Elsevier

Canadian Journal of Cardiology

Volume 28, Issue 6, November–December 2012, Pages 662-666
Canadian Journal of Cardiology

Review
Inflammation and Coronary Artery Disease: Insights From Genetic Studies

https://doi.org/10.1016/j.cjca.2012.05.014Get rights and content

Abstract

Recent genome-wide association studies (GWASs) have provided a vast amount of new information relevant to the myriad of biological pathways related to atherosclerosis and its progression. Although atherosclerosis is a complex process, both GWASs and candidate gene studies add support to the hypothesis that proinflammatory pathways, involving both innate and adaptive immunity, play a causal role in coronary artery disease (CAD) and its clinical manifestations. Recent GWASs have identified several inflammation-related loci associated with CAD risk. These include CXCL2, encoding an atheroprotective chemokine, and a region near HLA-C in the major histocompatibility locus on chromosome 6p21. The ABO locus, also linked to CAD risk by the GWAS approach, is related to multiple phenotypes, including plasma interleukin-6 (IL-6) levels. Finally, relevant to inflammation, the 9p21 CAD risk locus appears to play a role in interferon-gamma signalling. Candidate gene studies also support a causative role of inflammation pathways in atherosclerosis. Of note, a common loss of function coding variant in the IL-6 receptor gene (IL6R) is associated with a reduction in CAD risk.

Résumé

Les récentes études d'association pangénomiques (GWAS: genome-wide association studies) ont fourni une quantité importante de nouvelles informations ayant rapport à la myriade de voies biologiques liées à l'athérosclérose et à sa progression. Même si l'athérosclérose est un processus complexe, les GWAS et les études des gènes candidats appuient l'hypothèse que les voies proinflammatoires impliquant l'immunité innée et l'immunité acquise jouent un rôle causal dans la maladie coronarienne (MC) et ses manifestations cliniques. Les récentes GWAS ont identifiées plusieurs locus liés à l'inflammation qui sont associés au risque de MC. Ceux-ci incluent la CXCL2, codant une chimiokine athéroprotectrice, et une région près du HLA-C dans le locus du complexe majeur d'histocompatibilité sur le chromosome 6p21. Le locus ABO, aussi lié au risque de MC par l'approche des GWAS, est associé à des phénotypes multiples, incluant les concentrations plasmatiques d'interleukine 6 (IL-6). Finalement, en ce qui concerne l'inflammation, le locus 9p21 relatif au risque de MC semble jouer un rôle dans la signalisation de l'interféron gamma. Les études des gènes candidats contribuent également au rôle causal des voies inflammatoires de l'athérosclérose. Notamment, une perte commune de fonction codant le variant au récepteur IL-6 (IL-6R) est associée à une réduction du risque de MC.

Section snippets

Chromosome 9p21 Locus for CAD

The first robust association with CAD identified by the GWAS approach was a 58-kb region on the chromosome 9p21.3 locus identified by 3 independent groups, including our own, in 2007.1, 2, 3 The 9p21 locus is significant in that it is a common variant of high effect size with a risk allele frequency of close to 50%. Thus 25% of Europeans carry 2 copies of the risk allele and have a 50% increased risk of CAD in general and a 2-fold increased risk of premature CAD.1, 4 This locus is also

9p21 Link to Inflammation

Recently, Harismendy and colleagues have identified 2 SNPs within the 9p21 locus that disrupt a signal transducer and activator of transcription 1 (STAT1) binding site in a predicted long-range enhancer that physically interacts with the CDKN2A/B locus and an interval downstream of interferon IFNA2.14 In HUVEC cells, interferon-gamma activation affects chromatin structure and transcriptional regulation of the 9p21 locus, including STAT1 binding, long-range enhancer interactions, and expression

GWASs for CAD: 5 Years of Progress

In the 5 years since the 9p21 discovery in 2007, additional GWASs and large meta-analyses have identified over 30 additional loci of smaller effect size but with genome-wide(P < 5 × 10−8) significance. This success has been built on large collaborative efforts, including the Myocardial Infarction Genomics Consortium,15 the Coronary Artery Disease Genome-Wide Replication and Meta-analysis (CARDIoGRAM) consortium,4 the Coronary Artery Disease Consortium,16 and others. Novel CAD risk loci

GWAS Signals for Inflammation: CXCL12, ABO, and MHC

Although cholesterol accumulation in the arterial wall is an early event in the development of atherosclerosis, it is well accepted that atherosclerosis is driven by a chronic inflammatory process,17 elicited in part by subendothelial lipoprotein retention18, 19 and involving innate and adaptive immune responses.20, 21 The recruitment of activated macrophages and T cells into and within atherosclerotic lesions is guided by endothelial leukocyte adhesion molecules and chemoattractants.

Other Genetic Signals for Inflammation and CAD

Smaller candidate gene studies have reported associations with MHC2TA encoding the MHC class II transactivator29 and genes involved in proinflammatory leukotriene synthesis.30 Although LTA, an MHC class III gene encoding lymphotoxin α, was previously linked to myocardial infarction,31 this association was not confirmed by other studies, including our own.27, 32

The IL-6 receptor (IL-6R) pathway is a proximal regulator of inflammation cascades.33 Soluble IL-6 activates the membrane-bound IL-6R in

Conclusions

Recent GWASs have provided a vast amount of new information relevant to the myriad of biological pathways related to atherosclerosis and its progression. Many years of bioinformatic and laboratory analysis will be required to unravel the functional nature of these findings. Although atherosclerosis is a complex process, both GWASs and candidate gene studies add support to the hypothesis that proinflammatory pathways play a causal role in CAD and its clinical manifestations.

Funding Sources

Supported by a Merck Frosst Canada/University of Ottawa Chair in Atherosclerosis Research, Canadian Institutes of Health Research #MOP44360, #MOP2394901; Heart and Stroke Foundation of Ontario #T-7268 (RM).

Disclosures

The authors have no conflicts of interest to disclose.

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