Gastroenterology
Volume 132, Issue 5 , Pages 2045-2049, May 2007

Genome-Wide Association Studies Herald a New Era of Rapid Discoveries in Inflammatory Bowel Disease Research

  • Richard H. Duerr

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Richard H. Duerr, MD, Associate Professor of Medicine and Human Genetics, University of Pittsburgh, S724 BST, 3500 Terrace Street, Pittsburgh, PA 15261. fax: (412) 383-8753.

University of Pittsburgh, Pittsburgh, Pennsylvania

Article Outline

 

See “IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease” by Tremelling M, Cummings F, Fisher SA, Mansfield J, Gwilliam R, Keniry A, Nimmo ER, Drummond H, Onnie CM, Prescott NJ, Sanderson J, Bredin F, Berzuini C, Forbes A, Lewis CM, Cardon L, Deloukas P, Jewell D, Mathew CG, Parkes M, and Satsangi J on page 1657; and “A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn’s disease and is independent of CARD15 and IBD5” by Prescott NJ, Fisher SA, Franke A, Hampe J, Onnie CM, Soars D, Bagnall R, Mirza MM, Sanderson J, Forbes A, Mansfield JC, Lewis CM, Schreiber S, and Mathew CG on page 1665.

The pathogenesis of the inflammatory bowel diseases (IBD), namely, Crohn’s disease (CD) and ulcerative colitis (UC), involves a complex interplay of genetic, environmental, and immunologic factors. A large body of evidence supports the hypothesis that ubiquitous, commensal intestinal bacteria trigger an inappropriate, overactive, and ongoing mucosal immune response that mediates intestinal tissue damage in genetically susceptible individuals.1

Early attempts to identify IBD genes focused primarily on functional candidates, especially human leukocyte antigen (HLA) variants. These studies had variable and inconclusive results, although a meta-analysis provided evidence for modest associations of HLA class II variants with CD and UC.2, 3 Genome-wide linkage analysis became feasible in the 1990s, and 11 IBD genome-wide linkage scans in families with multiple IBD-affected members plus a meta-analysis of 10 of these scans published between 1996 and 2004 identified several IBD linkage regions.4, 5

The first major advance in IBD genetics research, and a major milestone in IBD research overall, occurred in 2001 when CD-associated polymorphisms were discovered in caspase recruitment domain-containing protein 15 (CARD15), a gene located within the widely replicated IBD1 linkage region on chromosome 16.6, 7 Three independent CD-associated CARD15 polymorphisms—rs2066844, rs2066845, and rs2066847—encode amino acid substitutions (Arg702Trp, Gly908Arg) or truncation of the terminal 33 amino acids (Leu1007fsinsC), respectively, in nucleotide-binding oligomerization domain containing 2 (Nod2). Nod2 is an intracellular sensor for muramyl dipeptide (MDP), which is a component of bacterial peptidoglycan.8, 9, 10 The CD-associated Nod2 variants are located in or near the leucine-rich-repeat, MDP-sensing domain of Nod2, and all of them, especially the Leu1007fsinsC variant, are associated with decreased responses to peptidoglycan or MDP stimulation.8, 9, 10, 11, 12, 13, 14 The discovery of CD-associated functional polymorphisms in CARD15 provides further evidence that at least some cases of CD result from an abnormal immune response to enteric bacterial flora.

Later in 2001, a CD-associated 250-kilobase haplotype within the IBD5 linkage region on chromosome 5q31 was discovered.15 Subsequently, a two-locus risk haplotype formed by rs1050152 (Leu503Phe) in the solute carrier family (organic cation transporter) 22, member 4 (SLC22A4) gene, and rs2631367 (G-207C) in the solute carrier family (organic cation transporter) 22, member 5 (SLC22A5) gene, was reported to account for the IBD5 association, and these 2 single nucleotide polymorphisms (SNPs) were reported to decrease transporter activity or promoter activity, respectively.16 However, the reported functional effects have not been confirmed, and other studies have shown equivalent evidence for association with other SNPs spanning the IBD5 risk haplotype.15, 17, 18, 19

