title: Frequency variation among sub-Saharan populations in virus restriction gene, BST-2 proximal promoter polymorphisms: implications for HIV-1 prevalence differences among African countries.
abstract: The present study reports promoter variants in four sub-Saharan African populations that may affect BST-2 gene regulation. Recently, an in/del within the BST-2 promoter has been associated with HIV-1 disease progression in a Spanish cohort. Hence, we sequenced the proximal promoter region of the BST-2 gene in 581 individuals from South Africa, Zimbabwe, Malawi, and Cameroon. Seven SNPs were identified: rs28413176 (+26i6/Δ6); rs28413175 (-160i1/Δ1), -187A>G (nucleotide position -17516614); rs28413174 (-193G>A); rs73921425 (-199G>A); rs12609479 (-201C>T); and rs112492472 (-225C>T). The -199A and -225T alleles showed interesting trends across the sub-Saharan continent. Using predictive bioinformatics tools, we show that allelic variation at -199 and -201 potentially affect key transcription factor binding sites including bHLH, c-Myb, and E47. Importantly, data available from the ENCODE study gave further credence to our hypothesis of transcriptional regulation of BST-2 by a bHLH TF such as Mxi1. The possible repressive transcriptional effect of Mxi1 combined with the allelic frequency trend seen at -199 between African populations overlays well with current HIV-1 prevalence data, and may be a contributing factor to this phenomenon. The differences in HIV-1 prevalence in African countries could be, in part, due to distribution of genetic variants that affect susceptibility to HIV-1. Our findings therefore have substantive value for the design of future diagnostics for global health oriented diagnostics for HIV-1 susceptibility, and rational therapeutics on the critical path to personalized medicine in the African continent. As HIV-1 epidemiology vastly impacts human populations around the world, the population genomics strategy we have utilized herein can have value for other global regions as well.
authors.affiliation: 1 Division of Human Genetics, Faculty of Health Sciences, University of Cape Town , Observatory, Cape Town, South Africa .
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Skelton
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Kampira
authors.forename: Ambroise A
authors.initials: AA
authors.lastname: Wonkam
authors.forename: Kudakwashe K
authors.initials: KK
authors.lastname: Mhandire
authors.forename: Johnstone J
authors.initials: JJ
authors.lastname: Kumwenda
authors.forename: Kerina K
authors.initials: KK
authors.lastname: Duri
authors.forename: Collet C
authors.initials: CC
authors.lastname: Dandara
mesh_terms: D017954:Africa South of the Sahara / Q000453:epidemiology; D000483:Alleles; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D044383:Black People / Q000235:genetics; D015331:Cohort Studies; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000453:epidemiology* / Q000235:genetics*; D015497:HIV-1; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D015995:Prevalence; D011401:Promoter Regions, Genetic; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2