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

<div><p>Survival bias may unduly impact genetic association with complex diseases; gene-specific survival effects may further complicate such investigations. Coronary artery disease (CAD) is a complex phenotype for which little is understood about gene-specific survival effects; yet, such information can offer insight into refining genetic associations, improving replications, and can provide candidate genes for both mortality risk and improved survivorship in CAD. Building on our previous work, the purpose of this current study was to: evaluate <i>LSAMP</i> SNP-specific hazards for all-cause mortality post-catheterization in a larger cohort of our CAD cases; and, perform additional replication in an independent dataset. We examined two <i>LSAMP</i> SNPs—rs1462845 and rs6788787—using CAD case-only Cox proportional hazards regression for additive genetic effects, censored on time-to-all-cause mortality or last follow-up among Caucasian subjects from the Catheterization Genetics Study (CATHGEN; <i>n</i> = 2,224) and the Intermountain Heart Collaborative Study (IMHC; <i>n</i> = 3,008). Only after controlling for age, sex, body mass index, histories of smoking, type 2 diabetes, hyperlipidemia and hypertension (<i>HR</i> = 1.11, 95%<i>CI</i> = 1.01–1.22, <i>p</i> = 0.032), rs1462845 conferred significantly increased hazards of all-cause mortality among CAD cases. Even after controlling for multiple covariates, but in only the primary cohort, rs6788787 conferred significantly improved survival (<i>HR</i> = 0.80, 95% <i>CI</i> = 0.69–0.92, <i>p</i> = 0.002). Post-hoc analyses further stratifying by sex and disease severity revealed replicated effects for rs1462845: even after adjusting for aforementioned covariates and coronary interventional procedures, males with severe burden of CAD had significantly amplified hazards of death with the minor variant of rs1462845 in both cohorts (<i>HR</i> = 1.29, <i>95% CI</i> = 1.08–1.55, <i>p</i> = 0.00456; replication <i>HR</i> = 1.25, <i>95% CI</i> = 1.05–1.49, <i>p</i> = 0.013). Kaplan-Meier curves revealed unique cohort-specific genotype effects on survival. Additional analyses demonstrated that the homozygous risk genotype (‘A/A’) fully explained the increased hazard in both cohorts. None of the post-hoc analyses in control subjects were significant for any model. This suggests that genetic effects of rs1462845 on survival are unique to CAD presence. This represents formal, replicated evidence of genetic contribution of rs1462845 to increased risk for all-cause mortality; the contribution is unique to CAD case status and specific to males with severe burden of CAD.</p></div

Kaplan–Meier survival curves for IMHC males with severe CAD by genotype for <i>LSAMP</i> SNP rs6788787.

<p><i>X</i>-axis displays the number of days from catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan–Meier survival probability by genotype. A is the minor allele; GG, wild-type genotype (reference; black curve); GA, heterozygous genotype; and AA, risk homozygous genotype (red curve). No significant differences were found in any statistical modeling (data not shown).</p

Kaplan–Meier survival curves for 5a) CATHGEN and 5b) IMHC Caucasian control subjects by genotype for LSAMP SNP rs1462845.

<p><i>X</i>-axis displays the number of days from index catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan-Meier survival probability by genotype. G is the minor allele; AA, wild-type genotype (reference; black curve); AG, heterozygous genotype (blue curve); and GG, risk homozygous genotype (red curve). No significant differences were found in any statistical modeling (data not shown).</p

Kaplan–Meier survival curves for CATHGEN males with severe CAD by genotype for <i>LSAMP</i> SNP rs6788787.

<p><i>X</i>-axis displays the number of days from catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan–Meier survival probability by genotype. A is the minor allele; GG, wild-type genotype (reference; black curve); GA, heterozygous genotype; and AA, risk homozygous genotype (red curve). Only after controlling for covariates was this model significant for reduced hazards of death by genotype (<i>HR</i> = 0.71, <i>95% CI</i> = 0.54–0.93, <i>p</i> = 0.0148, additive genetic model).</p

Kaplan–Meier survival curves for IMHC males with severe CAD by genotype for <i>LSAMP</i> SNP rs6788787.

<p><i>X</i>-axis displays the number of days from catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan–Meier survival probability by genotype. A is the minor allele; GG, wild-type genotype (reference; black curve); GA, heterozygous genotype; and AA, risk homozygous genotype (red curve). This model did not demonstrate significant genotype effects on survival probability (<i>HR</i> = 1.04, <i>95% CI</i> = 0.83–1.29, <i>p</i> = 0.752, additive genetic model).</p

Hazards of Death in Caucasian Control Subjects.

<p>Hazards of Death in Caucasian Control Subjects.</p

Post-hoc Power Analyses.

<p>Post-hoc Power Analyses.</p

Kaplan–Meier survival curves for CATHGEN males with severe CAD by genotype for <i>LSAMP</i> SNP rs1462845.

<p><i>X</i>-axis displays the number of days from index catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan-Meier survival probability by genotype. G is the minor allele; AA, wild-type genotype (reference; black curve); AG, heterozygous genotype (blue curve); and GG, risk homozygous genotype (red curve). Hazards of all-cause mortality were significant for each addition of the G risk allele (<i>HR</i> = 1.39, <i>95% CI</i> = 1.16–1.66, <i>p</i> = 0.0003, additive genetic model).</p

Hazards of Death by SNP (Additive) in Caucasian Males with Severe Burden of CAD.

<p>Hazards of Death by SNP (Additive) in Caucasian Males with Severe Burden of CAD.</p

<i>LSAMP</i> SNP Characteristics.

<p><i>LSAMP</i> SNP Characteristics.</p