Genetic Susceptibility to Breast Cancer in Sub-Saharan African Populations.
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ABSTRACT:
SUBMITTER: Hayat M
PROVIDER: S-EPMC8509920 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThere is growing support for the use of genetic risk scores (GRS) in routine clinical settings. Due to the limited diversity of current genomic discovery samples, there are concerns that the predictive power of GRS will be limited in non-European ancestry populations. GRS for cardiometabolic traits were evaluated in sub-Saharan Africans in comparison with African Americans and European Americans.MethodsWe evaluated the predictive utility of GRS for 12 cardiometabolic traits in sub-Saharan Africans (AF; n = 5200), African Americans (AA; n = 9139) and European Americans (EUR; n = 9594). GRS were constructed as weighted sums of the number of risk alleles. Predictive utility was assessed using the additional phenotypic variance explained and the increase in discriminatory ability over traditional risk factors [age, sex and body mass index (BMI)], with adjustment for ancestry-derived principal components.ResultsAcross all traits, GRS showed up to a 5-fold and 20-fold greater predictive utility in EUR relative to AA and AF, respectively. Predictive utility was most consistent for lipid traits, with percentage increase in explained variation attributable to GRS ranging from 10.6% to 127.1% among EUR, 26.6% to 65.8% among AA and 2.4% to 37.5% among AF. These differences were recapitulated in the discriminatory power, whereby the predictive utility of GRS was 4-fold greater in EUR relative to AA and up to 44-fold greater in EUR relative to AF. Obesity and blood pressure traits showed a similar pattern of greater predictive utility among EUR.ConclusionsThis work demonstrates the poorer performance of GRS in AF and highlights the need to improve representation of multiple ethnic populations in genomic studies to ensure equitable clinical translation of GRS.
| S-EPMC8407873 | biostudies-literature
Project description:Orofacial clefts (OFCs) are congenital dysmorphologies of the human face and oral cavity, with a global incidence of 1 per 700 live births. These anomalies exhibit a multifactorial pattern of inheritance, with genetic and environmental factors both playing crucial roles. Many loci have been implicated in the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries, through genome-wide association studies and candidate gene studies. However, few populations of African descent have been studied to date. Here, the authors show evidence of an association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia, and Nigeria). The authors genotyped 48 single-nucleotide polymorphisms that were selected from previous genome-wide association studies and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1,070 unaffected relatives, and 1,078 unrelated controls. The authors also directly sequenced 7 genes in 184 nonsyndromic OFC (NSOFC) cases and 96 controls from Ghana. Population-specific associations were observed in the case-control analyses of the subpopulations, with West African subpopulations (Ghana and Nigeria) showing a similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, P = 5.10 × 10(-3)), 8q24 (rs987525, P = 1.22 × 10(-3)), and VAX1 (rs7078160, P = 0.04) were nominally associated with NSCL/P, and MSX1 (rs115200552, P = 0.01), TULP4 (rs651333, P = 0.04), CRISPLD2 (rs4783099, P = 0.02), and NOG1 (rs17760296, P = 0.04) were nominally associated with NSCPO. Moreover, 7 loci exhibited evidence of threshold overtransmission in NSOFC cases through the transmission disequilibrium test and through analyses of the family-based association for disease traits. Through DNA sequencing, the authors also identified 2 novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29 In conclusion, the authors have shown evidence for the association of many loci with NSCL/P and NSCPO. To the best of this knowledge, this study is the first to demonstrate any of these association signals in any African population.
| S-EPMC5076758 | biostudies-literature
Project description:Studies of large sets of single nucleotide polymorphism (SNP) data have proven to be a powerful tool in the analysis of the genetic structure of human populations. In this work, we analyze genotyping data for 2841 SNPs in 12 sub-Saharan African populations, including a previously unsampled region of southeastern Africa (Mozambique). We show that robust results in a world-wide perspective can be obtained when analyzing only 1000 SNPs. Our main results both confirm the results of previous studies, and show new and interesting features in sub-Saharan African genetic complexity. There is a strong differentiation of Nilo-Saharans, much beyond what would be expected by geography. Hunter-gatherer populations (Khoisan and Pygmies) show a clear distinctiveness with very intrinsic Pygmy (and not only Khoisan) genetic features. Populations of the West Africa present an unexpected similarity among them, possibly the result of a population expansion. Finally, we find a strong differentiation of the southeastern Bantu population from Mozambique, which suggests an assimilation of a pre-Bantu substrate by Bantu speakers in the region.
