Non-communicable disease risk in black South Africans: dissecting the role of glucocorticoids
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Date
2021
Authors
Dlamini, Siphiwe Ndumiso
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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
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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
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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
Description
A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy (Paediatrics) to the Faculty of Health Sciences, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, 2021