Crohn’s Disease in Caucasians and African Americans, as Defined by Clinical Predictors and Single Nucleotide Polymorphisms

Kanaan, Ziad; Ahmad, Surriya; Roberts, Henry L.; Girdler, Steven J; Pan, Jianmin; Shesh, N.; Weller, E. Brooks; Galandiuk, Susan

doi:10.1016/s0027-9684(15)30195-4

Cited by 6 publications

(3 citation statements)

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“…A total of 33 articles, 20,23,24,[27][28][29][30][31]33,35,37,38,[40][41][42]44,47,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] involving 8110 cases and 11,900 controls (Table 2), were included to the meta-analysis regarding the genetic effect of the The overall genetic risk suggested significant protection for the AA genotype (OR G ¼ 0.46; 95% CI, 0.41-0.52). The subgroup analysis on adults 16 20,23,24,[27][28][29][30]33,35,37,38,41,[47][48][49][50]…”

Section: Il23r Variant Rs11209026 and Disease Susceptibilitymentioning

confidence: 99%

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ATG16L1 and IL23R Variants and Genetic Susceptibility to Crohnʼs Disease

Grigoras

Ziakas

Jayamani

et al. 2015

Inflammatory Bowel Diseases

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Background: Autophagy and regulation of IL-23 signaling pathways have been implicated in the pathogenesis of Crohn's disease (CD). We studied the mode of inheritance and reviewed the association of 2 polymorphic variants of ATG16L1 and IL23R with CD.Methods: We searched the PubMed and ISI Web of Science databases (up to May 2014) for pertinent articles. We included all studies that had a casecontrol design, with cases having CD and controls being healthy and reported full genotype frequencies for the ATG16L1 and/or IL23R variant of interest. We quantified the relative genetic risk using the model-free approach of the generalized odds ratio metric (OR G ) and reported 95% precision estimates. Also, we explored the mode of inheritance using the degree of dominance h-index.Results: Fifty-one studies fulfilled these requirements and were included in the analysis. These studies involved 12,762 patients and 16,735 controls evaluating the association of ATG16L1 (rs2241880 p.Thr300Ala) and 8110 patients and 11,900 controls evaluating the association of IL23R (rs11209026 p. Arg381Gln) with CD. The ATG16L1 variant rs2241880 was associated with increased susceptibility to CD (combined OR G ¼ 1.38; 95% confidence interval, 1.29-1.48) and a nondominant mode of inheritance (suggesting that the effect of heterozygosity lies exactly in the middle of extreme homozygotes, h ¼ 0). The IL23R variant rs11209026 was associated with significant protection (OR G ¼ 0.46; 95% confidence interval, 0.41-0.53) and a recessive mode of inheritance, indicating that the effect of a heterozygous genotype would lie close to the wild-type homozygous genotype. In subgroup analysis, the significant effects persisted across Caucasian ancestry studies and pediatric populations but were lacking across studies in Asian populations.Conclusions: The ATG16L1 variant rs2241880 was associated with 38% increase in the risk for CD for higher mutational load, whereas IL23R variant rs11209026 decreased the risk by 54% for higher mutational load. The mode of inheritance for ATG16L1 variant demonstrated perfect additivity for genetic risk, whereas it showed recessiveness for the IL23R variant. This analysis permits risk stratification for CD based on the mutational status and highlight the need for additional studies in certain populations. (Inflamm Bowel Dis 2015;21:768-776)

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Section: Il23r Variant Rs11209026 and Disease Susceptibilitymentioning

confidence: 99%

“…Nine control populations deviated from HWE equilibrium, 42,44,[50][51][52]54,56,57,59 and the combined effects were recalculated after genotype correction with their expected distribution. These effects did not change after correcting for HWE deviations, and they appear in brackets in Table 3.…”

Section: Il23r Variant Rs11209026 and Disease Susceptibilitymentioning

confidence: 99%

ATG16L1 and IL23R Variants and Genetic Susceptibility to Crohnʼs Disease

Grigoras

Ziakas

Jayamani

et al. 2015

Inflammatory Bowel Diseases

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“…However, compared to hundreds of IBD genetic studies in Caucasian populations including massive GWA mega-analyses and replication studies like the Caucasian Immunochip Study (CIS) 2 , only a handful of IBD-associated gene variations have been evaluated in African Americans (AAs), in relatively small sample sizes of a few hundred cases and controls, and only for CD, not UC 5-7 .…”

Section: Introductionmentioning

confidence: 99%

Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans

et al. 2015

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Background & Aims Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. Methods We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the US; additional controls were collected from 4 other immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease (CD), 361 with ulcerative colitis (UC), 62 with IBD type-unknown (IBDU), and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. Results The strongest associations were observed between UC and HLA rs9271366 (P=7.5e–6), CD and 5p13.1 rs4286721 (P=3.0e–6), and IBD and KAT2A rs730086 (P=2.3e–6). Additional suggestive associations (P<4.2e-5) were observed between CD and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2 open reading frame 43; and between UC and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P<3.1e-4) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P<3.9e–4) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2–15q23, and 16p12.2–16p12.1. Network analyses showed significant enrichment (false discovery rate <1e–5) in genes that encode members of the JAK–STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. Conclusions In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we found evidence for loci and variants not previously associated with IBD. The complex genetic factors that determine risk for or protection from IBD in different populations require further study.

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