Abstract 9989: Integration of Genetics with Metabolomics Identifies a Novel Gene Associated with Risk of Incident Cardiovascular Events: TRAF3IP2
Background: Despite strong heritability, the genetic architecture of cardiovascular (CV) disease remains incompletely characterized. Plasma metabolite concentrations are heritable and have been associated with risk of CV events. We sought to identify novel genes for CV event risk using metabolic profiles as intermediate phenotypes.
Methods: From a genome-wide association study of multiple metabolites performed in the KORA population, we selected a single nucleotide polymorphism (SNP; rs174399, located in the intronic region of TRAF3IP2) strongly associated with short-chain dicarboxylacylcarnitine levels (metabolites that predict CV events). We genotyped this SNP in 3404 patients presenting for cardiac catheterization who also had quantification of 60 metabolites using mass-spectroscopy. Association between the SNP and short-chain dicarboxylacylcarnitine levels was tested using linear regression. Its association with CV events (death/MI) over a median of 5.4 years follow-up was tested using multivariable Cox proportional hazards regression adjusted for 11 clinical variables.
Results: The association of rs174399 (T/C) with levels of the short-chain dicarboxylacylcarnitine C5-DC validated in our cohort (dominant P=0.01; additive P=0.03), but the association with C6-DC was not (dominant P=0.11; additive P=0.19). Rs174399 was also associated with values of a principal components analysis-derived metabolic factor consisting of multiple short-chain dicarboxylacylcarnitines (dominant P=0.01; additive P=0.08). The minor allele, C, was associated with higher concentrations of both C5-DC and values of the short-chain dicarboxylacylcarnitine factor. It was also associated with greater risk of death or MI (HR 1.17, [1.05-1.31], P=0.006) and death alone (HR 1.15 [1.02-1.30], P=0.03).
Conclusions: Integrating genetics with metabolomics in a large CV study, we have identified a novel gene that predicts risk of CV events. This gene which encodes TRAF3 interacting protein 2, a protein involved in regulating responses to cytokines by members of the Rel/NF-kappaB transcription factor family, may serve as a good biological candidate to mediate CV risk through a metabolic pathway reported on by short-chain dicarboxylacylcarnitines.
- © 2011 by American Heart Association, Inc.