Abstract 2077: A Novel GWAS Atherosclerosis Locus Regulates Plasma Levels of CXCL12
Background Genome wide association studies (GWAS) of single nucleotide polymorphisms (SNPs) revealed many novel loci associated with myocardial infarction (MI). A highly replicated SNP (rs1746048, combined p-value 5.4×10−10) maps downstream of CXCL12, a chemokine with putative anti-inflammatory & anti-atherogenic functions. It is unknown whether variation at this locus relates to the CXCL12 gene or to plasma protein levels of CXCL12.
Methods To seek evidence in humans for possible regulation of CXCL12 by the downstream GWAS signal, we examined the association of SNPs in the GWAS region with plasma CXCL12 levels in a subset (n=546) of PennCATH, a Caucasian, angiographic case-control study (n=1504; 509 acute cases, 497 chronic cases, & 498 angiographically normal controls). CXCL12 was measured by commercial assay. Genotyping was performed using Affymetrix 6.0 array (GWAS region) & ITMAT-CARE-BROAD candidate gene array (in the CXCL12 gene). Statistical analysis of plasma levels by genotype was tested using unpaired T-test, and age & sex adjusted linear regression.
Results PennCATH replicated association of the CXCL12 GWAS region with MI (rs1147878, p<0.001). The top reported GWAS CAD SNP (rs1746048) showed an association with plasma levels (p=0.007) as did top PennCATH rs1147878 (p=0.001). Homozygosity at risk allele rs1746048, positively associated with CAD (OR 1.21), was associated with lower plasma CXCL12 levels (2.15 ng/mL ± 0.53 vs 2.40 ± 0.52, p<0.001) compared to wild types (Table 1⇓). The converse relationship was observed with rs1147878 (OR CAD 0.81; plasma CXCL12 2.42 ± 0.55 vs. 2.25 ± 0.48, p<0.001) suggesting that CXCL12 may be an atheroprotective gene.
Conclusions We show for the first time that there is a relationship between variation in a novel GWAS atherosclerosis locus downstream of CXCL12, and plasma protein levels of CXCL12. This implicates the CXCL12 gene as being causal in this GWAS CAD signal and that plasma CXCL12 levels may be atheroprotective.