Variants in four genes associated with lipid levels: a study in African populations

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Masters (Med) in Human Genetics. Johannesburg, 2018.Non-communicable diseases, including cardiovascular disease (CVD), are on the rise in African populations. High serum LDL cholesterol (LDL-C) levels is a risk factor for CVD, but the contribution of high LDL-C levels to CVD in African populations remains poorly understood. Genetic variation in the LDLR, APOB, PCSK9 and LDLRAP1 genes is known to be associated with alteration in LDL-C levels in many populations. This study aims to examine whether genetic variants in these four genes are associated with differing LDL-C levels in African populations, considering LDL-C as a polygenic trait. Publicly available African whole genome sequence data were interrogated, and variants were selected for genotyping using functional predictive bioinformatics tools. Participants (n=1000) from the AWI-Gen study were selected using a case-control study design based on clinical cut-offs of LDL-C levels (500 with LDL-C>3.5 mmol/l, 500 with LDL-CG (OR 0.5866, pA (OR 0.6898, p=0.04). The minor alleles G and A, were associated with lower LDL-C levels, suggesting gain of function effects. The variant alleles at both loci are extremely rare in European populations (MAF