Exome sequencing identifies SLC36A4 and SLC4A8 as novel genes influencing the distribution of HDL-cholesterol in West Africans and African Americans.
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Date
2015
Authors
Bentley, A.R.
Shriner, D.
Tekola Ayele, F.
Doumatey, A.P.
Mullikin, J.C.
NISC
Adebamowo, C.
Oli, J.
Fasanmade, O.
Johnson, T.
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Much of the genetic epidemiology of high-density lipoprotein cholesterol (HDLC) in individuals of African ancestry has focused on replicating findings identified in those of European ancestry, an approach which may miss African ancestry-specific variation. Also, HDLC is influenced by both genetic and non-genetic factors, motivating study of individuals with similar ancestry living in different environments, such as West Africans (WA) and African Americans (AA). We conducted whole exome sequencing on individuals at the extremes (5th and 95th percentiles) of the HDLC distribution of samples of WA (n=98 [low], n=100 [high]) and AA (n=57 [low], n=60 [high]). Consistent with previous observations, the mean HDLC was lower in WA than AA (low: 19 vs. 27 mg/dl; high: 75 vs. 96 mg/dl). Common variants (MAF > 0.05) were analyzed in regression models of risk of being in the low group after adjustment for age, sex, and the first principal component. No variants reached statistical significance in the analysis of either WA or AA. We conducted gene-based analysis using SKAT with covariates as described above and statistical significance set at p=2.3 × 10-6 (α=0.05/21,711 genes). Among the WA, SLC36A4 (solute carrier family 36 (proton /amino acid symporter) member 4 was associated with low HDLC (p=1.6 × 10-7). Variants in this gene were not associated with HDLC among AA, but variants in a different solute carrier, SLC4A8, were (p=3.9 × 10-7). Adjusting for body mass index reduced the statistical significance of the SLC4A8 association in AA (p=1.0 × 10-3), but had virtually no effect on the SLC36A4 association in WA. To our knowledge, this is the first report of the contribution of either SLC4A8 or SLC36A4 to HDLC distribution. The different findings among WA and AA despite ~80% genome-wide shared ancestry are of interest. A potential explanation is that the variants interrogated were not identical in the two groups (e.g., only 77% of the SLC36A4 and 52% of the SLC4A8 variants were observed in both WA and AA samples). Alternatively, the differences may result from the European admixture in AA or genetic effects that manifest differently depending on the environment (e.g. the obesogenic environment of AA). This work highlights the importance of studying the genetic determinants of HDLC in African ancestry populations, as it may reveal novel mechanisms that contribute to the distribution of this trait.
Description
Poster presented at the 2015 American Society of Human Genetics Annual Meeting held at Baltimore Convention Center, Baltimore, MD from 6th-10th October, 2015.
Keywords
Exome sequencing , SLC36A4 genes , SLC36A8 genes , HDL cholesterol , Africans , African-Americans
Citation
Bentley, A.R., Shriner, D., Tekola-Ayele, F., Doumatey, A.P., Mullikin, J.C., NISC folks, Adebamowo, C., Oli, J., Fasanmade, O.A., Johnson, T., Amoah, A., Agyenim-Boateng, K., Eghan Jr, B.A., Adeyemo, A.A. & Rotimi, C.N. (2015). Exome sequencing identifies SLC36A4 and SLC4A8 as novel genes influencing the distribution of HDL cholesterol in West Africans and African Americans.