The CARD15 and IBD5 associations explain only a small proportion of the genetic risk for IBD, suggesting that additional IBD susceptibility loci exist, but comparatively little additional IBD gene-hunting progress was made since the 2001 discovery of these 2 risk loci until recently. The determination of the human genome’s 3 billion base pair DNA sequence and identification of most of the 20,000–25,000 human genes20; the International HapMap project’s cataloguing of nearly 4 million common human SNPs and correlations between linked SNPs, allowing selection of nonredundant “tag” SNPs for genetic association studies21; and the development of technologies for rapid and cost-effective genome-wide analysis of genetic differences between people with illness and controls have provided the potential for rapid progress in identifying genetic factors underlying heritable common human diseases. Three recent genome-wide association studies in CD are among the earliest successful applications of the new genomic knowledge and technologies.22, 23, 24

In the first genome-wide association study in CD, the National Institute of Diabetes & Digestive & Kidney Diseases IBD Genetics Consortium (NIDDK IBDGC) performed association analyses of 308,332 autosomal SNPs in 547 non-Jewish, European-ancestry patients with ileal CD and 548 non-Jewish controls.22 Two SNPs in CARD15 and a third SNP, rs11209026, which encodes an amino acid substitution (Arg381Gln) in a subunit of the receptor for the pro-inflammatory interleukin (IL)-23 cytokine (IL23R), showed significant allelic association after conservative Bonferroni correction. The uncommon glutamine allele of Arg381Gln had a significantly lower allele frequency in patients with CD compared with controls, suggesting that it confers strong protection against CD. Nine other SNPs in IL23R and in the intergenic region between IL23R and the adjacent IL-12 receptor, beta-2 (IL12RB2) gene had nominal association P values < .0001. The NIDDK IBDGC replicated these associations in an independent case-control cohort consisting of 401 patients with ileal CD and 433 controls, all of Jewish ancestry, and in a third cohort of 883 nuclear families containing 1119 IBD (CD, UC, or indeterminate IBD) affected offspring. In the family-based association analyses, association between IL23R markers and CD was found in non-Jewish and Jewish families, and association with UC was found in non-Jewish families, but not the small group of Jewish families. In conditional case-control association analyses stratified on carriage of the glutamine allele of Arg381Gln, multiple IL23R region SNPs showed residual association evidence.

Hampe et al23 subsequently reported their association analyses of 7159 nonsynonymous SNPs with a minor allele frequency ≥1% (out of 19,779 attempted nonsynonymous SNPs) in 735 patients with CD and 368 controls from northern Germany.23 Seventy-two SNPs with P ≤ .01 in allelic tests for disease association were studied further in 380 German trios of parents and their CD-affected offspring, 498 independent CD-affected individuals and 1032 independent controls. The rs2241880 variant in the ATG16 autophagy related 16-like 1 (S cerevesiae) (ATG16L1) gene, which encodes an Ala to Thr substitution at various amino acid positions, depending on which ATG16L1 splice isoform is referenced (hereafter referred to as Ala197Thr according to the entry in the National Center for Biotechnology Information dbSNP), was significantly associated with CD in a case-control allelic association test (P = 1.6 × 10−5) and in a family-based transmission/disequilibrium test (P = 2.7 × 10−5). The Hampe et al23 study also replicated associations with SLC22A4 Leu503Phe and CARD15 Gly908Arg (the CARD15 Arg702Trp and Leu1007fsinsC variants were not tested successfully). No other coding or splice site variants were found upon resequencing ATG16L1 exons, splice sites, and the promoter region in 47 CD-affected individuals. Logistic regression and haplotype analyses of 28 additional genotyped tag SNPs in the replication cohorts suggested that the Ala197Thr variant explains virtually all of the association evidence at the ATG16L1 locus. Association between CD and the Ala197Thr variant was also found in another independent cohort of 509 cases and 656 controls from the United Kingdom (allelic association test P = .0004). There was no significant evidence for association of the ATG16L1 Ala197Thr variant in 788 patients with UC and the 1032 independent controls from Germany.

