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The novel atherosclerosis locus at 10q11 regulates plasma CXCL12 levels

Nehal N. Mehta, Mingyao Li, Dilusha William, Amit V. Khera, Stephanie DerOhannessian, Liming Qu, Jane F. Ferguson, Catherine McLaughlin, Lalarukh Haris Shaikh, Rhia Shah, Parth N. Patel, Jonathan P. Bradfield, Jing He, Ioannis M. Stylianou, Hakon Hakonarson, Daniel J. Rader, Muredach P. Reilly
DOI: http://dx.doi.org/10.1093/eurheartj/ehr091 First published online: 17 March 2011

Aims Two single-nucleotide polymorphisms (SNPs), rs1746048 and rs501120, from genome wide association studies of coronary artery disease (CAD) map to chromosome 10q11 ∼80 kb downstream of chemokine CXCL12. Therefore, we examined the relationship between these two SNPs and plasma CXCL12 levels.

Methods and Results We tested the association of two SNPs with plasma CXCL12 levels in a two-stage study (n= 2939): first in PennCath (n= 1182), a Caucasian, angiographic CAD case–control study, and second in PennCAC (n= 1757), a community-based study of CAD risk factors. Plasma CXCL12 levels increased with age and did not vary by gender. There was no linkage disequilibrium between these two SNPs and SNPs within CXCL12 gene. However, CAD risk alleles at rs1746048 (C allele, P= 0.034; CC 2.33 ± 0.49, CT 2.27 ± 0.46, and TT 2.21 ± 0.52 ng/mL) and rs501120 (T allele, P= 0.041; TT 2.34 ± 0.49, CT 2.28 ± 0.46, and CC 2.23 ± 0.53 ng/mL) were associated with higher plasma levels of CXCL12 in age and gender adjusted models. In Stage 2, we confirmed this association (rs501120, T allele, P= 0.007), and meta-analysis strengthened this finding (n= 2939, P= 6.0 × 10−4). Finally, in exploratory analysis, the rs1746048 risk allele tended to have higher transcript levels of CXCL12 in human natural killer cells and the liver.

Conclusion Coronary artery disease risk alleles downstream of CXCL12 are associated with plasma protein levels of CXCL12 and appear to be related to CXCL12 transcript levels in two human cell lines. This implicates CXCL12 as potentially causal and supports CXCL12 as a potential therapeutic target for CAD.

  • Myocardial infarction
  • Cardiovascular genomics
  • Chemokines
  • CXCL12
  • Inflammation
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