The genetic basis for survivorship in coronary artery disease

Abstract

Survivorship is a trait characterized by endurance and virility in the face of hardship. It is largely considered a psychosocial attribute developed during fatal conditions, rather than a biological trait for robustness in the context of complex, age-dependent diseases like coronary artery disease (CAD). The purpose of this paper is to present the novel phenotype, survivorship in CAD as an observed survival advantage concurrent with clinically significant CAD. We present a model for characterizing survivorship in CAD and its relationships with overlapping time- and clinically-related phenotypes. We offer an optimal measurement interval for investigating survivorship in CAD. We hypothesize genetic contributions to this construct and review the literature for evidence of genetic contribution to overlapping phenotypes in support of our hypothesis. We also present preliminary evidence of genetic effects on survival in people with clinically significant CAD from a primary case-control study of symptomatic coronary disease. Identifying gene variants that confer improved survival in the context of clinically appreciable CAD may improve our understanding of cardioprotective mechanisms acting at the gene level and potentially impact patients clinically in the future. Further, characterizing other survival-variant genetic effects may improve signal-to-noise ratio in detecting gene associations for CAD.

Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship

“…A different hazard effect was seen with the rs6788787 variant; the hazards of death in CATHGEN Caucasians were significantly reduced for main effects of the gene ( HR = 0.81, 95% CI = 0.70–0.93, p = 0.0004) and after controlling for covariates ( HR = 0.80, 95% CI = 0.69–0.92, p = 0.002). While these CATHGEN findings were consistent with our pilot analyses of 1,885 CATHGEN subjects [ 11 ], these effects were not replicated in the IMHC dataset.…”

“…Post-hoc power estimates for the rs6788787 variant demonstrate reduced power across both cohorts, influenced by lower MAF and less events in smaller sub-strata groups ( n = 647 and 661 in CATHGEN and IMHC, respectively ( Table 5 ). As we have previously hypothesized [ 11 ], the high rate of sudden cardiac death as the initial presentation of CAD may contribute significantly to a reduction in CAD-related risk alleles in the population; this may influence the ability to adequately detect genetic associations for CAD. We currently do not have data to support an increased minor allele frequency for these LSAMP variants in a sudden cardiac death population; however, others have demonstrated this in silico [ 9 ].…”

“…Sudden death is often the initial presentation of coronary disease: 50% of men and 64% of women who die suddenly of coronary heart disease have had no previous symptoms [ 10 ]. Thus, we have hypothesized a role for survival effects in our case-control gene association studies of coronary artery disease [ 11 ]: those with early-onset, very severe disease, and/or greater familial burden are more likely to experience fatal events earlier in life (and before study capture). Because of the differential survival among cases with CAD and unaffected controls, biases resulting from the unobserved high-risk individuals are likely to affect the results of CAD association studies.…”

“…We previously described a novel phenotype for survivorship in CAD and provided preliminary evidence of survival-variant genetic effects unique to CAD-diagnosed individuals [ 11 ] in a biorepository from the Duke catheterization laboratory [CATHGEN] [ 12 , 13 ]. We demonstrated preliminary evidence of limbic-system associated membrane protein ( LSAMP ) SNP effects on time-to-all-cause mortality unique to sex, CAD case status, and CAD severity in a pilot evaluation of 1,885 subjects [ 11 ]. Building on our previous pilot study [ 11 ], the purpose of this current study was to evaluate select LSAMP SNP-specific hazards for all-cause mortality post-catheterization in a larger cohort of CAD cases and perform additional replication in an independent dataset.…”

“…We demonstrated preliminary evidence of limbic-system associated membrane protein ( LSAMP ) SNP effects on time-to-all-cause mortality unique to sex, CAD case status, and CAD severity in a pilot evaluation of 1,885 subjects [ 11 ]. Building on our previous pilot study [ 11 ], the purpose of this current study was to evaluate select LSAMP SNP-specific hazards for all-cause mortality post-catheterization in a larger cohort of CAD cases and perform additional replication in an independent dataset.…”