In the third genome-wide association study in CD, Libioulle et al24 performed allelic association analyses of 311,882 SNPs that were genotyped on the same platform used by the NIDDK IBDGC in 547 Caucasian CD patients from Belgium and 928 controls from Belgium and France. They also genotyped additional SLC22A4, SLC22A5, DLG5, TNFSF15, and ATG16L1 SNPs that were previously reported to be associated with IBD. This study replicated associations between CD and the CARD15, IL23R, and ATG16L1 loci and found evidence for association between CD and a 250-kilobase region of chromosome 5p13.1 containing 6 SNPs with association P values < 10−6. Four IL23R and 6 chromosome 5p13.1 region SNPs were genotyped in an additional cohort consisting of 1266 patients with CD and 559 controls, and associations between CD and both the IL23R and chromosome 5p13.1 loci were replicated. In a combined analysis of the genome-wide association and replication cohorts, Arg381Gln was the most significantly associated IL23R variant (P = 2.2 × 10−18), which is consistent with the NIDDK IBDGC’s results, and rs1373692 was the most significantly associated chromosome 5p13.1 variant (P = 2.1 × 10−12). Transmission/disequilibrium testing in trios of parents and their CD-affected offspring also showed evidence for association with both the IL23R and the chromosome 5p13.1 loci. Analyses of haplotypes formed by 111 SNPs spanning the 250-kilobase region of interest on chromosome 5p13.1 suggested that multiple variants within 3 adjacent haplotype blocks contribute to CD susceptibility. The CD-associated chromosome 5p13.1 SNPs span a region containing no known genes, but the authors discuss preliminary data suggesting that SNPs in this region are associated with expression levels of the nearby prostaglandin E receptor 4 (subtype EP4) (PTGER4). Finally, Libioulle et al24 found that IL23R Arg381Gln is also associated with UC, but found no significant evidence for association between UC and the ATG16L1 Ala197Thr or chromosome 5p13.1 rs4613763 variants.

In an extension of their CD genome-wide association study, the NIDDK IBDGC used the Cochran–Mantel–Haenszel test to analyze 304,413 SNPs genotyped in the non-Jewish ileal CD case-control cohort in which the IBD-associated IL23R locus was discovered22 and an independent Jewish ileal CD case-control cohort, with a combined total of 946 ileal CD cases and 977 controls included in the analysis.25 CARD15 and IL23R remained the most significantly associated loci, as previously reported.22 Genotyping was attempted for the most significantly associated SNP in 21 independently associated regions with P < 5 × 10−5 (not considering the CARD15 and IL23R regions) in an independent cohort of 883 nuclear families, which contained 650 individuals with ileal CD and their parents. Association testing of 18 SNPs (3 others were not genotyped successfully) revealed 6 that had significant evidence of replication. These 6 SNPs were genotyped in a third independent cohort containing 353 patients with ileal CD and 207 controls. Two SNPs, including the ATG16L1 Ala197Thr variant and a SNP in a region of chromosome 10q with no known genes, showed unequivocal evidence of replication considering combined analyses of the 2 replication cohorts (P < 5 × 10−8 and P < 5 × 10−7, respectively). These 2 SNPs also satisfied conservative criteria for genome-wide significance considering combined analyses of both replication cohorts and the genome-wide association cohort (P < 10−13 and P < 10−10, respectively). Three other SNPs showed significant but more modest evidence of replication (P < .01). Association mapping around ATG16L1 Ala197Thr found that the Ala197Thr variant can fully explain the association signal in this region, which is consistent with similar results reported in the Hampe et al paper.23 This NIDDK IBDGC study also showed evidence for expression of ATG16L1 in intestinal epithelial cells and for functional relevance of ATG16L1 in autophagy of Salmonella typhimurium. There was no significant evidence for association of ATG16L1 with UC or for epistatic interactions with the CARD15, IBD5, or IL23R genes. In addition, this NIDDK IBDGC study replicated the Libioulle et al associations between CD and the chromosome 5p13.1 rs1373692 and rs4613763 SNPs (P = 5.37 × 10−4 and P = 1.21 × 10−4, respectively).24

