Nature Communications 7 Article number: 12342 (2016); Published 9 August 2016; Updated 13 September 2016 The HTML version of this Article incorrectly listed the authors of the UK IBD Genetics ...Consortium and the NIDDK IBD Genetics Consortium individually in the main author list. This has now been corrected in the HTML; the PDF version of the paper was correct from the time of publication.
In the present study, we investigated the relationship between the KIR loci and the genes encoding their HLA ligands and genetic susceptibility to Crohn's disease (CD). Analyses of the interactions ...between KIR3DL1, KIR2DL1, KIR2DL2, and KIR2DL3 with their respective HLA ligands indicate that there is a protective effect for KIR2DL2 in the absence of its HLA ligand C1. Given that KIR2DL2 and KIR2DL3 segregate as alleles, we compared their genotypic distributions to expectations under Hardy-Weinberg Equilibrium (HWE) with regard to the HLA ligand C1 status. While all the genotypic distributions conform to expectations under HWE in controls, in C2 ligand homozygous cases there is significant deviation from HWE, with a reduction of KIR2DL2, KIR2DL3 heterozygotes. KIR2DL2, KIR2DL3 heterozygosity is the only genotypic combination that confers protection from CD. In addition to the protective effect (OR = 0.44, CI = 0.22-0.87; p = 0.018) observed in C2 ligand homozygotes, the KIR2DL2, KIR2DL3 genotype is predisposing (OR = 1.34, CI = 1.03-4.53; p = 0.031) in the presence of C1 ligand. A test for trend of HLA class I C ligand group genotypes with KIR2DL2, KIR2DL3 heterozygosity in cases and controls indicates that C1, C2 ligand group heterozygotes have an intermediate effect on predisposition. These results show for the first time that disease susceptibility may be related to heterozygosity at a specific KIR locus, and that HLA ligand genotype influences the relative effect of the KIR genotype.
We investigated candidate genomic regions associated with computed tomography (CT)–derived measures of adiposity in Hispanics from the Insulin Resistance Atherosclerosis Study Family Study (IRASFS). ...In 1,190 Hispanic individuals from 92 families 3 from the San Luis Valley, Colorado and San Antonio, Texas, we measured CT‐derived visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and visceral:subcutaneous ratio (VSR). A genome‐wide association study (GWAS) was completed using the Illumina HumanHap 300 BeadChip (∼317K single‐nucleotide polymorphisms (SNPs)) in 229 individuals from the San Antonio site (stage 1). In total, 297 SNPs with evidence for association with VAT, SAT, or VSR, adjusting for age and sex (P < 0.001), were genotyped in the remaining 961 Hispanic samples. The entire Hispanic cohort (n = 1,190) was then tested for association, adjusting for age, sex, site of recruitment, and admixture estimates (stage 2). In stage 3, additional SNPs were genotyped in four genic regions showing evidence of association in stage 2. Several SNPs were associated in the GWAS (P < 1 × 10−5) and were confirmed to be significantly associated in the entire Hispanic cohort (P < 0.01), including: rs7543757 for VAT, rs4754373 and rs11212913 for SAT, and rs4541696 and rs4134351 for VSR. Numerous SNPs were associated with multiple adiposity phenotypes. Targeted analysis of four genes whose SNPs were significant in stage 2 suggests candidate genes for influencing the distribution (RGS6) and amount of adiposity (NGEF). Several candidate loci, including RGS6 and NGEF, are associated with CT‐derived adipose fat measures in Hispanic Americans in a three‐stage genetic association study.
IntroductionScarcity of IBD in sub-Saharan Africa may reflect both differing population genetic disposition and exposure to environmental factors, however, little data relating to this has been ...published to date. Our aim was to perform genetic analyses of IBD in Zambian subjects.MethodsSaliva was collected in Oragene DNA collection tubes (DNAGenotek, Ottawa, Canada) from IBD cases and controls in the GI clinic of a tertiary hospital in Zambia and stored at 4C. DNA was extracted using the NucleoSpin Tissue kit (Macherey-Nagel) and genotyped using the H3Africa Consortium Array (Illumina). Genetic association for genotyped and imputed SNPs case-control binary variable was performed using logistic regression including principal components for population sub-structure as covariates (PLINKv1.9). Variant effect prediction and functional analysis were performed using the Ensembl platform and ClueGO software.ResultsGenotyping was performed on 16 cases (14 UC, 2 Crohn’s) and 29 controls. Variants were present on LSAMP and ELMO1 which have previously been described as novel risk loci for UC and IBD respectively in African American cohorts.(1, 2) A variant on IL23R (rs790631:G>A, allele frequency 8.6% cases and 25% controls, (p=3.44 x10-2, OR 0.283)) has previously been associated with increased risk of Crohn’s in a Caucasian population (3). No variants on NOD2, ATG16L1 or CARD9 were present.The SNP with the strongest association with IBD (OR 9.51) was rs3763236:G>A (allele frequency 63.8% cases and 15.6% controls), an intron variant on CNPY3, which encodes a toll-like receptor-specific chaperone protein and has not previously been identified as a risk locus for IBD. Functional pathway analysis (figure 1) shows pathways with significant enrichment which included Type 1 diabetes and the extra-cellular matrix which have previously been implicated in IBD.ConclusionsIBD risk loci that have previously been identified as African specific in African American cohorts are reflected in this small cohort of sub-Saharan African patients. These findings suggest that additional and larger studies are needed to determine the genetic architecture of under researched populations in which IBD is emerging.ReferencesBrant SR, Okou DT, Simpson CL, Cutler DJ, Haritunians T, Bradfield JP, et al. Genome-wide association study identifies African-specific susceptibility loci in African Americans with inflammatory bowel disease. Gastroenterology. 2017;152(1):206–17.e2.Cordero RY, Cordero JB, Stiemke AB, Datta LW, Buyske S, Kugathasan S, et al. Trans-ancestry, bayesian meta-analysis discovers 20 novel risk loci for inflammatory bowel disease in an African American, East Asian, and European cohort. Hum Mol Genet. 2022.Taylor KD, Targan SR, Mei L, Ippoliti AF, McGovern D, Mengesha E, et al. IL23R haplotypes provide a large population attributable risk for Crohn’s disease. Inflamm Bowel Dis. 2008;14(9):1185–91.Abstract P62 Figure 1Functional pathways with significant associationsFigure omitted. See PDF
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