Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-8004, USA.
Hum Mol Genet. 2012 Oct 15;21(20):4530-6. doi: 10.1093/hmg/dds282. Epub 2012 Jul 12.
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.
胰岛素抵抗（IR）是 2 型糖尿病（T2D）和其他代谢紊乱的关键决定因素。本全基因组关联研究（GWAS）旨在阐明 927 名非糖尿病非洲裔美国人空腹胰岛素（FI）和 IR 的遗传基础。对 5396838 个单核苷酸多态性（SNP）进行了关联分析，调整了年龄、性别、体重指数、高血压状态和前两个主成分。在非洲裔美国人中，P<5×10(-6)的基因分型 SNP（n=12）被推进到 570 名非糖尿病西非人中进行从头基因分型。我们在西非人中复制了 SC4MOL 和 TCERG1L 附近的 SNP。在 1497 名非洲裔美国人和西非人中的荟萃分析产生了 SC4MOL 基因中 SNP 的全基因组显著关联：rs17046216（FI 和 IR 的 P 值分别为 1.7×10(-8)和 2.9×10(-8)）；TCERG1L 基因附近的 rs7077836 是最高得分的 SNP（FI 和 IR 的 P 值分别为 7.5×10(-9)和 4.9×10(-10)）。在 MAGIC 研究（n=37037）中的计算机模拟复制显示，MYO5A 基因中的 rs34602777 存在微弱但显著的关联（调整后的 P 值为 0.0097）。此外，我们在欧洲人对 GCKR 的 IR 和 FI 以及四个 T2D 位点（FTO、IRS1、KLF14 和 PPARG）的变体的先前 GWAS 发现进行了复制，这些变体通过 IR 发挥作用。总之，SC4MOL 和 TCERG1L 附近的变体与该非洲裔美国人队列中的 FI 和 IR 相关，并在西非人中得到了复制。SC4MOL 在 2 型糖尿病动物模型中的表达降低，在脂质生物合成中起关键作用，这对能量代谢、肥胖和血脂异常的调节具有重要意义。TCERG1L 与血浆脂联素相关，脂联素是肥胖、炎症、IR 和糖尿病的关键调节因子。