In this issue of Gastroenterology, Tremelling et al26 contribute an additional strong replication of the CD association with IL23R in a large case-control cohort from Great Britain. The Tremelling et al observation that some IL23R region markers are also associated, albeit less dramatically, with UC is consistent with the NIDDK IBDGC22 and Libioulle et al24 results. Taken together, the NIDDK IBDGC,22 Libioulle et al,24 and Tremelling et al studies provide strong evidence that genetic variants in IL23R contribute to both CD and UC susceptibility. The IL23R Arg381Gln variant had the strongest evidence for association with CD in the NIDDK IBDGC,22 Libioulle et al,24 and Tremelling et al studies, but the NIDDK IBDGC22 and Tremelling et al studies also found that multiple IL23R region SNPs have association signals independent of Arg381Gln. The Tremelling et al results raise the possibility that IL23R SNPs have different patterns of relative contributions to CD and UC susceptibility (i.e., IL23R SNPs that confer the greatest risk for CD may not be the same IL23R SNPs that confer the greatest risk for UC).

IL-23 and the recently described T helper 17 (Th17) subset of IL-17–producing T cells have been implicated in promoting inflammatory responses that were previously attributed to IL-12 and the T helper 1 (Th1) subset of interferon-γ producing T cells in IBD and other diseases including psoriasis, multiple sclerosis, and rheumatoid arthritis.27, 28, 29 The apparent role of the IL-23/Th17 axis in these chronic inflammatory diseases, the association between IBD and variants in IL23R, and a recent report that IL23R variants are also associated with psoriasis30 suggest that IL23R may be a shared susceptibility locus for a variety of heritable immune-mediated diseases. The Tremelling et al observation that variants in IL23R are not associated with a specific phenotypic subgroup of IBD is consistent with the concept that IL23R is a generic IBD locus and may also confer susceptibility to a variety of other chronic inflammatory disorders.

Amino acid 381 is located in the cytoplasmic domain of the IL23R protein, 5 amino acids internal to the transmembrane domain.31 This position of Arg381Gln suggests that the protective effect of the uncommon glutamine allele against IBD could be due to disruption of IL-23 signaling and also suggests the possibility that future novel therapies that mimic the downstream effects of the glutamine allele could have efficacy in the treatment of IBD and other diseases in which the IL-23 immune pathway contributes to chronic inflammation. However, the common arginine allele of IL23R Arg381Gln is conserved between species and the IL-23/Th17 axis probably evolved to protect the host against extracellular pathogens,22, 27 so the uncommon glutamine allele and disruption of the IL-23 immune pathway could also be harmful under some circumstances, such as in host defense against pathogens. None of the other identified IBD-associated IL23R SNPs are coding variants. The NIDDK IBDGC study authors22 and Tremelling et al speculate that IBD-associated non-coding SNPs in IL23R could determine different splice isoforms of IL-23R.

