Background:Resistin, a protein linked with inflammation and cardiometabolic diseases, is one of few proteins for which genome-wide association studies consistently report variants within and near the coding gene (RETN). Here, we took advantage of the reduced linkage disequilibrium in African populations to infer genetic causality for circulating resistin levels by performing genome-wide association studies, whole-exome analysis, fine mapping, Mendelian randomization, and transcriptomic data analyses.Methods:Genome-wide association studies and fine-mapping analyses for resistin were performed in 5621 African-ancestry individuals, including 3754 continental Africans and 1867 African Americans. Causal variants identified were subsequently used as an instrumental variable in Mendelian randomization analyses for homeostatic modeling-derived insulin resistance index, body mass index, and type 2 diabetes.Results:The lead variant (rs3219175, in the promoter region of RETN) for the single locus detected was the same for continental Africans (P=5.0×10⁻¹¹¹) and for African Americans (9.5×10⁻³⁸), respectively explaining 12.1% and 8.5% of variance in circulating resistin. Fine-mapping analyses and functional annotation revealed this variant as likely causal affecting circulating resistin levels as a cis-eQTL increasing RETN expression. Additional variants regulating resistin levels were upstream of RETN with genes PCP2, STXBP2, and XAB2 showing the strongest association using integrative analysis of genome-wide association studies with transcriptomic data. Mendelian randomization analyses did not provide evidence for resistin increasing insulin resistance, body mass index, or type 2 diabetes risk in African-ancestry populations.Conclusions:Taking advantage of the fine-mapping resolution power of African genomes, we identified a single variant (rs3219175) as the likely causal variant responsible for most of the variability in circulating resistin levels. In contrast to findings in some other ancestry populations, we showed that resistin does not seem to increase insulin resistance and related cardiometabolic traits in African-ancestry populations.

中文翻译：

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循环抵抗素水平的遗传学，心血管疾病的生物标志物，由孟德尔随机化和非洲基因组的独特特征提供信息。

背景：抵抗素是一种与炎症和心脏代谢疾病相关的蛋白质，是全基因组关联研究一致报告编码基因 ( RETN)内和附近变异的少数蛋白质之一。）。在这里，我们通过进行全基因组关联研究、全外显子组分析、精细定位、孟德尔随机化和转录组数据分析，利用非洲人群中减少的连锁不平衡来推断循环抵抗素水平的遗传因果关系。在 5621 名非洲血统个体中进行了抵抗素的关联研究和精细定位分析，其中包括 3754 名非洲大陆人和 1867 名非裔美国人。确定的因果变异随后被用作孟德尔随机化分析的工具变量，用于稳态建模衍生的胰岛素抵抗指数、体重指数和 2 型糖尿病。 结果：主要变异（rs3219175，在RETN的启动子区域) 对于非洲大陆人 ( P =5.0×10 ^-111 ) 和非洲裔美国人 (9.5×10 ^-38 )，检测到的单个基因座相同，分别解释了循环抵抗素中 12.1% 和 8.5% 的变异。精细定位分析和功能注释表明，这种变异可能是影响循环抵抗素水平的原因，就像顺式 eQTL 增加RETN表达一样。调节抵抗素水平的其他变异体位于RETN的上游，带有PCP2、STXBP2和XAB2基因。使用转录组数据的全基因组关联研究的综合分析显示最强的关联。孟德尔随机分析没有提供抵抗素增加非洲血统人群的胰岛素抵抗、体重指数或 2 型糖尿病风险的证据。 ) 作为可能导致循环抵抗素水平变异的原因。与其他一些血统人群的发现相反，我们发现抵抗素似乎不会增加非洲血统人群的胰岛素抵抗和相关的心脏代谢特征。