| S-EPMC3039508 | biostudies-literature
Project description:BackgroundAlcohol drinking is linked to the development of breast cancer. However, there is little knowledge about the impact of alcohol consumption on breast cancer risk among African women.MethodsWe conducted a case-control study among 2,138 women with invasive breast cancer and 2,589 controls in Nigeria, Cameroon, and Uganda from 1998 to 2013. A structured questionnaire was used to collect information on alcohol consumption, defined as consuming alcoholic beverages at least once a week for six months or more. Logistic regression was used to estimate adjusted odds ratio (aOR) and 95% confidence interval (CI).ResultsAmong healthy controls, the overall alcohol consumption prevalence was 10.4%, and the prevalence in Nigeria, Cameroon, and Uganda were 5.0%, 34.6%, and 50.0%, respectively. Cases were more likely to have consumed alcohol (aOR?= 1.62, 95% CI: 1.33-1.97). Both past (aOR?= 1.54; 95% CI: 1.19-2.00) and current drinking (aOR?= 1.71; 95% CI: 1.30-2.23) were associated with breast cancer risk. A dose-response relationship was observed for duration of alcohol drinking (P-trend <0.001), with 10-year increase of drinking associated with a 54% increased risk (95% CI: 1.29-1.84).ConclusionWe found a positive relationship between alcohol consumption and breast cancer risk, suggesting that this modifiable risk factor should be addressed in breast cancer prevention programs in Africa.
| S-EPMC4157846 | biostudies-literature
Project description:More than 90% of children in Africa are infected with cytomegalovirus (CMV) by the age of 12 months. However, the high-frequency, immunodominant CD8+ T-cell responses that control CMV infection have not been well studied in African populations. We therefore sought to define the immunodominant CMV-specific CD8+ T-cell responses within sub-Saharan African study subjects. Among 257 subjects, we determined the CD8+ T-cell responses to overlapping peptides spanning three of the most immunogenic CMV proteins, pp65, IE-1 and IE-2, using IFN-? ELISpot assays. A bioinformatics tool was used to predict optimal epitopes within overlapping peptides whose recognition was statistically associated with expression of particular HLA class I molecules. Using this approach, we identified 16 predicted novel CMV-specific epitopes within CMV-pp65, IE-1 and IE-2. The immunodominant pp65-specific, IE-1, IE-2 responses were all either previously well characterised or were confirmed using peptide-MHC tetramers. The novel epitopes identified included an IE-2-specific epitope restricted by HLA*B*44:03 that induced high-frequency CD8+ T-cell responses (mean 3.4% of CD8+ T-cells) in 95% of HLA-B*44:03-positive subjects tested, in one individual accounting for 18.8% of all CD8+ T-cells. These predicted novel CMV-specific CD8+ T-cell epitopes identified in an African cohort will facilitate future analyses of immune responses in African populations where CMV infection is almost universal during infancy.
| S-EPMC5726643 | biostudies-literature
Project description:The CYP2D6 gene has been widely studied to characterize variants and/or star alleles, which account for a significant portion of variability in drug responses observed within and between populations. However, African populations remain under-represented in these studies. The increasing availability of high coverage genomes from African populations has provided the opportunity to fill this knowledge gap. In this study, we characterized computationally predicted novel CYP2D6 star alleles in 30 African subjects for whom DNA samples were available from the Coriell Institute. CYP2D6 genotyping and resequencing was performed using a variety of commercially available and laboratory-developed tests in a collaborative effort involving three laboratories. Fourteen novel CYP2D6 alleles and multiple novel suballeles were identified. This work adds to the growing catalogue of validated African ancestry CYP2D6 allelic variation in pharmacogenomic databases, thus laying the foundation for future functional studies and improving the accuracy of CYP2D6 genotyping, phenotype prediction, and the refinement of clinical pharmacogenomic implementation guidelines in African and global settings.
