Interleukin 35 Polymorphisms Are Associated with Decreased Risk of Premature Coronary Artery Disease, Metabolic Parameters, and IL-35 Levels: The Genetics of Atherosclerotic Disease (GEA) Study

Abstract

Interleukin 35 (IL-35) is a heterodimeric cytokine involved in the development of atherosclerosis. The aim of the present study was to establish if the polymorphisms of IL-12A and EBI3 genes that encode the IL-35 subunits are associated with the development of premature coronary artery disease (CAD) in Mexican individuals. The IL-12A and EBI3 polymorphisms were determined in 1162 patients with premature CAD and 873 controls. Under different models, the EBI3 rs428253 (OR = 0.831, Padd = 0.036; OR = 0.614, Prec = 0.033; OR = 0.591, Pcod2 = 0.027) and IL-12A rs2243115 (OR = 0.674, Padd = 0.010; OR = 0.676, Pdom = 0.014; OR = 0.698, Phet = 0.027; OR = 0.694, Pcod1 = 0.024) polymorphisms were associated with decreased risk of developing premature CAD. Some polymorphisms were associated with clinical and metabolic parameters. Significant different levels of IL-35 were observed in EBI3 rs4740 and rs4905 genotypes only in the group of healthy controls. In summary, our study suggests that the EBI3 and IL-12A polymorphisms play an important role in decreasing the risk of developing premature CAD; it also demonstrates the relationship of the EBI3 rs4740 and rs4905 genotypes with IL-35 levels in healthy individuals.

Innate Immunity in Coronary Disease. The Role of Interleukin-12 Cytokine Family in Atherosclerosis

“…In this study, three EBI3 gene polymorphisms (rs428253, rs4740, and rs4905) were evaluated; results showed that the EBI3 rs428253 polymorphism was associated with reduced risk of developing premature CAD. In this study, the authors also found that coronary patients showed significantly higher IL-35 levels than control subjects, and that the EBI3 rs4740 and rs4905 polymorphisms were associated with different levels of IL-35 110 . Nevertheless, considering that this is the first report that evaluates the role of EBI3 polymorphisms in premature CAD, the detected associations are not yet definitive, and replicate studies in independent populations are required.…”

“…Decreased levels of IL-35 have been reported in patients with acute coronary syndrome (unstable angina pectoris and acute myocardial infarction) compared to a chest pain syndrome group; IL-35 levels also positively correlated with left ventricular ejection fraction whose reduction is associated with heart failure 109 . In contrast, it has been recently reported that premature CAD patients have significantly higher IL-35 plasma levels compared to healthy controls with no personal o familial history of premature CAD, and without subclinical atherosclerosis evaluated by computed tomography (coronary calcium score = 0) 110 .…”

“…Only one study has heretofore evaluated the participation of IL-12A gene polymorphisms in the susceptibility to premature cardiovascular disease. A very recent report of the Mexican GEA study determined four IL-12A polymorphisms (rs2243115, rs2243123, rs583911, and rs568408) in 1162 patients with premature CAD and 873 controls 110 . In this study, after adjustment for age, gender, body mass index, and current smoking status, it was described that the IL-12A rs2243115 polymorphism was significantly associated with reduced risk of developing premature CAD under different inheritance models.…”

“…Furthermore, Zheng et al 144 found that the EBI3 rs4740 polymorphism is closely associated with susceptibility to pulmonary tuberculosis in Chinese subjects. As it was described for the IL-12A gene, only one study has addressed the participation of EBI3 gene polymorphisms in the susceptibility to premature cardiovascular disease 110 . In this study, three EBI3 gene polymorphisms (rs428253, rs4740, and rs4905) were evaluated; results showed that the EBI3 rs428253 polymorphism was associated with reduced risk of developing premature CAD.…”

CETP and LCAT Gene Polymorphisms Are Associated with High‐Density Lipoprotein Subclasses and Acute Coronary Syndrome

“…All subjects were asymptomatic and apparently healthy individuals without a family history of premature CAD or atherosclerosis recruited from June 2009 to June 2013 from blood bank donors and with the assistance of brochures posted in social service centers. The exclusion criteria included the use of antidyslipidemic or anti‐inflammatory drugs at the time of the study, congestive heart failure, and liver, renal, thyroid, or oncological disease (Posadas‐Sanchez et al, ). In addition, the control subjects had a coronary calcium score of “0” determined by computed tomography, indicating the absence of subclinical atherosclerosis in these individuals.…”