Molecular pathways associated with blood pressure and hexadecanedioate levels

Menni, C., Metrustry, S. J., Ehret, G., Dominiczak, A. F. , Chowienczyk, P., Spector, T. D., Padmanabhan, S. and Valdes, A. M. (2014) Molecular pathways associated with blood pressure and hexadecanedioate levels. PLoS ONE, 12(4), e0175479. (doi: 10.1371/journal.pone.0175479) (PMID:28403188) (PMCID:PMC5389832)

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The dicarboxylic acid hexadecanedioate is associated with increased blood pressure (BP) and mortality in humans and feeding it to rats raises BP. Here we aim to characterise the molecular pathways that influence levels of hexadecanedioate linked to BP regulation, using genetic and transcriptomic studies. The top associations for hexadecanedioate in a genome-wide association scan (GWAS) conducted on 6447 individuals from the TwinsUK and KORA cohorts were tested for association with BP and hypertension in the International Consortium for BP and in a GWAS of BP extremes. Transcriptomic analyses correlating hexadecanedioate with gene expression levels in adipose tissue in 740 TwinsUK participants were further performed. GWAS showed 242 SNPs mapping to two independent loci achieving genome-wide significance. In rs414056 in the SCLO1B1 gene (Beta(SE) = -0.088(0.006)P = 1.65 x 10−51, P < 1 x 10−51), the allele previously associated with increased risk of statin associated myopathy is associated with higher hexadecanedioate levels. However this SNP did not show association with BP or hypertension. The top SNP in the second locus rs6663731 mapped to the intronic region of CYP4Z2P on chromosome 1 (0.045(0.007), P = 5.49x10-11). Hexadecanedioate levels also correlate with adipose tissue gene-expression of the 3 out of 4 CYP4 probes (P<0.05) and of alcohol dehydrogenase probes (Beta(SE) = 0.12(0.02); P = 6.04x10-11). High circulating levels of hexadecanedioate determine a significant effect of alcohol intake on BP (SBP: 1.12(0.34), P = 0.001; DBP: 0.70(0.22), P = 0.002), while no effect is seen in the lower hexadecanedioate level group. In conclusion, levels in fat of ADH1A, ADH1B and CYP4 encoding enzymes in the omega oxidation pathway, are correlated with hexadecanedioate levels. Hexadecanedioate appears to regulate the effect of alcohol on BP.

Item Type:Articles
Keywords:Research Article, Biology and life sciences, Medicine and health sciences, Social sciences, Physical sciences
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna
Authors: Menni, C., Metrustry, S. J., Ehret, G., Dominiczak, A. F., Chowienczyk, P., Spector, T. D., Padmanabhan, S., and Valdes, A. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN (Online):1932-6203
Published Online:12 April 2017
Copyright Holders:Copyright © 2017 Menni et al.
First Published:First published in PLoS ONE 12(4):e0175479
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
676621Ancestry and biological informative markers for stratification of hypertension - The AIM HY studySandosh PadmanabhanMedical Research Council (MRC)MR/M016560/1RI CARDIOVASCULAR & MEDICAL SCIENCES
464051Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies.Anna DominiczakBritish Heart Foundation (BHF)RG/07/005/23633RI CARDIOVASCULAR & MEDICAL SCIENCES