Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
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.

PubMed Disclaimer

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

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678. - PMC - PubMed
    1. Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, Dixon RJ, Meitinger T, Braund P, Wichmann HE, Barrett JH, Konig IR, Stevens SE, Szymczak S, Tregouet DA, Iles MM, Pahlke F, Pollard H, Lieb W, Cambien F, Fischer M, Ouwehand W, Blankenberg S, Balmforth AJ, Baessler A, Ball SG, Strom TM, Braenne I, Gieger C, Deloukas P, Tobin MD, Ziegler A, Thompson JR, Schunkert H. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007;357:443–453. - PMC - PubMed
    1. Kathiresan S, Voight BF, Purcell S, Musunuru K, Ardissino D, Mannucci PM, Anand S, Engert JC, Samani NJ, Schunkert H, Erdmann J, Reilly MP, Rader DJ, Morgan T, Spertus JA, Stoll M, Girelli D, McKeown PP, Patterson CC, Siscovick DS, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Merlini PA, Berzuini C, Bernardinelli L, Peyvandi F, Tubaro M, Celli P, Ferrario M, Fetiveau R, Marziliano N, Casari G, Galli M, Ribichini F, Rossi M, Bernardi F, Zonzin P, Piazza A, Yee J, Friedlander Y, Marrugat J, Lucas G, Subirana I, Sala J, Ramos R, Meigs JB, Williams G, Nathan DM, MacRae CA, Havulinna AS, Berglund G, Hirschhorn JN, Asselta R, Duga S, Spreafico M, Daly MJ, Nemesh J, Korn JM, McCarroll SA, Surti A, Guiducci C, Gianniny L, Mirel D, Parkin M, Burtt N, Gabriel SB, Thompson JR, Braund PS, Wright BJ, Balmforth AJ, Ball SG, Hall AS, Linsel-Nitschke P, Lieb W, Ziegler A, Konig I, Hengstenberg C, Fischer M, Stark K, Grosshennig A, Preuss M, Wichmann HE, Schreiber S, Ouwehand W, Deloukas P, Scholz M, Cambien F, Li M, Chen Z, Wilensky R, Matthai W, Qasim A, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Epstein SE, Scheffold T, Berger K, Huge A, Martinelli N, Olivieri O, Corrocher R, McKeown P, Erdmann E, Konig IR, Holm H, Thorleifsson G, Thorsteinsdottir U, Stefansson K, Do R, Xie C, Siscovick D. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet. 2009;41:334–341. - PMC - PubMed
    1. Abi-Younes S, Sauty A, Mach F, Sukhova GK, Libby P, Luster AD. The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. Circ Res. 2000;86:131–138. - PubMed
    1. Zeiffer U, Schober A, Lietz M, Liehn EA, Erl W, Emans N, Yan ZQ, Weber C. Neointimal smooth muscle cells display a proinflammatory phenotype resulting in increased leukocyte recruitment mediated by P-selectin and chemokines. Circ Res. 2004;94:776–784. - PubMed

Substances