Abstract
In an animal model, new evidence has been reported supporting the role of raet1e as an atherosclerosis-associated gene. Our objective was to establish if raet1e polymorphisms are associated with the risk of developing premature coronary artery disease (CAD) or with the presence of cardiometabolic parameters. After an informatic analysis, five polymorphisms were chosen and determined in 1158 patients with premature CAD and 1104 controls using 5′ exonuclease TaqMan genotyping assays. Standardized questionnaires were applied to all participants to obtain family medical history, demographic information, history of nutritional habits, physical activity, alcohol consumption, and pharmacological treatment. The functional effect of the rs7756850 polymorphism was analyzed by luciferase assays. Under different models, adjusted by age, gender, body mass index, current smoking, and type 2 diabetes mellitus, the rs6925151 (OR = 1.250, pheterozygote = 0.026; OR = 1.268, pcodominant1 = 0.034), rs9371533 (OR = 1.255, pheterozygote = 0.024), rs7756850 (OR = 1.274, pheterozygote = 0.016; OR = 1.294, pcodominant1 = 0.031), and rs9383921 (OR = 1.232, pheterozygote = 0.037) polymorphisms were associated with increased risk of premature CAD. When compared to the rs7756850 G allele, the C allele showed a decreased luciferase activity. In premature CAD patients, associations with low levels of adiponectin, with a high presence of hypertension, and with high levels of gamma-glutamyltransferase and total cholesterol were observed. In healthy controls, associations with a decrease in LDL pattern B, aspartate aminotransaminase, and hypo-α-lipoproteinemia were detected. An association of the raet1e polymorphisms with an increased risk of developing premature CAD and with cardiometabolic parameters has been shown for the first time. In addition, the functional effect of the rs7756850 polymorphism was defined.
Highlights
Acute coronary artery disease (CAD) is the most common cause of death in industrialized countries, accounting for up to 40% of all deaths [1]
The CAC was not measured in pCAD patients because the presence of stents and previous coronary surgery results in artifacts that do not allow the correct interpretation of tomographic images; the CAC score of pCAD patients was not reported
Reat1e is a new gene recently associated with the development of atherosclerosis in animal models [9]
Summary
Acute coronary artery disease (CAD) is the most common cause of death in industrialized countries, accounting for up to 40% of all deaths [1]. Significant advances have been made in identifying chromosomal loci linked to genetic variations that confer susceptibility to CAD; both candidate-gene and genomewide association studies (GWAS) have been part of the strategies used [3,4,5]. Intercrosses and backcrosses between strains varying in complex disease-related traits have been performed, and quantitative trait locus (QTL) mapping has been used to identify the modifier loci [6]. Using this strategy, a region called Ath locus has been identified [7]. The role of raet in NKG2D system activation and, in consequence, in the production of pro- and anti-inflammatory cytokines could be the link between the molecule-encoding gene and the development of atherosclerosis. We included 5 polymorphisms in our study, which were selected for their possible functional effects and/or their informative nature (minor allele f requency > 5%)
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