Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium

Abstract

Background: Prognosis and survival are significant concerns for individuals with heart failure (HF). 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 4 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 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced 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 4 study populations of European ancestry (N=1645 deaths) and for the 2 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 1 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 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-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.

Figure 1

Plot of the expected and observed -log P-values from analyses of participants of European ancestry.

Figure 2

Among participants of European ancestry, the -log P-value of the additive genetic model for each SNP with a study size-weighted average minor allele frequency of greater than or equal to 3%, according to location in the 22 autosomal chromosomes. Horizontal line indicates the 5.0×10^-7 threshold of genome-wide significance.

Figure 3

Regional association plot for the genome-wide significant marker, rs12638540, in individuals of European ancestry. The top marker is presented in black font and neighboring variants are presented in different colors based on linkage disequilibrium: yellow: r² ≥ 0.2 and < 0.5; and white: r < 0.2. There were no SNPs in the area with LD ≥ 0.5 with the top marker.

Figure 4

Meta-analysis and study-specific hazards ratios and confidence intervals (α=5.0×10^-7) for rs12638540 associated with all-cause mortality in individuals of European ancestry.

Figure 5

Plot of the expected and observed -log P-values from analyses of participants of African ancestry.

Figure 6

Among participants of African ancestry, the -log P-value of the additive genetic model for each SNP with a study size-weighted average minor allele frequency of greater than or equal to 13.5%, according to location in the 22 autosomal chromosomes. Horizontal line indicates the 5.0×10^-7 threshold of genome-wide significance.