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

Siphiwe N Dlamini,Zané Lombard,Michèle Ramsay,Nigel J Crowther,Lisa K Micklesfield,Julia H Goedecke,Brian R Walker,Andrew A Crawford,Ananyo Choudhury,Shane A Norris

doi:10.3389/fgene.2021.687335

Abstract

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.

Highlights

Key cardiometabolic risk factors, including elevated waist circumference, blood pressure, and fasting blood glucose concentrations, and the presence of dyslipidemia, cluster to form the metabolic syndrome (Alberti et al, 2009)
The present study reports two novel genetic associations between single nucleotide polymorphisms (SNPs) at SERPINA6/A1 and key cardiometabolic risk factors in black South Africans
The rs17090691-G allele was associated with higher diastolic blood pressure in a combined sample of men and women, while the rs1051052-G allele was associated with higher high-density lipoprotein (HDL) cholesterol in women only

Summary

Introduction

Key cardiometabolic risk factors, including elevated waist circumference, blood pressure, and fasting blood glucose concentrations, and the presence of dyslipidemia, cluster to form the metabolic syndrome (Alberti et al, 2009). Population-based cross-sectional studies have suggested that circulating cortisol, the primary glucocorticoid in humans, is associated with a higher risk of presenting with the metabolic syndrome and its related cardiometabolic risk factors (Walker et al, 2000; Reynolds et al, 2003; Ward et al, 2003). Considering that cardiometabolic risk factors that form the metabolic syndrome are interrelated (Alberti et al, 2009), the CYP17A1 SNPs may be associated with elevated fasting blood glucose and the presence of dyslipidemia, but this hypothesis is yet to be tested

Objectives

Methods

Results

Conclusion