Genomic Variant in IL-37 Confers A Significant Risk of Coronary Artery Disease

Abstract

The interleukin 1 family plays an important role in the immune and inflammatory responses. Coronary artery disease (CAD) is a chronic inflammatory disease. However, the genetic association between IL-37, the seventh member of the IL-1 family, and CAD is unknown. Here we show that a single nucleotide polymorphism in the IL-37 gene (rs3811047) confers a significant risk of CAD. We have performed an association analysis between rs3811047 and CAD in two independent populations with 2,501 patients and 3,116 controls from China. Quantitative RT-PCR analysis has been performed to determine if the IL-37 expression level is influenced by rs3811047. We show that the minor allele A of rs3811047 is significantly associated with CAD in two independent populations under a recessive model (Padj = 5.51 × 10−3/OR = 1.56 in the GeneID Northernern population and Padj = 1.23 × 10−3/OR = 1.45 in the GeneID Central population). The association became more significant in the combined population (Padj = 9.70 × 10−6/OR = 1.47). Moreover, the association remains significant in a CAD case control population matched for age and sex. Allele A of rs3811047 shows significant association with a decreased mRNA expression level of IL-37 (n = 168, P = 3.78 × 10−4). These data suggest that IL37 is a new susceptibility gene for CAD, which provides a potential target for the prevention and treatment of CAD.

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout

“…Previous studies have shown that common genetic variation in IL37 has clinically relevant effects in inflammatory diseases. For example, rs3811047 is associated with the development of coronary artery disease and susceptibility to Mycobacterium tuberculosis infection 38 39. Additionally, rs2723187 has been associated with rapid degradation and significantly lower levels of IL-37 protein, with consequently reduced anti-inflammatory properties 40.…”

Short‐term interleukin‐37 treatment improves vascular endothelial function, endurance exercise capacity, and whole‐body glucose metabolism in old mice

“…To date, several studies have investigated the potential role of natural variants of the IL‐37 gene in human disease, including M. tuberculosis infection (Liu et al, ), coronary artery disease (Yin et al, ), and rheumatoid arthritis (Pei et al, ). In general, variants linked to increased production of IL‐37 and/or greater IL‐37 signaling are associated with lower disease burden.…”

Suppression of inflammation and acquired immunity by IL‐37

“…For example, the single nucleotide polymorphism (SNP) rs3811047 (threonine‐alanine change in amino acid 42 of exon 2) is associated with reduced disease severity in patients with rheumatoid arthritis . A different study in Chinese patients found that SNPs in the IL‐37 gene associated with decreased levels of expression confers a significant risk of coronary artery disease . In genetic carriers of IL‐37 haplotype2, most common among individuals of African descent, reduced levels of IL‐37 may predispose to the development of stronger inflammatory responses …”