AUTHOR=Agongo Godfred , Amenga-Etego Lucas , Nonterah Engelbert A. , Debpuur Cornelius , Choudhury Ananyo , Bentley Amy R. , Oduro Abraham R. , Rotimi Charles N. , Crowther Nigel J. , Ramsay Michèle ,  AWI-Gen and H3Africa , H3Africa  

TITLE=Candidate Gene Analysis Reveals Strong Association of CETP Variants With High Density Lipoprotein Cholesterol and PCSK9 Variants With Low Density Lipoprotein Cholesterol in Ghanaian Adults: An AWI-Gen Sub-Study

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.456661

DOI=10.3389/fgene.2020.456661

ISSN=1664-8021

ABSTRACT=<p>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 (<italic>ABCA1</italic>, <italic>LCAT</italic>, <italic>LPL</italic>, <italic>PON1</italic>, <italic>CETP</italic>, <italic>PCSK9</italic>, <italic>MVK</italic>, and <italic>MMAB</italic>) 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 <italic>CETP</italic>, <italic>LCAT</italic>, <italic>PCSK9</italic>, and <italic>PON1</italic> (MAF &gt; 0.05) were associated with HDL-C, LDL-C and TC levels at <italic>p</italic> &lt; 0.05. The lead variants for association with HDL-C were rs17231520 in <italic>CETP</italic> (β = 0.139, <italic>p</italic> &lt; 0.0001) and rs1109166 in <italic>LCAT</italic> (β = −0.044, <italic>p</italic> = 0.028). Lower LDL-C levels were associated with an intronic variant in <italic>PCSK9</italic> (rs11806638 [β = −0.055, <italic>p</italic> = 0.027]) and increased TC was associated with a variant in <italic>PON1</italic> (rs854558 [β = 0.040, <italic>p</italic> = 0.020]). <italic>In silico</italic> functional analyses indicated that these variants likely influence gene function through their effect on gene transcription. We replicated a strong association between <italic>CETP</italic> variants and HDL-C and between <italic>PCSK9</italic> variant and LDL-C in West Africans, with two potentially functional variants and identified three novel variants in linkage disequilibrium in <italic>PON1</italic> which were associated with increasing TC levels in Ghanaians.</p>