Abstract
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.
Highlights
Cardiovascular disease (CVD) is a major health risk accounting for over 17 million deaths globally each year
The aim of our study was to examine the genetic association of Single nucleotide variants (SNVs) and identify novel variants in the transcribed regions of eight genes previously associated with LDL-C, HDL-C, total cholesterol (TC), and TG and to perform a replication study for the associated SNVs in another African cohort
There was no significant difference in LDL-C (p = 0.427), TC (p = 0.093) and TG (p = 0.854) levels between men and women but HDL-C levels were significantly lower (p = 0.0009) among women
Summary
Cardiovascular disease (CVD) is a major health risk accounting for over 17 million deaths (about 30% of all deaths) globally each year. The distribution of serum lipids is known to differ among individuals with African ancestry compared to better-studied world populations. These differences persist in populations of substantial African ancestry living in different environmental backgrounds, supporting the expectation that these differences in distribution are genetically determined (Willer et al, 2013; Bentley and Rotimi, 2017). Evidence from candidate gene and genome-wide association studies (GWASs) on the influence of genetic polymorphisms on lipid level variations comes primarily from studies in cohorts of European origin, and an increasing number in Asians and populations of African descent, but few in sub-Saharan Africans (Willer et al, 2013; Dron and Hegele, 2016). Identifying the common genetic variants associated with lipid levels in populations in Africa will assist in the detection of individuals at higher risk for dyslipidemia
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