Genetics of hypertension: Implications of single nucleotide polymorphism(s) in African populations and beyond.
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ABSTRACT:
SUBMITTER: Skeete J
PROVIDER: S-EPMC8031023 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The continuing decline in forest elephant (Loxodonta cyclotis) numbers due to poaching and habitat reduction is driving the search for new tools to inform management and conservation. For dense rainforest species, basic ecological data on populations and threats can be challenging and expensive to collect, impeding conservation action in the field. As such, genetic monitoring is being increasingly implemented to complement or replace more burdensome field techniques. Single-nucleotide polymorphisms (SNPs) are particularly cost-effective and informative markers that can be used for a range of practical applications, including population census, assessment of human impact on social and genetic structure, and investigation of the illegal wildlife trade. SNP resources for elephants are scarce, but next-generation sequencing provides the opportunity for rapid, inexpensive generation of SNP markers in nonmodel species. Here, we sourced forest elephant DNA from 23 samples collected from 10 locations within Gabon, Central Africa, and applied double-digest restriction-site-associated DNA (ddRAD) sequencing to discover 31,851 tags containing SNPs that were reduced to a set of 1,365 high-quality candidate SNP markers. A subset of 115 candidate SNPs was then selected for assay design and validation using 56 additional samples. Genotyping resulted in a high conversion rate (93%) and a low per allele error rate (0.07%). This study provides the first panel of 107 validated SNP markers for forest elephants. This resource presents great potential for new genetic tools to produce reliable data and underpin a step-change in conservation policies for this elusive species.
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Project description:Pharmacogenomics aims to reveal variants associated with drug response phenotypes. Genes whose roles involve the absorption, distribution, metabolism, and excretion of drugs, are highly polymorphic between populations. High coverage whole genome sequencing showed that a large proportion of the variants for these genes are rare in African populations. This study investigated the impact of such variants on protein structure to assess their functional importance. We used genetic data of CYP3A5 from 458 individuals from sub-Saharan Africa to conduct a structural bioinformatics analysis. Five missense variants were modeled and microsecond scale molecular dynamics simulations were conducted for each, as well as for the CYP3A5 wildtype and the Y53C variant, which has a known deleterious impact on enzyme activity. The binding of ritonavir and artemether to CYP3A5 variant structures was also evaluated. Our results showed different conformational characteristics between all the variants. No significant structural changes were noticed. However, the genetic variability seemed to act on the plasticity of the protein. The impact on drug binding might be drug dependant. We concluded that rare variants hold relevance in determining the pharmacogenomics properties of populations. This could have a significant impact on precision medicine applications in sub-Saharan Africa.
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Project description:Hypertension, including secondary and essential hypertension (EH) variants, is a multifactorial disease, affecting more than one billion people worldwide. Secondary hypertension results from mutations in the putative gene KLHL3 (Kelch-like protein 3); however, it has not been reported whether the KLHL3 gene polymorphisms are associated with EH. Here, we investigated the association between KLHL3 (rs2301708 and rs7444370) polymorphisms and EH in the Chinese Han population.This case-control study included 522 subjects-260 patients with EH and 262 normotensive controls matched for age, gender, body mass index (BMI), hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), and levels of Na, K, and Cl. The distribution of functional rs2301708 and rs7444370 polymorphisms within the KLHL3 gene was assessed through polymerase chain reaction (PCR) and restriction-fragment length polymorphism (RFLP).There was no significant difference in allelic and genotypic frequencies of KLHL3 rs2301708 between the EH and normotensive groups; however, the rs7444370 T allele and CT genotype in females was significantly associated with a protective effect against EH (P = .001, P = .002; P = .019, P = .052), and the haplotype CT of rs2301708 and rs7444370 among females in the EH group was less than in the normotensive group (P = .000; P = .007).The KLHL3 rs7444370 variant could be a protective factor in the pathogenesis of females' EH.
