Journal Article

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

Guanjie Chen, Amy Bentley, Adebowale Adeyemo, Daniel Shriner, Jie Zhou, Ayo Doumatey, Hanxia Huang, Edward Ramos, Michael Erdos, Norman Gerry, Alan Herbert, Michael Christman and Charles Rotimi

in Human Molecular Genetics

Volume 21, issue 20, pages 4530-4536
Published in print October 2012 | ISSN: 0964-6906
Published online July 2012 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/dds282
Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans

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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.

Journal Article.  4384 words.  Illustrated.

Subjects: Genetics and Genomics

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