| S-EPMC9605556 | biostudies-literature
Project description:Background and objectivesRecessive inheritance of African-specific APOL1 kidney risk variants is associated with higher risk of nondiabetic kidney disease, progression to kidney failure, and early-onset albuminuria that precedes eGFR decline. The effect of APOL1 risk variants on kidney disease in continental Africans is understudied. Objectives of this study were to determine APOL1 risk allele prevalence and associations between APOL1 genotypes and kidney disease in West, East, and South Africa.Design, setting, participants, & measurementsThis cross-sectional population-based study in four African countries included 10,769 participants largely aged 40-60 years with sociodemographic and health information, anthropometry data, and blood and urine tests for biomarkers of kidney disease. APOL1 risk alleles were imputed from the H3Africa genotyping array, APOL1 risk allele and genotype frequencies were determined, and genetic associations were assessed for kidney disease. Kidney disease was defined as the presence of eGFR <60 ml/min per 1.73 m2, albuminuria, or a composite end point including eGFR <60 ml/min per 1.73 m2 and/or albuminuria.ResultsHigh G1 allele frequencies occurred in South and West Africa (approximately 7%-13%). G2 allele frequencies were highest in South Africa (15%-24%), followed by West Africa (9%-12%). Associations between APOL1 risk variants and albuminuria were significant for recessive (odds ratio, 1.63; 95% confidence interval, 1.25 to 2.12) and additive (odds ratio, 1.39; 95% confidence interval, 1.09 to 1.76) models. Associations were stronger for APOL1 G1/G1 genotypes versus G0/G0 (odds ratio, 3.87; 95% confidence interval, 2.16 to 6.93) compared with either G2/G2 (odds ratio, 1.65; 95% confidence interval, 1.09 to 2.51) or G1/G2 (odds ratio, 1.24; 95% confidence interval, 0.83 to 1.87). No association between APOL1 risk variants and eGFR <60 ml/min per 1.73 m2 was observed.ConclusionsAPOL1 G1 and G2 alleles and high-risk genotype frequencies differed between and within West and South Africa and were almost absent from East Africa. APOL1 risk variants were associated with albuminuria but not eGFR <60 ml/min per 1.73 m2. There may be differential effects of homozygous G1 and G2 genotypes on albuminuria that require further investigation.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_05_16_CJN14321121.mp3.
| S-EPMC9269651 | biostudies-literature
Project description:Breast Cancer genetic study in African ancestry populations
| PRJNA700713 | ENA
Project description:Breast Cancer genetic study in African ancestry populations
| PRJNA700712 | ENA
Project description:We examined the geospatial dimension of delays to diagnosis of breast cancer in a prospective study of 1541 women newly diagnosed in the African Breast Cancer-Disparities in Outcomes (ABC-DO) Study. Women were recruited at cancer treatment facilities in Namibia, Nigeria, Uganda and Zambia. The baseline interview included information used to generate the geospatial features: urban/rural residence, travel mode to treatment facility and straight-line distances from home to first-care provider and to diagnostic/treatment facility, categorized into country/ethnicity (population)-specific quartiles. These factors were investigated in relation to delay in diagnosis (≥3 months since first symptom) and late stage at diagnosis (TNM: III, IV) using logistic regression, adjusted for population group and sociodemographic characteristics. The median (interquartile range) distances to first provider and diagnostic and treatment facilities were 5 (1-37), 17 (3-105) and 62 (5-289) km, respectively. The majority had a delay in diagnosis (74%) and diagnosis at late stage (64%). Distance to first provider was not associated with delay in diagnosis or late stage at diagnosis. Rural residence was associated with delay, but the association did not persist after adjustment for sociodemographic characteristics. Distance to the diagnostic/treatment facility was associated with delay (highest vs lowest quartile: odds ratio (OR) = 1.56, 95% confidence interval (CI) = 1.08-2.27) and late stage (overall: OR = 1.47, CI = 1.05-2.06; without Nigerian hospitals where mostly local residents were treated: OR = 1.73, CI = 1.18-2.54). These findings underscore the need for measures addressing the geospatial barriers to early diagnosis in sub-Saharan African settings, including providing transport or travel allowance and decentralizing diagnostic services.
| S-EPMC8048597 | biostudies-literature