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<0.001) and this may explain why they have not previously been reported in LDL-C association studies. Since African populations, in general, have reduced LDL-C levels these variants could be African-specific LDL-C associated variants and may suggest a unique gene-environment interaction. Using a limited number of potentially functional variants in African populations and after extensive adjustment for potential covariates, significant associations were detected with variants in two of the four genes studied.LG201

Genetic associations between serum low LDL-cholesterol levels and variants in LDLR, APOB, PCSK9 and LDLRAP1 in African populations.

Non-communicable diseases, including cardiovascular diseases (CVDs), are increasing in African populations. High serum low density lipoprotein cholesterol (LDL-cholesterol) levels are a known risk factor for CVDs in European populations, but the link remains poorly understood among Africans. This study investigated the associations between serum LDL-cholesterol levels and selected variants in the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and low density lipoprotein receptor adaptor protein 1 (LDLRAP1) genes in some selected African populations. Nineteen SNPs were selected from publicly available African whole genome sequence data based on functional prediction and allele frequency. SNPs were genotyped in 1000 participants from the AWI-Gen, study selected from the extremes of LDL-cholesterol level distribution (500 with LDL-cholesterol>3.5 mmol/L and 500 with LDL-cholesterol<1.1 mmol/L). The minor alleles at five of the six associated SNPs were significantly associated (P<0.05) with lower LDL-cholesterol levels: LDLRAP1 rs12071264 (OR 0.56, 95% CI: 0.39-0.75, P = 2.73x10-4) and rs35910270 (OR 0.78, 95% CI: 0.64-0.94, P = 0.008); APOB rs6752026 (OR 0. 55, 95% CI: 0.41-0.72, P = 2.82x10-5); LDLR: rs72568855 (OR 0.47, 95% CI: 0.27-0.82, P = 0.008); and PCSK9 rs45613943 (OR = 0.72, 95% CI: 0.58-0.88, P = 0.001). The minor allele of the sixth variant was associated with higher LDL-cholesterol levels: APOB rs679899 (OR 1.41, 95% CI: 1.06-1.86, P = 0.016). A replication analysis in the Africa America Diabetes Mellitus (AADM) study found the PCSK9 variant to be significantly associated with low LDL-cholesterol levels (Beta = -0.10). Since Africans generally have lower LDL-cholesterol levels, these LDL-cholesterol associated variants may be involved in adaptation due to unique gene-environment interactions. In conclusion, using a limited number of potentially functional variants in four genes, we identified significant associations with lower LDL-cholesterol levels in sub-Saharan Africans

Correction: Genetic associations between serum low LDL-cholesterol levels and variants in LDLR, APOB, PCSK9 and LDLRAP1 in African populations.

[This corrects the article DOI: 10.1371/journal.pone.0229098.]

Building skills and resources for genomics, epigenetics, and bioinformatics research for Africa: Report of the joint 11th conference of the african society of human genetics and 12th H3 Africa consortium, 2018

The 11th Congress of the African Society of Human Genetics (AfSHG) was held from September 16, 2018 to September 21, 2018, in conjunction with the 12th Human Heredity and Health in Africa (H3Africa) Consortium meeting in Kigali, Rwanda. The event was organized by the AfSHG in partnership with the Rwanda Society of Human Genetics and the University of Rwanda. A 2-day workshop on the application of next-generation sequencing technologies for analyzing monogenic disease in African populations was organized as part of the conference (September 22, 2018-September 23, 2018, Kigali, Rwanda). The theme of the conference was "Building skills and resources for genomics, epigenetics and bioinformatics research for Africa."The conference served as a platform to bring together members from country-specific Societies of Human Genetics, including Rwanda, Cameroon, Democratic Republic of Congo, Egypt, Mali, Senegal, and South Africa, and included 435 delegates from 38 countries, including 29 African countries that attended the conference. A major topic of discussion was how to bridge the gap between the emerging knowledge on genomics and Omics in African populations. The importance of understanding the role of genetic variation in disease causation and susceptibility among Africans was a constant theme during the meeting, as was the need to develop research infrastructure and resources to enhance healthcare systems, so that they are not left behind in the genomic revolution. It was concluded that there is a need to inspire more African scientists to train and work as investigators, clinicians, and genetic counselors in the field of human genetics in Africa. Local investments, and South-South and South-North collaboration were identified as the key drivers for the successful implementation of research and development on the continent.SCOPUS: ar.jinfo:eu-repo/semantics/publishe