| S-EPMC6531237 | biostudies-literature
Project description:As the ancestral homeland of our species, Africa contains elevated levels of genetic diversity and substantial population structure. Importantly, African genomes are heterogeneous: They contain mixtures of multiple ancestries, each of which have experienced different evolutionary histories. In this review, we view population genetics through the lens of admixture, highlighting how multiple demographic events have shaped African genomes. Each of these historical vignettes paints a recurring picture of population divergence followed by secondary contact. First, we give a brief overview of genetic variation in Africa and examine deep population structure within Africa, including the evidence of ancient introgression from archaic "ghost" populations. Second, we describe the genetic legacies of admixture events that have occurred during the past 10,000 years. This includes gene flow between different click-speaking Khoe-San populations, the stepwise spread of pastoralism from eastern to southern Africa, multiple migrations of Bantu speakers across the continent, as well as admixture from the Middle East and Europe into the Sahel region and North Africa. Furthermore, the genomic signatures of more recent admixture can be found in the Cape Peninsula and throughout the African diaspora. Third, we highlight how natural selection has shaped patterns of genetic variation across the continent, noting that gene flow provides a potent source of adaptive variation and that selective pressures vary across Africa. Finally, we explore the biomedical implications of population structure in Africa on health and disease and call for more ethically conducted studies of genetic variation in Africa.
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Project description:Primary Objective:
Correlation of the skin and/or eye toxicity grade secondary to Cetuximab or Panitumumab and the SNP profile of the Epidermal Growth Factor Receptor (EGFR) domain III region.
Secondary Objectives:
Correlation of SNP profile with indicators of tumour response parameters, such as radiological response, duration of response, time to progression (TTP), overall survival (OS) time, incidence of non-dermatological adverse events.
| 2135070 | ecrin-mdr-crc
Project description:IntroductionAfrican Americans have a higher incidence of venous thromboembolism (VTE) than European descent individuals. However, the typical genetic risk factors in populations of European descent are nearly absent in African Americans, and population-specific genetic factors influencing the higher VTE rate are not well characterized.MethodsWe performed a candidate gene analysis on an exome-sequenced African American family with recurrent VTE and identified a variant in Protein S (PROS1) V510M (rs138925964). We assessed the population impact of PROS1 V510M using a multicenter African American cohort of 306 cases with VTE compared to 370 controls. Additionally, we compared our case cohort to a background population cohort of 2203 African Americans in the NHLBI GO Exome Sequencing Project (ESP).ResultsIn the African American family with recurrent VTE, we found prior laboratories for our cases indicating low free Protein S levels, providing functional support for PROS1 V510M as the causative mutation. Additionally, this variant was significantly enriched in the VTE cases of our multicenter case-control study (Fisher's Exact Test, P = 0.0041, OR = 4.62, 95% CI: 1.51-15.20; allele frequencies - cases: 2.45%, controls: 0.54%). Similarly, PROS1 V510M was also enriched in our VTE case cohort compared to African Americans in the ESP cohort (Fisher's Exact Test, P = 0.010, OR = 2.28, 95% CI: 1.26-4.10).ConclusionsWe found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case-control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population-specific genetic risk factor for VTE in African Americans.
| S-EPMC5023936 | biostudies-literature
Project description:Hypertension is the leading cause of cardiovascular disease in the United States, affecting up to one-third of adults. When compared to other ethnic or racial groups in the United States, African Americans and other people of African descent show a higher incidence of hypertension and its related comorbidities; however, the genetics of hypertension in these populations has not been studied adequately. Several genes have been identified to play a role in the genetics of hypertension. They include genes regulating the renin-aldosterone-angiotensin system (RAAS), such as Sodium Channel Epithelial 1 Beta Subunit (SCNN1B), Armadillo Repeat Containing 5 (ARMC5), G Protein-Coupled Receptor Kinase 4 (GRK4), and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D). In this review, we focus on recent genetic findings available in the public domain for potential differences between African Americans and other populations. We also cover some recent and relevant discoveries in the field of low-renin hypertension from our laboratory at the National Institutes of Health. Understanding the different genetics of hypertension among various groups is essential for effective precision-guided medical therapy of high blood pressure.
| S-EPMC6429313 | biostudies-literature