Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK.
Nat Genet. 2011 Jun 26;43(8):753-60. doi: 10.1038/ng.866.
Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
全基因组关联研究已经确定了 32 个影响体重指数的位点，但这一指标并不能区分瘦体重和脂肪量。为了确定肥胖相关位点，我们对来自 36626 个人的约 250 万个 SNP 与体脂肪百分比之间的关联进行了荟萃分析，并在 39576 个人中对 14 个最显著（P < 10(-6)）的独立位点进行了随访。我们证实了 FTO 中先前确定的肥胖相关位点（P = 3 × 10(-26)），并鉴定出与体脂肪百分比相关的两个新位点，一个位于 IRS1 附近（P = 4 × 10(-11)），另一个位于 SPRY2 附近（P = 3 × 10(-8)）。这两个位点都包含与脂肪细胞生理学有潜在联系的基因。值得注意的是，IRS1 附近的降低体脂肪的等位基因与 IRS1 表达降低以及代谢特征受损有关，包括内脏脂肪与皮下脂肪比例增加、胰岛素抵抗、血脂异常、糖尿病和冠心病风险增加以及脂联素水平降低。我们的研究结果为肥胖和胰岛素抵抗提供了新的见解。
