Abstract P141: A Novel GWAS Locus Influences Microvascular Response to Acute Psychological Stress

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Background: Excessive peripheral microvascular constriction during acute psychological stress, measured using peripheral arterial tonometry reflects similar changes in coronary blood flow and is a predictor of adverse cardiovascular outcomes. The ratio of digital pulse wave amplitude during stress compared to rest (sPAT) is used to estimate the degree of microvascular response to stress. We sought to determine if genetic factors contribute to the degree of microvascular constriction during mental stress. Methods: A total of 642 post-MI and stable CAD subjects from two prospective cohort studies underwent mental stress testing with a standardized public speaking stressor. Digital pulse wave amplitude was continuously measured using PAT and the stress/rest PAT ratio (sPAT) of pulse wave amplitude during mental stress/baseline was calculated. Genotyping was performed using Illumina’s Multi-Ethnic Genotyping Array (MEGA) platform and imputed to the 1000 Genome reference panel. Race stratified genome-wide association studies (GWAS) of sPAT were conducted using linear regression of additive genetic mode adjusted for age, sex and population stratification in the two cohorts. A trans-ethnic meta-analysis integrated the four sets GWAS results. Results: Mean age was 63±9; 65% male, 35% Black. We identified two SNPs in linkage disequilibrium on chr4:185503564 and chr4:185491706 rs13353812 (with 35% and 28% allele frequency, respectively) that were associated with greater sPAT ratio ( P = 1.42E-08). The mean sPAT ratio during mental stress for subjects with none, one and two AT insertion alleles of SNP chr4:185503564 were 0.67, 0.76 and 0.93, respectively, an average of 12% (P < 0.001), per allele. Results were similar for G insertion alleles of SNP rs13353812. The nearest gene of the sPAT-associated locus is CASP3 which encodes caspase, an essential protein for apoptosis signaling and brain and hematopoietic stem cell development. Conclusion: We have identified a genetic basis for stress-induced vasomotion. Presence of the chr4:185503564 allele is associated with less vasoconstriction during mental stress, and thus may be protective against long term cardiovascular risk. These findings need further exploration.