Non-communicable disease risk in black South Africans: dissecting the role of glucocorticoids

Abstract

Background: Circulating glucocorticoid concentrations are associated with the metabolic syndrome and its components in non-Africans. Likewise, common variants at CYP17A1 and SERPINA6/A1, two loci that were linked to the inter-individual variations in circulating glucocorticoid concentrations, have also been associated with the components of the metabolic syndrome in non-Africans. However, there is a dearth of studies in populations of African ancestry. The present study aimed to investigate relationships between circulating glucocorticoid concentrations, and CYP17A1 and SERPINA6/A1 single nucleotide polymorphisms (SNPs), and the metabolic syndrome and its components, in Africans, whose phenotype and genetic profiles differ to Europeans. Methods: Firstly, an epidemiological study was conducted to determine the associations between circulating corticosterone and cortisol concentrations, and the metabolic syndrome and its individual components in 1104 adult men and women of African ancestry. A pilot study was then conducted to investigate the relationships between common variants at previously identified CYP17A1 and SERPINA/A1 genetic loci, and the metabolic syndrome and its components in 858 adult women of African ancestry. In the final study, I tested these genetic associations in a larger sample (n = 4431) which included both men and women of African ancestry, but also included SNPs at CYP17A1 and SERPINA6/A1 loci that had not been previously identified. In the same study, the hypothesis that these genetic association studies were mediated by circulating glucocorticoids was also investigated in a subsample of 877 men and women. Results: The epidemiology study demonstrated glucocorticoid- and sex-specific relationships between fasting serum glucocorticoid concentrations and the metabolic syndrome and its components, in men and women of African ancestry. Fasting serum vii cortisol concentrations were associated with greater odds of having the metabolic syndrome and higher systolic and diastolic blood pressure, but lower LDL and higher HDL cholesterol concentrations, in both men and women. In contrast, fasting corticosterone concentrations were only associated with higher insulin sensitivity, in men and women, but not independently of BMI. Sex-specific associations were observed, such that both fasting serum cortisol and corticosterone concentrations were associated with higher fasting plasma glucose and HbA1c concentrations in men, but lower HbA1c concentrations in women. The pilot study, which was conducted in women only, demonstrated that rs2749527 and rs7147098, two SERPINA6/A1 SNPs that were previously associated with circulating cortisol concentrations in Europeans, were also associated with higher fasting plasma glucose and diastolic blood pressure, respectively. In the final genetic association study, CYP17A1 SNPs (n = 2) were associated with higher waist circumference in both men and women. Other CYP17A1 SNPs (n = 5) were associated with fasting insulin and the homeostatic model assessment of insulin resistance in men only, whilst other CYP17A1 SNPs (n = 2) were associated with higher fasting cortisol concentrations in women only. In the same study, SERPINA6/A1 SNPs (n = 2) were associated with diastolic blood pressure in both men and women, while in women only, different SERPINA6/A1 SNPs (n = 5) were associated with lower high density lipoprotein (HDL) cholesterol, and another SNP (n = 1) with higher HDL cholesterol. Conclusions: The study demonstrated evidence of association between circulating glucocorticoid concentrations and the metabolic syndrome and its components in a population of African ancestry. These findings support the hypothesis that glucocorticoids play a role in the development of the metabolic syndrome. The study demonstrated for the first time in individuals of African ancestry that the associations of corticosterone with the components of the metabolic syndrome were not similar to those observed with viii cortisol. Hence, the findings also support the hypothesis that corticosterone has a distinct role in human health and disease. The main and novel finding in the overall thesis was that the associations between circulating glucocorticoid concentrations, SERPINA6/A1 and CYP17A1 SNPs, and key components of the metabolic syndrome, exhibited sex specificity in individuals of African ancestry. Therefore, future studies investigating the metabolic syndrome and its components in populations of African ancestry should include assessment of sex interactions