ET (Endothelin)-1 and Ischemic Heart Disease: A Mendelian Randomization Study.

Abstract

ET (endothelin)-1 is a vasoconstrictive peptide. ET receptor antagonists are used to treat pulmonary hypertension. Whether ET-1 is a target of intervention in cardiovascular disease or a symptom of vascular damage is unclear. A genetic variant promoting ET-1 expression was recently found positively associated with ischemic heart disease (IHD).1 Here, we used separate sample Mendelian randomization (MR), that is, instrumental variable analysis with genetic instruments, to assess whether ET-1 is associated with IHD and for completeness with myocardial infarction (MI) and some of their major risk factors. We obtained 3 single nucleotide polymorphisms (SNPs; rs4253238 [ KLKB1 ], rs2731672 [ F12 ], and rs5370 [ EDN1 ]) strongly ( P value<5×10−8) and independently ( r 2<0.01) associated with CT-pro-ET-1 (C-terminal-pro-endothelin-1), a biomarker of ET-1, from a genome-wide association study in 6674 people of European ancestry, mean age 49 years, 47% men, adjusted for age and sex, with no evidence of population stratification.2 These 3 SNPs explained 14.3% of the variance in CT-pro-ET-1.2 rs2731672 was not available for all outcomes, so was replaced with a correlated ( r 2=0.93 using LDlink with 1000 Genomes catalog for Europeans) proxy, rs2545801 ( F12 ). We applied these genetic predictors of CT-pro-ET-1 to the largest publically available extensively genotyped IHD case (n≤76014)–control (n≤264785) study (largely based on the UK Biobank SOFT CAD, CARDIoGRAMplusC4D 1000 Genomes, and the MIGen/CARDIoGRAM Exome chip study) …