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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.

Variations in lipid levels are attributed partly to genetic factors. Genome-wide association studies (GWASs) mainly performed in European, African American and Asian cohorts have identified variants associated with LDL-C, HDL-C, total cholesterol (TC) and triglycerides (TG), but few studies have been performed in sub-Saharan Africans. This study evaluated the effect of single nucleotide variants (SNVs) in eight candidate loci (ABCA1, LCAT, LPL, PON1, CETP, PCSK9, MVK, and MMAB) on lipid levels among 1855 Ghanaian adults. All lipid levels were measured directly using an automated analyser. DNA was extracted and genotyped using the H3Africa SNV array. Linear regression models were used to test the association between SNVs and log-transformed lipid levels, adjusting for sex, age and waist circumference. In addition Bonferroni correction was performed to account for multiple testing. Several variants of CETP, LCAT, PCSK9, and PON1 (MAF > 0.05) were associated with HDL-C, LDL-C and TC levels at p < 0.05. The lead variants for association with HDL-C were rs17231520 in CETP (β = 0.139, p < 0.0001) and rs1109166 in LCAT (β = −0.044, p = 0.028). Lower LDL-C levels were associated with an intronic variant in PCSK9 (rs11806638 [β = −0.055, p = 0.027]) and increased TC was associated with a variant in PON1 (rs854558 [β = 0.040, p = 0.020]). In silico functional analyses indicated that these variants likely influence gene function through their effect on gene transcription. We replicated a strong association between CETP variants and HDL-C and between PCSK9 variant and LDL-C in West Africans, with two potentially functional variants and identified three novel variants in linkage disequilibrium in PON1 which were associated with increasing TC levels in Ghanaians.

IntroductionAtherosclerosis is a key contributor to the burden of cardiovascular diseases (CVDs) and many epidemiological studies have reported on the effect of smoking on carotid intima-media thickness (cIMT) and its subsequent effect on CVD risk. Gene-environment interaction studies have contributed towards understanding some of the missing heritability of genome-wide association studies. Gene-smoking interactions on cIMT have been studied in non-African populations (European, Latino-American, and African American) but no comparable African research has been reported. Our aim was to investigate smoking-SNP interactions on cIMT in two West African populations by genome-wide analysis.Materials and methodsOnly male participants from Burkina Faso (Nanoro = 993) and Ghana (Navrongo = 783) were included, as smoking was extremely rare among women. Phenotype and genotype data underwent stringent QC and genotype imputation was performed using the Sanger African Imputation Panel. Smoking prevalence among men was 13.3% in Nanoro and 42.5% in Navrongo. We analyzed gene-smoking interactions with PLINK after adjusting for covariates: age and 6 PCs (Model 1); age, BMI, blood pressure, fasting glucose, cholesterol levels, MVPA, and 6 PCs (Model 2). All analyses were performed at site level and for the combined data set.ResultsIn Nanoro, we identified new gene-smoking interaction variants for cIMT within the previously described RCBTB1 region (rs112017404, rs144170770, and rs4941649) (Model 1: p = 1.35E-07; Model 2: p = 3.08E-08). In the combined sample, two novel intergenic interacting variants were identified, rs1192824 in the regulatory region of TBC1D8 (p = 5.90E-09) and rs77461169 (p = 4.48E-06) located in an upstream region of open chromatin. In silico functional analysis suggests the involvement of genes implicated in biological processes related to cell or biological adhesion and regulatory processes in gene-smoking interactions with cIMT (as evidenced by chromatin interactions and eQTLs).DiscussionThis is the first gene-smoking interaction study for cIMT, as a risk factor for atherosclerosis, in sub-Saharan African populations. In addition to replicating previously known signals for RCBTB1, we identified two novel genomic regions (TBC1D8, near BCHE) involved in this gene-environment interaction.

Single nucleotide polymorphism arrays have created new possibilities for performing genome-wide studies to detect genomic regions harboring sequence variants that affect complex traits. However, the majority of validated SNPs for which allele frequencies have been estimated are limited primarily to European breeds. The objective of this study was to perform SNP discovery in three South African indigenous breeds (Afrikaner, Drakensberger, and Nguni) using whole genome sequencing. DNA was extracted from blood and hair samples, quantified and prepared at 50 ng/μl concentration for sequencing at the Agricultural Research Council Biotechnology Platform using an Illumina HiSeq 2500. The fastq files were used to call the variants using the Genome Analysis Tool Kit. A total of 1,678,360 were identified as novel using Run 6 of 1000 Bull Genomes Project. Annotation of the identified variants classified them into functional categories. Within the coding regions, about 30% of the SNPs were non-synonymous substitutions that encode for alternate amino acids. The study of distribution of SNP across the genome identified regions showing notable differences in the densities of SNPs among the breeds and highlighted many regions of functional significance. Gene ontology terms identified genes such as MLANA, SYT10, and CDC42EP5 that have been associated with coat color in mouse, and ADAMS3, DNAJC3, and PAG5 genes have been associated with fertility in cattle. Further analysis of the variants detected 688 candidate selective sweeps (ZHp Z-scores ≤ -4) across all three breeds, of which 223 regions were assigned as being putative selective sweeps (ZHp scores ≤-5). We also identified 96 regions with extremely low ZHp Z-scores (≤-6) in Afrikaner and Nguni. Genes such as KIT and MITF that have been associated with skin pigmentation in cattle and CACNA1C, which has been associated with biopolar disorder in human, were identified in these regions. This study provides the first analysis of sequence data to discover SNPs in indigenous South African cattle breeds. The information will play an important role in our efforts to understand the genetic history of our cattle and in designing appropriate breed improvement programmes.