Abstract 13230: Convergence of CXCL12 and PHACTR1: Novel Genome Wide Signals for Myocardial Infarction Regulate Plasma CXCL12 Levels
Background: Recent genome wide association studies have shown association between coronary artery disease (CAD) / myocardial infarction (MI) and common variation at locus 10q11 (8.1x10-9) downstream from CXCL12, an inflammatory cytokine; and at locus 6p24 (3.1x10-8) near gene PHACTR1, a phosphatase-related enzyme. Genetic variation at 10q11 also relates to plasma levels of CXCL12. However, other factors involved in regulation of CXCL12 are poorly understood. Therefore, we performed a genome-wide association study of plasma CXCL12 levels to better understand the biology and relationship to MI.
Methods and Findings: We measured plasma CXCL12 levels (ELISA, R&D) in a subset of the angiographic study, PennCath (n=1182, 406 with acute MI, 386 with chronic CAD, 390 angiographically normal controls). Genotyping was performed using the Affymetrix 6.0 chip. All samples & SNPs passed stringent QC; there was no significant population stratification (lambda=1.00085). There were multiple SNPs strongly associated (p value <10-5) with plasma CXCL12. These SNPs mapped to chromosome (chr) 6p24.1 (PHACTR1, top SNP rs202071, p=5.14x10-7, beta-coefficient -0.145), chr 6p21.3 (HIST1H2BC, rs13206443, 2.19x10-7, 0.322), chr 5q11.2 (ITGA1,rs10044180, p=2.29x10-6,-0.123), and 11q23.2 at (ZW10, rs2279996, p=3.42x10-6, 0.169). These associations remained robust after adjustment for age, gender, CAD, DM, and HTN.
Conclusions: We show a number of independent genetic associations with CXCL12 plasma levels, and reveal PHACTR-1in potential trans-regulation of CXCL12as well as CAD/MI. Ongoing studies to replicate these associations and to examine how these novel loci relate to CAD/MI and each other may reveal novel regulatory pathways in CAD and MI.
- © 2010 by American Heart Association, Inc.