoro K, et al. Association study of TNFSF15 polymorphisms in Japanese patients with inflammatory bowel disease. Gut. 2006;55:1527–1528.
  • Yang S-K, Lim J, Chang HS, et al. Association of TNFSF15 with Crohn’s disease in Koreans. Am J Gastroenterol. 2008;103:1437–1442.
  • Hong SN, Park C, Park SJ, et al. Deep resequencing of 131 Crohn’s disease associated genes in pooled DNA confirmed three reported variants and identified eight novel variants. Gut. 2016;65:788–796.
  • Thiébaut R, Kotti S, Jung C, et al. TNFSF15 polymorphisms are associated with susceptibility to inflammatory bowel disease in a new European cohort. Am J Gastroenterol. 2009;104:384–391.
  • Latiano A, Palmieri O, Latiano T, et al. Investigation of multiple susceptibility loci for inflammatory bowel disease in an Italian cohort of patients. PLoS One. 2011;6:e22688.
  • Ślebioda TJ, Kmieć Z. Tumour necrosis factor superfamily members in the pathogenesis of inflammatory bowel disease. Mediators Inflamm. 2014;2014:1–15.
  • Hedl M, Abraham C. A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8-induced IL-1. Proc Natl Acad Sci USA. 2014;111:13451–13456.
  • Yang D-H, Yang S-K, Song K, et al. TNFSF15 is an independent predictor for the development of Crohn’s disease-related complications in Koreans. J Crohns Colitis. 2014;8:1315–1326.
  • Takedatsu H, Michelsen KS, Wei B, et al. TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation. Gastroenterology. 2008;135:552–567.
  • Goyette P, Boucher G, Mallon D, et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet. 2015;47:172–179.
  • Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372:793–795.
  • Gerich ME, McGovern DP. Towards personalized care in IBD. Nat Rev Gastroenterol Hepatol. 2014;11:287–299.
  • Ng PC, Murray SS, Levy S, et al. An agenda for personalized medicine. Nature. 2009;461:724–726.
  • Plevy S, Silverberg MS, Lockton S, et al. Combined serological, genetic, and inflammatory markers differentiate non-IBD, Crohn’s disease, and ulcerative colitis patients. Inflamm Bowel Dis. 2013;19:1139–1148.
  • Ahmad T, Armuzzi A, Bunce M, et al. The molecular classification of the clinical manifestations of Crohn’s disease. Gastroenterology. 2002;122:854–866.
  • Brant SR, Picco MF, Achkar JP, et al. Defining complex contributions of NOD2/CARD15 gene mutations, age at onset, and tobacco use on Crohn’s disease phenotypes. Inflamm Bowel Dis. 2003;9:281–289.
  • Newman B, Silverberg MS, Gu X, et al. CARD15 and HLA DRB1 alleles influence susceptibility and disease localization in Crohn’s disease. Am J Gastroenterol. 2004;99:306–315.
  • Cleynen I, González JR, Figueroa C, et al. Genetic factors conferring an increased susceptibility to develop Crohn’s disease also influence disease phenotype: results from the IBDchip European Project. Gut. 2013;62:1556–1565.
  • Adler J, Rangwalla SC, Dwamena BA, et al. The prognostic power of the NOD2 genotype for complicated Crohn’s disease: a meta-analysis. Am J Gastroenterol. 2011;106:699–712.
  • Cleynen I, Boucher G, Jostins L, et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2016;387:156–167.
  • Amre DK, Mack DR, Morgan K, et al. Autophagy gene ATG16L1 but not IRGM is associated with Crohn’s disease in Canadian children. Inflamm Bowel Dis. 2009;15:501–507.
  • Fowler EV, Doecke J, Simms LA, et al. ATG16L1 T300A shows strong associations with disease subgroups in a large Australian IBD population: further support for significant disease heterogeneity. Am J Gastroenterol. 2008;103:2519–2526.
  • Latiano A, Palmieri O, Cucchiara S, et al. Polymorphism of the IRGM gene might predispose to fistulizing behavior in Crohn’s disease. Am J Gastroenterol. 2009;104:110–116.
  • Okazaki T, Wang MH, Rawsthorne P, et al. Contributions of IBD5, IL23R, ATG16L1, and NOD2 to Crohn’s disease risk in a population-based case-control study: evidence of gene-gene interactions. Inflamm Bowel Dis. 2008;14:1528–1541.
  • Satsangi J, Welsh KI, Bunce M, et al. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet. 1996;347:1212–1217.
  • Silverberg MS, Mirea L, Bull SB, et al. A population- and family-based study of Canadian families reveals association of HLA DRB1*0103 with colonic involvement in inflammatory bowel disease. Inflamm Bowel Dis. 2003;9:1–9.
  • Haritunians T, Taylor KD, Targan SR, et al. Genetic predictors of medically refractory ulcerative colitis. Inflamm Bowel Dis. 2010;16:1830–1840.
  • Dubinsky MC, Kugathasan S, Kwon S, et al. Multidimensional prognostic risk assessment identifies association between IL12B variation and surgery in Crohn’s disease. Inflamm Bowel Dis. 2013;19:1662–1670.
  • Siegel CA, Horton H, Siegel LS, et al. A validated web-based tool to display individualised Crohn’s disease predicted outcomes based on clinical, serologic and genetic variables. Aliment Pharmacol Ther. 2016;43:262–271.
  • Chouchana L, Narjoz C, Beaune P, et al. Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2012;35:15–36.
  • Yang S-K, Hong M, Baek J, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014;46:1017–1020.
  • Colombel JF, Ferrari N, Debuysere H, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology. 2000;118:1025–1030.
  • Dewit O, Moreels T, Baert F, et al. Limitations of extensive TPMT genotyping in the management of azathioprine-induced myelosuppression in IBD patients. Clin Biochem. 2011;44:1062–1066.
  • Kakuta Y, Naito T, Onodera M, et al. NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. Pharmacogenomics J. 2016;16:280–285.
  • Asada A, Nishida A, Shioya M, et al. NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease. J Gastroenterol. 2016;51:22–29.
  • Heap GA, Weedon MN, Bewshea CM, et al. HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet. 2014;46:1131–1134.
  • Jurgens M, Laubender RP, Hartl F, et al. Disease activity, ANCA, and IL23R genotype status determine early response to infliximab in patients with ulcerative colitis. Am J Gastroenterol. 2010;105:1811–1819.
  • Hlavaty T, Pierik M, Henckaerts L, et al. Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn’s disease. Aliment Pharmacol Ther. 2005;22:613–626.
  • Hlavaty T, Ferrante M, Henckaerts L, et al. Predictive model for the outcome of infliximab therapy in Crohn’s disease based on apoptotic pharmacogenetic index and clinical predictors. Inflamm Bowel Dis. 2007;13:372–379.
  • Arijs I, Li K, Toedter G, et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut. 2009;58:1612–1619.
  • Arijs I, Quintens R, Van Lommel L, et al. Predictive value of epithelial gene expression profiles for response to infliximab in Crohn’s disease. Inflamm Bowel Dis. 2010;16:2090–2098.
  • Dubinsky MC, Mei L, Friedman M, et al. Genome wide association (GWA) predictors of anti-TNFalpha therapeutic responsiveness in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2010;16:1357–1366.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.