title: Molecular pathways associated with blood pressure and hexadecanedioate levels.
abstract: 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.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom.
authors.forename: Cristina
authors.identifier: http://orcid.org/0000-0001-9790-0571
authors.initials: C
authors.lastname: Menni
authors.affiliation: Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Metrustry
authors.affiliation: Cardiology, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Ehret
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.affiliation: Department of Clinical Pharmacology, King's College London, London, United Kingdom.
authors.forename: Phil
authors.initials: P
authors.lastname: Chowienczyk
authors.affiliation: Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.affiliation: Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom.|Academic Rheumatology Clinical Sciences Building, Nottingham City Hospital, Nottingham, United Kingdom.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects; D001794:Blood Pressure; D002460:Cell Line; D005260:Female; D015870:Gene Expression; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000235:genetics*; D010169:Palmitic Acids / Q000097:blood*; D020641:Polymorphism, Single Nucleotide
chemical_list: D010169:Palmitic Acids; C012346:hexadecanedioic acid