The association of LDLR and PCSK9 variants with LDL-c levels in a black South African population in epidemiological transition
Van Zyl, Tertia
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Background Elevated concentrations of low-density lipoprotein cholesterol (LDL-c) are a major risk factor for the development of coronary artery disease (CAD) because of their role in the progression of atherosclerosis. The black South African population is known to have had historically low LDL-c and in the past there was almost no CAD in the population. However, as this population moves through the nutrition transition, LDL-c levels are increasing. LDL-c levels are regulated by the LDL receptors, which is the major protein involved with transporting cholesterol across cell membranes in humans. Proprotein convertase subtilisinlike/kexin type 9 (PCSK9) is another protein involved with the regulation of LDL-c through its role in assisting with the degradation of the LDL receptor. Variants in both genes can cause elevated or lowered LDL-c levels. Very little information is available on the frequency or presence of variants in the low-density lipoprotein receptor (LDLR) and PCSK9 gene in the black South African population and on how these variants associate with LDL-c. The main aim of the study was thus to determine novel and existing genetic variants in these two genes and to describe the manner in which they associate with plasma LDL-c levels in a black South African population undergoing an epidemiological transition. Methods The 2005 baseline data from the Prospective Urban and Rural (PURE) study population were used in this study. The study population consisted of apparently healthy black volunteers form the North West province of South Africa, aged 35 to 60 years. Thirty individuals were randomly chosen from the 1860 volunteers to determine the presence of known and novel variants in these genes by automated bidirectional sequencing. The promoter region, exons and flanking regions were sequenced and variants were identified utilising CLC DNA Workbench. Deoxyribonucleic acid (DNA) samples for 1500 individuals of the PURE study population were genotyped by means of a Golden Gate Genotyping Assay. Analyses of covariance (ANCOVA) were used to test for associations between the different genotypes in both the LDLR and PCSK9 genes and LDL-c levels. Haplotypes were generated by using the confidence intervals on the software programme, HaploView. A genetic risk score (GRS) was determined by including variants which associated significantly with LDL-c. The GRS, the haplotypes and the variants that associated significantly with LDL-c were used in separate linear regression models with variants which correlated with LDL-c to determine how all these variables contribute to the differences in LDL-c levels. Results and discussion Novel and known variants were identified in both the genes and in total 52 variants were genotyped. Rare variants such as rs17249141 and rs28362286 were detected in the study population and are associated with low levels of LDL-c. The variants identified in the LDLR gene were situated largely in regulatory regions such as the promoter, intron and 3'untranslated regions. Haplotypes in the LDLR gene with the highest frequency associated with lower LDL-c levels, which could contribute to the study population's low mean LDL-c level. Haplotypes identified in the PCSK9 gene had a weaker association with LDL-c levels. The minor allele frequencies of many of the variants differed from those of the European population and therefore the importance of population-specific research cannot be sufficiently emphasised. The GRS, haplotypes and variants used in the regression models to determine whether they contributed to predicting the variance in LDL-c in the study population made a small contribution to explaining this. BMI best explained the variance in LDL-c levels. Older women with a body mass index (BMI)>25kg/m2 were identified as being at greater risk of developing elevated LDL-c levels than the rest of the study population. Heterozygote carriers of variant, rs28362286, had 0.787 mmol/L lower LDL-c than carriers of the wild type and this is associated with a reduced risk of developing CAD. Conclusion and recommendation When considering the results mentioned above, adding genetic analysis to explaining the variance in LDL-c levels seems to have its limitations, but the study included only two of many genes that play a role in the metabolism and regulation of LDL-c levels. Incorporating more genes and more variants into analyses and prediction models will add greater value to defining LDL-c levels. Rarer variants with a large impact on protein function, such as rs28362286, have a greater effect on LDL-c levels and could predict the variance better than the common variants. Risk factors such as BMI can also still be trusted to indicate which individuals or groups are at risk of developing elevated LDL-c levels. Health advice should be given to appropriate target groups such as older women with a BMI >25kg/m2 in order to prevent CAD from becoming a burden in this population.
- Health Sciences