Genetic variants from lipid-related pathways and risk for incident myocardial infarction

Abstract

Background: Circulating lipids levels, as well as several familial lipid metabolism disorders, are strongly associated with initiation and progression of atherosclerosis and incidence of myocardial infarction (MI).

Objectives: We hypothesized that genetic variants associated with circulating lipid levels would also be associated with MI incidence, and have tested this in three independent samples.

Setting and subjects: Using age- and sex-adjusted additive genetic models, we analyzed 554 single nucleotide polymorphisms (SNPs) in 41 candidate gene regions proposed to be involved in lipid-related pathways potentially predisposing to incidence of MI in 2,602 participants of the Swedish Twin Register (STR; 57% women). All associations with nominal P<0.01 were further investigated in the Uppsala Longitudinal Study of Adult Men (ULSAM; N = 1,142).

Results: In the present study, we report associations of lipid-related SNPs with incident MI in two community-based longitudinal studies with in silico replication in a meta-analysis of genome-wide association studies. Overall, there were 9 SNPs in STR with nominal P-value <0.01 that were successfully genotyped in ULSAM. rs4149313 located in ABCA1 was associated with MI incidence in both longitudinal study samples with nominal significance (hazard ratio, 1.36 and 1.40; P-value, 0.004 and 0.015 in STR and ULSAM, respectively). In silico replication supported the association of rs4149313 with coronary artery disease in an independent meta-analysis including 173,975 individuals of European descent from the CARDIoGRAMplusC4D consortium (odds ratio, 1.03; P-value, 0.048).

Conclusions: rs4149313 is one of the few amino acid changing variants in ABCA1 known to associate with reduced cholesterol efflux. Our results are suggestive of a weak association between this variant and the development of atherosclerosis and MI.

Figure 1. Kaplan-Meier survival function for rs4149313 and survival of MI in STR (A) and ULSAM (B).

Survival function of MI for individuals having no (A/A; blue line); one (A/G; red line) or two (G/G; green line) risk alleles at ABCA1 rs4149313 locus.

Figure 2. Forest plot for independent replication of association between rs4149313 and CAD in CARDIoGRAMplusC4D.

Fixed-effect meta-analysis was applied for effect of rs4149313 on CAD in CARDIoGRAMplusC4D consortium. The diamond in the bottom represents the confidence interval of this independent replication.

Figure 3. Region plot of the ABCA1 locus (chromosome 9 co-ordinates 106157871–107157392) in the Swedish Twin Registry.

The SNP rs4149313 with the strongest association is marked by a bright blue diamond. Each rhomb represents a SNP and the brightness represents the extent of linkage disequilibrium with the lead SNP. The recombination rates are marked with yellow lines. Relevant genes and genomic coordinates are shown below the plots. Plots were generated using SNAP (http://www.broadinstitute.org/mpg/snap/ldplot.php. Accessed 2013 Mar 1.) and based on HapMap CEU release 22, NCBI B36 assembly, dbSNP build 126.