The 9p21 locus does not affect risk of coronary artery disease through induction of type 1 interferons.

J Am Coll Cardiol

Department of Cardiovascular Sciences, University of Leicester, British Heart Foundation Cardiovascular Research Centre, Glenfield Hospital, Leicester, United Kingdom; National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. Electronic address:

Published: October 2013

Objectives: The study objective was to determine whether the coronary artery disease (CAD)-associated genotype at chromosome 9p21 modulates basal or induced expression of type I interferons (IFN-I).

Background: The mechanism responsible for the association between common variants in chromosome 9p21.3 and CAD remains unclear. It has been reported that the CAD risk locus is rich in enhancer-like elements and that chromosome looping can lead to its physical proximity with the IFN-I gene cluster, raising the possibility that the locus influences CAD risk by modulating expression of IFN-Is.

Methods: We examined whether genotype at the lead CAD-associated single nucleotide polymorphism (rs1333049) in 9p21 was associated with: 1) basal levels of IFN-I in plasma from 148 healthy male subjects; 2) induction of IFN-I by Toll-like receptor stimulants in peripheral blood mononuclear cells of 60 healthy volunteers assessed by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, Western blot, and IFN-I bioassay; and 3) enhancer activity of predicted IFN regulatory factor 3/7 binding sites within the 9p21 CAD risk region in reporter assays.

Results: No significant effects of 9p21 genotype were observed for plasma levels of IFN-α, IFN-α21, or CXCL10, or leukocyte induction of IFN-α, IFN-α21, IFN-β, CXCL10, or total IFN-I measured at the mRNA, protein, and biological activity levels. There was also no enhancement of reporter activity by predicted IFN regulatory factor 3/7 binding sites in the CAD risk locus of either genotype.

Conclusions: The mechanism underlying the association between common 9p21 variants and CAD does not involve differential regulation of IFN-I responses.

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http://dx.doi.org/10.1016/j.jacc.2013.07.031DOI Listing

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