Abstract 17372: Are There Any Causal Relations Between Growth Differentiation Factor 15 and Outcomes in Patients With Acute Coronary Syndrome? - A Report From the Plato Gwas Study
Background: Levels of growth differentiation factor 15 (GDF-15) are strongly associated with cardiovascular outcomes in patients with acute coronary syndrome. We hypothesized that there is a relationship between GDF-15 gene polymorphisms and adverse events in patients with coronary artery disease.
Methods: Plasma and whole blood for DNA extraction were obtained at entry in 10013 patients in the PLATO study (mean age 63 years, 31% women). The level of GDF-15 was determined by immunoassay (Roche). SNPs associated with GDF-15 level were identified by a genome wide association study. A Mendelian randomization approach was used to investigate the causal relationship between three GDF-15-related SNPs (rs17725099, rs74180880, rs1055150) and with outcomes.
Results: Levels of GDF-15 were associated with the composite endpoint of CV death, MI and stroke, HR for 1 SD increase in GDF-15: 1.33, 95% CI 1.24-1.43, p<0.0001, and the separate endpoints CV death (HR for 1 SD increase: 1.71, 95% CI 1.56-1.88, p<0.0001), MI (HR for 1 SD increase: 1.15, 95% CI 1.05-1.26, p=0.0039), and non-CABG major bleeding (HR for 1 SD increase: 1.41, 95% CI 1.26-1.58, p<0.0001), but not with stroke. The top hit, rs17725099, was associated with a median GDF-15 concentration of: 1406 ng/L (G/G, n=5644, 56.5%), 1653 ng/L (G/A, n=3714, 37.2%) and 1899 ng/L (A/A, n=611, 6.2%). In models adjusting for base-line characteristics and risk factors for recurrent CV disease, the effect of moving from no minor allele (G/G) to one minor allele (G/A) for rs17725099 was associated with a hazard ratio of 1.26 (95% CI 1.02-1.54, p=0.032) for all-cause mortality and 1.37 (95% CI 1.09-1.71, p=0.007) for non-CABG major bleeding. There were no significant effects of moving from no minor allele (G/G) to two minor alleles (A/A) for the composite end point, however predicted a lower CV mortality rate. No association between rs74180880, rs1055150 and outcomes were detected.
Conclusion: Despite the strong associations between circulating GDF-15 levels and outcomes and between gene polymorphisms and GDF-15 levels, there were no clear evidence of associations between genetic regulation of GDF-15 and CV outcomes. Further studies are warranted to investigate the associations between GDF-15 gene polymorphism and CV outcome.
- © 2013 by American Heart Association, Inc.