Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the CHARGE Consortium

Background —Prognosis and survival are significant concerns for individuals with heart failure (HF). In order to better understand the pathophysiology of HF prognosis, the association between 2,366,858 single nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from four community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. Methods and Results —Participants were 2,526 individuals of European ancestry and 466 individuals of African ancestry who suffered an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the four study populations of European ancestry (N=1,645 deaths) and for the two populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10 -7 . Meta-analytic findings among individuals of European ancestry revealed one genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 ( CMTM7 , p = 3.2x10 -7 ). Eight additional loci in individuals of European ancestry and four loci in individuals of African ancestry were identified by high-signal SNPs (p -5 ), but did not meet genome-wide significance. Conclusions —This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.