The Prescott et al32 paper in this issue of Gastroenterology provides an additional strong replication of the association between ATG16L1 Ala197Thr (rs2241880, referred to as T300A in their paper because they referenced a different splice isoform) and CD in a large British case-control cohort. Prescott et al found that the ATG16L1 Ala197Thr variant is associated specifically with ileal CD with or without colonic involvement but not with colonic only disease, even after correction in their analyses for other variables that are known to contribute to ileal disease. This finding parallels the results from previous analyses of CARD15 variants in phenotypic subgroups of CD. In contrast with the Hampe et al,23 Libioulle et al,24 and NIDDK IBDGC25 studies, Prescott et al also report modest evidence for association between ATG16L1 Ala197Thr and UC. Prescott et al make the point that the genotype relative risks observed for UC in their study indicate that approximately 1500 case-control pairs would be required for 80% power to detect a significant association, so the lack of association in the other studies may be due to a lack of power. In addition, Prescott et al show that their data fit best with a recessive model with increased risk for CD conferred by the genotype encoding homozygosity for the alanine allele, which differs from the gene dosage model that fits best with CARD15 data. They found no significant evidence for interaction between the ATG16L1 Ala197Thr variant and CD-associated CARD15 variants or a tag for the IBD5 haplotype. They present odds ratios for various combinations of CARD15, IBD5 haplotype, and ATG16L1 genotypes and note that homozygosity for risk alleles at all 3 loci confers an odds ratio of 20.4 (95% confidence interval, 8.71–47.7) for CD.

The association between CD and the ATG16L1 Ala197Thr variant strongly suggests that variation in the biological process of autophagy is involved in the pathogenesis of CD. Autophagy is a process involving lysosomal degradation of cellular organelles and proteins and is necessary to maintain a balance of biogenesis and turnover of cellular components. Autophagy also appears to be important in innate and adaptive immune responses to pathogens.33 The ATG16L1 association, together with the NIDDK IBDGC’s demonstration of functional relevance of ATG16L1 in autophagy of S typhimurium, provides another line of evidence that the pathogenesis of CD involves an abnormal response to enteric bacterial flora.

Over the past several months, nearly a century after the first published report of familial occurrences of IBD in 1909,34 genome-wide association studies have discovered several new IBD susceptibility loci that have implicated specific biological pathways, including some that had not been considered previously in the pathogenesis of IBD.22, 23, 24, 25 These rapid advances in IBD research, enabled by the Human Genome Project,20 the International HapMap project,21 and new genome-wide genotyping technologies, have eclipsed decades of research efforts by a large international community of investigators that had previously identified only 2 widely replicated genetic risk loci for CD (CARD15 and IBD5). The IL23R, ATG16L1, chromosome 5p13.1, and chromosome 10q loci identified in the 3 published CD genome-wide association studies22, 23, 24, 25 can now join CARD15 and IBD5 on a rapidly growing list of strongly replicated CD susceptibility loci. The IL23R locus also shows replicated, albeit more modest, association with UC and may also be important in other chronic inflammatory diseases.30

Other “low-hanging fruit” may be harvested in other ongoing or future IBD genome-wide association studies, but it is likely that many true associations are buried in the noise from thousands of SNP loci that have only modest evidence for association in genome-wide studies of hundreds of thousands of SNPs. For example, the best tags for the established IBD5 association are among thousands of SNPs that showed only modest association (P < .01) in the NIDDK IBDGC’s genome-wide association study.25 Joint analyses of the growing number of genome-wide association studies in IBD would be helpful to bolster the evidence for and prioritize the follow-up of SNPs with modest evidence for association that does not clearly stand out from the background noise in individual studies. The genome-wide association study approach of performing broad, unbiased screening for the contribution of common genetic variation to disease susceptibility promises to lead to the discovery of additional IBD susceptibility loci and biological pathways important in IBD pathogenesis.

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PII: S0016-5085(07)00608-7

doi:10.1053/j.gastro.2007.03.082

Refers to article:

  • A Nonsynonymous SNP in ATG16L1 Predisposes to Ileal Crohn’s Disease and Is Independent of CARD15 and IBD5

    Natalie J. Prescott, Sheila A. Fisher, Andre Franke, Jochen Hampe, Clive M. Onnie, Dianne Soars, Richard Bagnall, Muddassar M. Mirza, Jeremy Sanderson, Alastair Forbes, John C. Mansfield, Cathryn M. Lewis, Stefan Schreiber, Christopher G. Mathew
    Gastroenterology May 2007 (Vol. 132, Issue 5, Pages 1665-1671)

Gastroenterology
Volume 132, Issue 5 , Pages 2045-2049, May 2007

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