Computational analysis of candidate disease genes and variants for Salt-sensitive hypertension in indigenous Southern Africans
KAUST DepartmentComputational Bioscience Research Center (CBRC)
MetadataShow full item record
AbstractMultiple factors underlie susceptibility to essential hypertension, including a significant genetic and ethnic component, and environmental effects. Blood pressure response of hypertensive individuals to salt is heterogeneous, but salt sensitivity appears more prevalent in people of indigenous African origin. The underlying genetics of salt-sensitive hypertension, however, are poorly understood. In this study, computational methods including text- and data-mining have been used to select and prioritize candidate aetiological genes for salt-sensitive hypertension. Additionally, we have compared allele frequencies and copy number variation for single nucleotide polymorphisms in candidate genes between indigenous Southern African and Caucasian populations, with the aim of identifying candidate genes with significant variability between the population groups: identifying genetic variability between population groups can exploit ethnic differences in disease prevalence to aid with prioritisation of good candidate genes. Our top-ranking candidate genes include parathyroid hormone precursor (PTH) and type-1angiotensin II receptor (AGTR1). We propose that the candidate genes identified in this study warrant further investigation as potential aetiological genes for salt-sensitive hypertension. © 2010 Tiffin et al.
CitationTiffin N, Meintjes A, Ramesar R, Bajic VB, Rayner B (2010) Computational Analysis of Candidate Disease Genes and Variants for Salt-Sensitive Hypertension in Indigenous Southern Africans. PLoS ONE 5: e12989. doi:10.1371/journal.pone.0012989.
PublisherPublic Library of Science (PLoS)
PubMed Central IDPMC2946338
- Contrasting associations between aldosterone synthase gene polymorphisms and essential hypertension in blacks and in whites.
- Authors: Zhu H, Sagnella GA, Dong Y, Miller MA, Onipinla A, Markandu ND, MacGregor GA
- Issue date: 2003 Jan
- Patterns of genetic variation in the hypertension candidate gene GRK4: ethnic variation and haplotype structure.
- Authors: Lohmueller KE, Wong LJ, Mauney MM, Jiang L, Felder RA, Jose PA, Williams SM
- Issue date: 2006 Jan
- [A cross-racial analysis on the susceptible gene polymorphisms of salt-sensitive hypertension].
- Authors: Lu JP, Zhang L, Wang W
- Issue date: 2010 Oct
- A population study of ethnic variations in the angiotensin-converting enzyme I/D polymorphism: relationships with gender, hypertension and impaired glucose metabolism.
- Authors: Sagnella GA, Rothwell MJ, Onipinla AK, Wicks PD, Cook DG, Cappuccio FP
- Issue date: 1999 May
- Blood pressure variation in blacks: genetic factors.
- Authors: Grim CE, Robinson M
- Issue date: 1996 Mar
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