Background:
Reperfusion following ischemia due to sudden cardiac arrest (SCA) is necessary for survival, but results in additional injury to affected tissues. Regulation of apoptosis has been shown to be important in determining the extent of reperfusion injury. Caspases (CASP) are essential enzymes in the apoptotic cascade and we therefore hypothesized that genetic variation in these enzymes might influence cardiac and brain resuscitation after SCA. To test this, we examined three genes (CASP2, CASP3, CASP9) in a population-based study of SCA survival.
Methods:
Subjects (mean age 67, 80% male, of European descent) were out-of-hospital SCA patients found in ventricular fibrillation (VF) and attended by paramedics in King County, WA (n=1614). To investigate cardiac resuscitation, we compared subjects who survived to hospital admission (n=827) with those who did not (n=787); for brain resuscitation, we compared subjects who survived to hospital discharge (n=448) with those who did not (n=1166). Associations of 19 SNPs were examined using logistic regression comparing each additional copy of the minor allele. Based on
a priori
hypotheses, models were adjusted for: age; gender; time from 911 call to arrival of emergency medical services; whether the event was witnessed; occurred in public; and whether bystander CPR was administered. We used within-gene permutation tests to adjust p-values for multiple comparisons.
Results:
Two SNPs in CASP3 were associated with SCA survival. The A allele of rs4647688 (minor allele frequency (MAF) 0.20) was associated with lower rates of survival to hospital admission (OR (95% CI), adjusted p-value: 0.78 (0.65, 0.93),
p
=0.043). The T allele of rs2705897 (MAF 0.26) was associated with a higher rate of survival to hospital admission (1.27 (1.07, 1.51),
p
=0.049). These two SNPs are in almost complete linkage equilibrium (r
2
=0.091). No SNPs in CASP3 were significantly associated with survival to hospital discharge, and no SNPs in CASP2 or CASP9 were significantly associated with either outcome.
Conclusions:
CASP3 variants are associated with SCA survival in this population. Further work is needed to explore the effect of these variants on regulation of apoptosis during reperfusion following VF arrest, and to replicate these findings in other populations.