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

Huang, Chengrui; Haritunians, Talin; Okou, David T.; Cutler, David J.; Zwick, Michael E.; Taylor, Kent D.; Datta, Lisa W.; Maranville, Joseph C.; Liu, Zhenqiu; Ellis, Shannon; Chopra, Pankaj; Alexander, Jonathan; Baldassano, Robert N.; Cross, Raymond K.; Dassopoulos, Themistocles; Dhere, Tanvi; Duerr, Richard H.; Hanson, John S.; Hou, Jason K.; Hussain, Sunny Z.; Isaacs, Kim L.; Kachelries, Kelley E; Kader, Howard A.; Kappelman, Michael D.; Katz, Jeffrey A.; Kellermayer, Richárd; Kirschner, Barbara S.; Kuemmerle, John F.; Kumar, Archana; Kwon, John H.; Lazarev, Mark; Mannon, Peter J.; Moulton, Dedrick E.; Osuntokun, B. O.; Patel, Ashish; Rioux, John D.; Rotter, Jerome I.; Saeed, Shehzad Ahmed; Scherl, Ellen; Silverberg, Mark S.; Silverman, Ann L.; Targan, Stephan R.; Valentine, John F.; Wang, Ming‐Hsi; Simpson, Claire L.; Bridges, S. Louis; Kimberly, Robert P.; Rich, Stephen S.; Cho, Judy H.; Rienzo, Anna Di; Kao, Linda; McGovern, Dermot; Brant, Steven R.; Kugathasan, Subra

doi:10.1053/j.gastro.2015.07.065

Cited by 65 publications

(55 citation statements)

References 36 publications

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“…4 We found significant replication in AAs for maximal established single-nucleotide polymorphisms (SNPs) at 5 European loci for IBD and Crohn’s disease (CD) ( FCGR2A and PTGER4 for IBD; IL23R , NOD2 , and IKZF3 for CD) and for ulcerative colitis (UC) at HLA rs9271366, congruent with the maximal East Asian HLA association. We also observed strong association signals at PTGER4 , IL12B , and STAT3A/STAT5 for SNPs independent of established European association signals.…”

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confidence: 72%

“…We again observed African-specific IBD associations at STAT3 , but not as strong in the meta-analysis (ie, rs12721583 GWAS2; P = 5.0 × 10 −6 ; meta P = 8.2 × 10 −5 ) as in our previous report. 4 All associations with P values < 6.5 × 10 −5 in either GWAS are shown in Supplementary Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…Samples with IBD from GWAS1 (n = 1258 IBD cases [843 CD, 368 UC, 47 unclassified]) were recruited by Johns Hopkins Multicenter African American IBD Study (coordinated by Johns Hopkins IBD Genetics Research Center of the National Institute of Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium with recruitment from 13 collaborating IBD centers and 4 other IBD Genetics Consortium Genetics Research Centers 4,12 ) and at Cedars-Sinai Medical Center IBD Center. Control AA subjects of GWAS1 (n = 1678) were derived from the dbGaP Health and Retirement Study, a longitudinal panel study sponsored by the National Institute on Aging.…”

Section: Methodsmentioning

confidence: 99%

“…No loci, however, had SNPs with evidence of GWS association nor were any African-specific loci established, although we found suggestive evidence ( P < 4 × 10 −5 with consideration for the relatively small number of SNPs evaluated) for 3 potential novel loci (ie, C2orf43 , HDAC11 , and LINC00994 ). 4 …”

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confidence: 99%

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Re: Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease

Misra

Arebi

2017

Gastroenterology

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BACKGROUND & AIMS The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10−8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. RESULTS We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10−6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide signifi-cance on conditioning), IL12B, PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. CONCLUSIONS We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

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confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Re: Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease

Misra

Arebi

2017

Gastroenterology

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“…However, genetics is only part of the IBD etiology story and, in fact, even the IBD genetics story differs between racial groups [9][10][11][12] . Whilst we have always believed that genetics may be the one constant when it comes to disease etiology, trans-ethnic studies undertaken around the world show that different polymorphisms in different genes are associated with increased risk of developing IBD for different racial groups.…”

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confidence: 99%

IBD and Environment: Are There Differences between East and West

Gearry

2016

Dig Dis

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Background: The inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis (UC) occur worldwide with differences in epidemiology, etiology and phenotype between regions. Breakthroughs have occurred in IBD genetics, although the genes that predispose to IBD differ between racial groups. What do we know about the ‘envirotype' of those who develop IBD, and are there differences between the East and the West? Key Messages: The strongest IBD risk factor identified to date is a family history of IBD. Whilst likely representing an underlying genetic predisposition, it may also reflect shared environmental factors amongst family members. Cigarette smoking increases the risk of developing CD, whilst smoking is less common in those who develop UC. Having ceased smoking increases the risk of developing UC subsequently. Unlike the West, cigarette smoking appears to play a lesser role in the East. Other environmental risk factors are inconsistent. Studies of migrant populations moving from regions of low to high IBD incidence point to early life as a key time for environmental triggers. In these populations, it is the second generation (those born in the high incidence region) with higher IBD incidence rates than their parents. Early life environmental exposures have been studied exhaustively but, except for having been breastfed, few putative early childhood environmental risk factors have been shown consistently to alter the risk of developing IBD. Conclusions: The identification of IBD environmental risk factors remains elusive in both the East and West. In the West, case-control studies are unlikely to move the field forward without multi-level (phenotype, genotype, diet history, ‘envirotype' and microbiome) data, ideally collected prospectively. Cohort studies (such as the Genes, Environment, Microbiome project) may address some of these issues. However, in the East where IBD incidence is still increasing, well-designed comprehensive case-control studies may identify differences that give an insight into the ‘envirotype' driving IBD incidence.

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Diet, gut microbes, and the pathogenesis of inflammatory bowel diseases

Dolan

Chang

2016

Molecular Nutrition Food Res

103

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The rising incidence of inflammatory bowel diseases in recent decades has notably paralleled changing lifestyle habits in Western nations, which are now making their way into more traditional societies. Diet plays a key role in IBD pathogenesis, and there is a growing appreciation that the interaction between diet and microbes in a susceptible person contributes significantly to the onset of disease. In this review, we examine what is known about dietary and microbial factors that promote IBD. We summarize recent findings regarding the effects of diet in IBD epidemiology from prospective population cohort studies, as well as new insights into IBD-associated dysbiosis. Microbial metabolism of dietary components can influence the epithelial barrier and the mucosal immune system, and understanding how these interactions generate or suppress inflammation will be a significant focus of IBD research. Our knowledge of dietary and microbial risk factors for IBD provides important considerations for developing therapeutic approaches through dietary modification or re-shaping the microbiota. We conclude by calling for increased sophistication in designing studies on the role of diet and microbes in IBD pathogenesis and disease resolution in order to accelerate progress in response to the growing challenge posed by these complex disorders.

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

Cited by 65 publications

References 36 publications

Re: Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease

Re: Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease

IBD and Environment: Are There Differences between East and West

Diet, gut microbes, and the pathogenesis of inflammatory bowel diseases

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