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Review
. 2011 Apr;32(8):963-71.
doi: 10.1093/eurheartj/ehr091. Epub 2011 Mar 17.

The novel atherosclerosis locus at 10q11 regulates plasma CXCL12 levels

Nehal N Mehta  1 , 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
Affiliations
Review

The novel atherosclerosis locus at 10q11 regulates plasma CXCL12 levels

Nehal N Mehta et al. Eur Heart J. 2011 Apr.

Abstract

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.

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Figures

Figure 1
Figure 1
The genomic region analysed surrounding the CXCL12 region. (A) Linkage disequilibrium in PennCath in the CXCL12 region, with arrows demarcating the region from around CXCL12 to the genome-wide association studies region. The asterisk denotes the haplotype block which contains rs1746048 and rs501120. (B) A magnified view of the haplotype block containing rs1746048 and rs501120 from the HapMap CEU population. The asterisk corresponds to the same position as the PennCath linkage disequilibrium plot, and the green arrowhead denotes rs1746048.
Figure 2
Figure 2
Two published coronary artery disease single-nucleotide polymorphisms and surrounding regions, including two recombinant hotspots around CXCL12. Each single-nucleotide polymorphism is shown with linkage disequilibrium (r2) and recombination rates at these loci using HapMap CEU data; vertical dashed lines demarcate a linkage disequilibrium block in which r2 > 0.8.
See this image and copyright information in PMC

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