Contribution of higher risk genes and European admixture to Crohn's disease in African Americans.
ABSTRACT BACKGROUND: African Americans (AAs) are an admixed population of West African (WA) and European ancestry (EA). Crohn's disease (CD) susceptibility genes have not been established. We therefore evaluated the contribution of European admixture and major established risk genes to AA CD. METHODS: Ninety-seven admixture informative markers were genotyped for ancestry estimates using STRUCTURE. Overall, 354 AA CD cases and 354 ethnicity-matched controls were genotyped for total 21 single nucleotide polymorphisms (SNPs) in ATG16L1, NOD2, IBD5, IL23R and IRGM by TaqMan or direct sequencing. Association was evaluated by logistic regression, adjusted for ancestry. RESULTS: Mean EA was similar among the CD cases and controls (20.9% and 20.4%, respectively, P = 0.58). No significant admixture differences were observed among 211 to 227 cases stratified by phenotypic subclassifications including onset, surgery, site, and behavior. CD was associated with NOD2 carrier (6.93% CD, 2.15% Controls, P = 0.007), ATG16L1 Thr300Ala (36.1% CD, 29.3% Controls, P = 0.003), SLC22A4 and SLC22A5 (IBD5 locus) functional SNPs (Leu503Phe [10.5% CD, 7.6% Controls, P = 0.05] and g-207c [41.3% CD, 35.7% Controls, P = 0.03], respectively), and IL23R rs2201841 (18.2% CD, 13.8% Controls, P = 0.03), but not IRGM variants, nor three African ancestral NOD2 nonsynonymous variants. IBD5 risk was recessive. An all-minor allele IBD5 haplotype from EA was associated (P = 0.05), whereas a more common haplotype isolating g-207c was not. CONCLUSIONS: Specific functional gene variations contribute significantly to AA CD risk. Established NOD2, SLC22A4-A5, and ATG16L1 variants show increased CD risk, with IBD5 recessive. Although CD is more common in whites, European admixture is similar among AA cases and controls. (Inflamm Bowel Dis 2012;).
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ABSTRACT: The epidemiology of inflammatory bowel disease (IBD) is poorly characterized in minorities in the U.S. We sought to enumerate the burden of IBD among racial and ethnic groups using national-level data. Data from the National Health Interview Survey was used to calculate prevalence and incidence of IBD among adults (≥18years) in 1999. The Nationwide Inpatient Sample was queried to ascertain rates of IBD-related hospitalizations and the Underlying Cause of Death Database was accessed to quantify IBD-related mortality. An estimated 1,810,773 adult Americans were affected by IBD yielding a prevalence of 908/100,000, which was higher in Non-Hispanic Whites (1099/100,000) compared with Non-Hispanic Blacks (324/100,000), Hispanics (383/100,000), and non-Hispanic Other (314/100,000). Relative to Non-Hispanic Whites, the odds ratios for having a diagnosis of IBD associated with being Non-Hispanic Black, Hispanic, and Other Non-Hispanic race after adjusting for age, sex, and geographic region were 0.33 (95% CI: 0.19 - 0.57), 0.45 (95% CI: 0.26 - 0.77), and 0.34 (95% CI: 0.12 - 0.93), respectively. IBD incidence was similarly lower in Non-Hispanic Blacks (24.9/100,000) and Hispanics (9.9/100,000) compared to Non-Hispanic Whites (70.2/100,000). The ratio of IBD hospitalizations to prevalence was disproportionately higher among Non-Hispanic Blacks (7.3%) compared with Non-Hispanic Whites (3.0%) and Hispanics (2.7%). Similarly, the ratio of IBD-related mortality was greater in Non-Hispanic Blacks (0.061%) compared to Non-Hispanic Whites (0.036%) and Hispanics (0.026%). IBD disease burden is lower in ethnic minorities compared to Non-Hispanic Whites. However, IBD-related hospitalizations and deaths seem disproportionately high in Non-Hispanic Blacks.Journal of Crohn s and Colitis 09/2013; · 3.39 Impact Factor
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ABSTRACT: Polymorphisms in immunity-related GTPase family M (IRGM) gene may be associated with inflammatory bowel disease (IBD) by affecting autophagy. However, the genetic association studies on three common variants in IRGM gene (rs13361189, rs4958847 and rs10065172) have shown inconsistent results. The PubMed and Embase were searched up to June 5, 2013 for studies on the association between three IRGM polymorphisms and IBD risk. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Finally, we performed a meta-analysis of 25 eligible studies in 3 SNPs located at IRGM gene by using a total of 20590 IBD cases and 27670 controls. The analysis showed modest significant association for the rs13361189, rs4958847 and rs10065172 variants in Crohn's disease (CD): the risk estimates for the allele contrast were OR=1.306 (1.200-1.420), p=5.2×10(-10), OR=1.182 (1.082-1.290), p=0.0002, and OR=1.248 (1.057-1.473), p=0.009 respectively (still significant when the p value was Bonferroni adjusted to 0.017). When stratified by ethnicity, significantly increased CD risk was observed in Europeans, but not in Asians. Conversely, there was no association of rs13361189 or rs4958847 variant with risk of ulcerative colitis (UC). These results indicated that autophagy gene-IRGM polymorphisms appear to confer susceptibility to CD but not UC, especially in Europeans. Our data may provide further understanding of the role of autophagy in the pathogenesis of CD.PLoS ONE 01/2013; 8(11):e80602. · 3.73 Impact Factor
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ABSTRACT: The incidence of autoimmune pathologies is increasing worldwide. This has stimulated interest on their etiopathogenesis, caused by a complex interaction of genetic and environmental factors. With the advent of genome-wide linkage, candidate gene and genome wide association studies, risk polymorphisms in autophagy-related genes were discovered in several autoimmune conditions suggesting the possible contribution of autophagy to their etiopathogenesis. Autophagy represents the principal catabolic process mediated by lysosomes used by eukaryotic cells and is strictly regulated by proteins belonging to the Atg family. The function of autophagy has been well characterized in various tissues and systems, but its role in the regulation of innate and adaptive immune systems has been only recently discovered. It plays a fundamental role in the modulation of thymocyte selection and in the generation of T lymphocyte repertoire by participating to the intracellular antigen presentation on MHC class-II molecules by thymic epithelial cells. Furthermore, the generation of mice knockout for specific autophagy-related genes induced several immunological alterations, including defects in B and T cell compartments and in T cell activation. In this review we report recent evidence on the role of authophagy in autoimmunity and discuss its relevance to the pathogenesis of these diseases. We finally highlight that future research may disclose potential new therapeutic targets for the treatment of this category of disorders by modulating the autophagic pathway.Autoimmunity reviews 10/2013; · 6.37 Impact Factor