Browsing by Author "Hayat, Mahtaab"

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The contribution of common genetic variants to breast cancer risk in South African black populations
(University of the Witwatersrand, Johannesburg, 2023-08) Hayat, Mahtaab; Brandenburg, Jean-Tristan; Ramsay, Michèle; Mathew, Christopher
Breast cancer is the second most common cancer in South African black women. The contribution of common genetic variants to breast cancer risk is well studied in non-African populations, but little is known about their role in resident African populations, and there are no published genome-wide association studies (GWAS) on breast cancer in Africa. This PhD thesis aimed to determine the contribution of common genetic variants to breast cancer in a South African black population. A GWAS was carried out in 2,573 black female breast cancer patients from the Johannesburg Cancer Study and 744 population-matched, female controls from the AWI-Gen study. All participants were from Soweto, Johannesburg, South Africa. Samples were genotyped on the H3Africa SNP array. Replication testing was done of existing loci from European and African American (AA) populations in the resident African data, and loci from the resident African data in European and AA populations. A meta-analysis was carried out with an AA population. Finally, existing polygenic risk scores (PRSs) were tested in the resident African dataset. Three variants at two loci were strongly associated with breast cancer in this study. Two variants (rs77422433, p-value=2.89x10-08, odds ratio (OR):0.46, 95% confidence interval (95%CI): 0.40-0.52 and rs112410019, p-value=3.01x10-08, OR: 0.47, 95%CI: 0.41-0.53) were located within the DNA repair gene XRCC5. These variants were not previously associated with breast cancer, suggesting that it may be an African specific risk locus. The second locus is on chromosome 16 in CES5A (rs3859109, p-value=4.54x10-08, OR=0.70, 95%CI: 0.68-0.73), and had not previously been associated with breast cancer. None of these SNPs were replicated in European and AA populations. The meta-analysis with AA data revealed strong association of an intergenic SNP with breast cancer (rs139299680, pmeta=7.25x10-08) on chromosome 3. A polygenic risk score (PRS) developed in European populations demonstrated poor transferability to this African dataset. This GWAS is the first to be conducted in a resident black African population. This study suggests that there may be African-specific genetic risk factors for African breast cancer, and that large genome-wide studies in African populations are essential to develop a comprehensive understanding of the genetics of breast cancer in Africa.
Variants in four genes associated with lipid levels: a study in African populations
(2018) Hayat, Mahtaab
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-C<1.1 mmol/l). Genotyping was carried out on 19 selected SNPs chosen from across the four genes. Logistic regression analysis revealed that, after adjusting for sex, fasting glucose levels, BMI and geographic region, the minor alleles at two SNPs remained significantly associated (p<0.05) with low LDL-C levels - LDLRAP1 rs12071264, c.533-22A>G (OR 0.5866, p<0.01) and APOB rs6752026, c.433G>A (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.