Abstract 13073: Chr10q11 Atherosclerosis Locus Modulation of Plasma and Adipose CXCL12 to in vivo Inflammation
Recent genome wide association studies (GWAS) have shown association between coronary artery disease (CAD) / myocardial infarction (MI) and common variation at locus 10q11 downstream from CXCL12, an inflammatory cytokine. We have shown that genetic variation at 10q11 SNP rs501120 also relates to plasma levels of CXCL12. However, other factors involved in regulation of CXCL12 in human are poorly understood. Therefore, to understand potential in vivo regulation of plasma CXCL12 levels, we tested the effect of acute inflammation on plasma CXCL12 levels. We measured plasma CXCL12 levels over twelve hours (ELISA, R&D) in the Genetics of Evoked responses to Niacin and Endotoxemia (GENE) study participants (n=300, 66% Caucasian) who were exposed to low-dose (1ng/kg of purified lipopolysaccharide (LPS)) and and genotyped at rs501120. Within subject analysis of variance as well as fractional polynomial regression was performed in GENE to understand change in plasma CXCL12 levels over time and by rs501120 genotype. In GENE (mean age 25+/-7.8; mean BMI 24.2 +/- 3.1), plasma CXCL12 levels decreased in response to low-dose endotoxemia, with the nadir at 4 hours following LPS. This response was related to common variation at the CAD/MI risk allele rs501120 (ANOVA F 6.1, p<0.001, Figure 1). These findings were similar to plasma CXCL12 levels observed during acute MI in another study. We demonstrate a drop in plasma CXCL12 levels in response to evoked in vivo inflammation in human. The inflammatory decrement in plasma CXCL12 was greater in carriers of the CAD risk allele. These data suggest modulation by chr10q11 CAD alleles of the acute negative inflammatory regulation of CXCL12 in humans. These experimental and genomic data may reveal novel regulatory pathways in CAD and MI.
- © 2011 by American Heart Association, Inc.