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Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans.

ABSTRACT: Insulin resistance (IR) is a key determinant of type 2 diabetes (T2D) and other metabolic disorders. This genome-wide association study (GWAS) was designed to shed light on the genetic basis of fasting insulin (FI) and IR in 927 non-diabetic African Americans. 5 396 838 single-nucleotide polymorphisms (SNPs) were tested for associations with FI or IR with adjustments for age, sex, body mass index, hypertension status and first two principal components. Genotyped SNPs (n = 12) with P < 5 × 10(-6) in African Americans were carried forward for de novo genotyping in 570 non-diabetic West Africans. We replicated SNPs in or near SC4MOL and TCERG1L in West Africans. The meta-analysis of 1497 African Americans and West Africans yielded genome-wide significant associations for SNPs in the SC4MOL gene: rs17046216 (P = 1.7 × 10(-8) and 2.9 × 10(-8) for FI and IR, respectively); and near the TCERG1L gene with rs7077836 as the top scoring (P = 7.5 × 10(-9) and 4.9 × 10(-10) for FI and IR, respectively). In silico replication in the MAGIC study (n = 37 037) showed weak but significant association (adjusted P-value of 0.0097) for rs34602777 in the MYO5A gene. In addition, we replicated previous GWAS findings for IR and FI in Europeans for GCKR, and for variants in four T2D loci (FTO, IRS1, KLF14 and PPARG) which exert their action via IR. In summary, variants in/near SC4MOL, and TCERG1L were associated with FI and IR in this cohort of African Americans and were replicated in West Africans. SC4MOL is under-expressed in an animal model of T2D and plays a key role in lipid biosynthesis, with implications for the regulation of energy metabolism, obesity and dyslipidemia. TCERG1L is associated with plasma adiponectin, a key modulator of obesity, inflammation, IR and diabetes.

SUBMITTER: Chen G

PROVIDER: S-EPMC3459464 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans.

Chen Guanjie G Bentley Amy A Adeyemo Adebowale A Shriner Daniel D Zhou Jie J Doumatey Ayo A Huang Hanxia H Ramos Edward E Erdos Michael M Gerry Norman N Herbert Alan A Christman Michael M Rotimi Charles C

Human molecular genetics 20120712 20

Insulin resistance (IR) is a key determinant of type 2 diabetes (T2D) and other metabolic disorders. This genome-wide association study (GWAS) was designed to shed light on the genetic basis of fasting insulin (FI) and IR in 927 non-diabetic African Americans. 5 396 838 single-nucleotide polymorphisms (SNPs) were tested for associations with FI or IR with adjustments for age, sex, body mass index, hypertension status and first two principal components. Genotyped SNPs (n = 12) with P < 5 × 10(-6) ...[more]

PMID: 22791750

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Project description:Background & aimsThe 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.MethodsWe 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.ResultsWe 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 significance 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.ConclusionsWe 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.

Project description:BackgroundAfrican Americans have a high risk for type 2 diabetes (T2D) and insulin resistance. Studies among other population groups have identified DNA methylation loci associated with insulin resistance, but data in African Americans are lacking. Using DNA methylation profiles of blood samples obtained from the Illumina Infinium® HumanMethylation450 BeadChip, we performed an epigenome-wide association study to identify DNA methylation loci associated with insulin resistance among 136 non-diabetic, unrelated African American men (mean age 41.6 years) from the Howard University Family Study.ResultsWe identified three differentially methylated positions (DMPs) for homeostatic model assessment of insulin resistance (HOMA-IR) at 5% FDR. One DMP (cg14013695, HOXA5) is a known locus among Mexican Americans, while the other two DMPs are novel-cg00456326 (OSR1; beta = 0.027) and cg20259981 (ST18; beta = 0.010). Although the cg00456326 DMP is novel, the OSR1 gene has previously been found associated with both insulin resistance and T2D in Europeans. The genes HOXA5 and ST18 have been implicated in biological processes relevant to insulin resistance. Differential methylation at the significant HOXA5 and OSR1 DMPs is associated with differences in gene expression in the iMETHYL database. Analysis of differentially methylated regions (DMRs) did not identify any epigenome-wide DMRs for HOMA-IR. We tested transferability of HOMA-IR associated DMPs from five previous EWAS in Mexican Americans, Indian Asians, Europeans, and European ancestry Americans. Out of the 730 previously reported HOMA-IR DMPs, 47 (6.4%) were associated with HOMA-IR in this cohort of African Americans.ConclusionsThe findings from our study suggest substantial differences in DNA methylation patterns associated with insulin resistance across populations. Two of the DMPs we identified in African Americans have not been reported in other populations, and we found low transferability of HOMA-IR DMPs reported in other populations in African Americans. More work in African-ancestry populations is needed to confirm our findings as well as functional analyses to understand how such DNA methylation alterations contribute to T2D pathology.

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Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans.

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Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans.

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