Menni Cristina, Metrustry Sarah J, Ehret Georg, Dominiczak Anna F, Chowienczyk Phil, Spector Tim D, Padmanabhan Sandosh, Valdes Ana M
Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom.
Cardiology, Geneva University Hospital, Geneva, Switzerland.
PLoS One. 2017 Apr 12;12(4):e0175479. doi: 10.1371/journal.pone.0175479. eCollection 2017.
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.
二元羧酸十六烷二酸与人类血压升高和死亡率增加有关，给大鼠喂食十六烷二酸会使其血压升高。在此，我们旨在通过基因和转录组学研究来确定影响与血压调节相关的十六烷二酸水平的分子途径。在对来自双胞胎英国队列和KORA队列的6447名个体进行的全基因组关联研究（GWAS）中，针对十六烷二酸的顶级关联，在国际血压联盟以及极端血压的GWAS中，测试了其与血压和高血压的关联。进一步对740名双胞胎英国参与者的脂肪组织中十六烷二酸与基因表达水平进行了转录组分析。GWAS显示242个单核苷酸多态性（SNP）映射到两个独立位点并达到全基因组显著性。在SCLO1B1基因中的rs414056（β（标准误）=-0.088（0.006），P = 1.65×10 - 51，P <1×10 - 51）中，先前与他汀类药物相关肌病风险增加相关的等位基因与较高的十六烷二酸水平相关。然而，该SNP与血压或高血压无关联。第二个位点rs6663731中的顶级SNP映射到1号染色体上CYP4Z2P的内含子区域（0.045（0.007），P = 5.49×10 - 11）。十六烷二酸水平还与4个CYP4探针中的3个以及乙醇脱氢酶探针的脂肪组织基因表达相关（P<0.05）（β（标准误）= 0.12（0.02）；P = 6.04×10 - 11）。高循环水平的十六烷二酸决定了酒精摄入对血压有显著影响（收缩压：1.12（0.34），P = 0.001；舒张压：0.70（0.22），P = 0.002），而在低十六烷二酸水平组中未观察到影响。总之，ω氧化途径中编码ADH1A、ADH1B和CYP4的酶在脂肪中的水平与十六烷二酸水平相关。十六烷二酸似乎调节酒精对血压的影响。
