Table_3_Associations Between CYP17A1 and SERPINA6/A1 Polymorphisms, and Cardiometabolic Risk Factors in Black South Africans.DOCX

Research in European and Asian populations has reported associations between single nucleotide polymorphisms (SNPs) in CYP17A1 and SERPINA6/A1 and circulating glucocorticoid concentrations, and some key cardiometabolic risk factors. This study aimed to investigate these associations in black South African adults, who are disproportionally affected by the metabolic syndrome and its related cardiometabolic risk factors. The dataset included black South African adults (n = 4,431; 56.7% women) from the AWI-Gen study, genotyped on the H3A genotyping array and imputed using the African reference panel at the Sanger imputation service. From the imputed data, 31 CYP17A1 SNPs and 550 SERPINA6/A1 SNPs were extracted. The metabolic syndrome and its components were defined using the 2009 harmonized guidelines. Serum glucocorticoid concentrations were measured in a subset of 304 men and 573 women, using a liquid chromatography-mass spectrometry method. Genetic associations were detected using PLINK. Bonferroni correction was used to control for multiple testing. A SNP at SERPINA6/A1, rs17090691 (effect allele G), was associated with higher diastolic blood pressure (BP) in all adults combined (p = 9.47 × 10−6). Sex-stratified analyses demonstrated an association between rs1051052 (effect allele G), another SERPINA6/A1 SNP, and higher high-density lipoprotein (HDL) cholesterol concentrations in women (p = 1.23 × 10−5). No association was observed between these variants and glucocorticoids or between any of the CYP17A1 SNPs and metabolic outcomes after adjusting for multiple testing. Furthermore, there were no associations between any of the SNPs tested and the metabolic syndrome. This study reports novel genetic associations between two SNPs at SERPINA6/A1 and key cardiometabolic risk factors in black South Africans. Future replication and functional studies in larger populations are required to confirm the role of the identified SNPs in the metabolic syndrome and assess if these associations are mediated by circulating glucocorticoids.

已有针对欧洲和亚洲人群的研究报道了CYP17A1与SERPINA6/A1基因中的单核苷酸多态性（single nucleotide polymorphisms, SNPs）与循环糖皮质激素浓度、以及部分关键心血管代谢危险因素间的关联。本研究旨在探究南非黑人成年人群体中的这类关联——该群体受代谢综合征及其相关心血管代谢危险因素影响的比例远超平均水平。本数据集纳入了来自AWI-Gen研究的南非黑人成年人（n=4431；其中女性占比56.7%），所有受试者均通过H3A基因分型芯片完成基因分型，并依托桑格基因型填充服务的非洲参考面板进行基因型填充。从填充后的基因型数据中，共提取出31个CYP17A1基因SNPs以及550个SERPINA6/A1基因SNPs。本研究依据2009年统一版指南定义代谢综合征及其各组分表型。针对研究亚组中的304名男性与573名女性受试者，采用液相色谱-质谱联用法检测其血清糖皮质激素浓度。本研究采用PLINK软件检测遗传关联，并通过Bonferroni校正控制多重检验偏差。SERPINA6/A1基因上的rs17090691位点（效应等位基因为G）与全体受试者的舒张压升高显著相关（p=9.47×10^-6）。性别分层分析显示，SERPINA6/A1基因的另一SNP位点rs1051052（效应等位基因为G）与女性受试者的高密度脂蛋白（high-density lipoprotein, HDL）胆固醇水平升高显著相关（p=1.23×10^-5）。经多重检验校正后，未发现上述变异位点与糖皮质激素水平存在关联，也未观察到任何CYP17A1基因SNPs与代谢结局间存在显著关联。此外，本研究未发现本次检测的全部SNP位点与代谢综合征存在任何关联。本研究揭示了南非黑人群体中SERPINA6/A1基因的两个SNP位点与关键心血管代谢危险因素间的新型遗传关联。未来需在更大规模人群中开展验证性研究与功能学研究，以明确本次鉴定的SNPs在代谢综合征中的作用，并评估上述关联是否通过循环糖皮质激素介导。