The Impact on Coronary Artery Disease of Common Polymorphisms Known to Modulate Responses to Pathogens

Abstract

SummaryThere are two distinct models to explain how genetic variants contributing to cardiovascular disease may have arisen. Firstly, variants may result from random, initially neutral, mutations whose effects are largely revealed in postreproductive individuals in industrialized societies. Alternatively, the introduced variants may confer an adaptive advantage in certain circumstances. Resistance to pathogens is one of the strongest selection pressures on human proteins. To determine whether this evolutionary pressure has made a large contribution to heart disease we tested whether seventeen polymorphisms in fourteen innate-immunity genes, with documented evidence of modulating response to pathogens, had an impact on heart disease. Genotyping was performed in 1,598 CAD subjects (ACS or stable angina) and 332 controls. The TLR4 399Ile allele had the greatest impact on ACS risk (uncorrected p = 0.006); however there was no evidence overall that the resistance alleles cumulatively influenced the risk of ACS compared to controls or stable angina patients (p = 0.12, and p = 0.40, respectively). We did note a significant interaction between age at onset of disease and combined resistance allele carriership when the ACS and nonthrombotic, stable angina groups were compared (p = 0.04, 16 d.f.). This suggests that innate immunity factors could have a greater impact on thrombus formation among younger CAD patients

Common Variants of Vitamin D Receptor Gene Polymorphisms and Susceptibility to Coronary Artery Disease: A Systematic Review and Meta-Analysis

“…Of these, 3 studies were performed in Caucasians (cases, 1,853; controls, 678) [27,29,30], and 1 study was performed in East-Asians (cases, 215; controls, 67) [28]. The results of pooled ORs in different analysis models are shown in Table 3.…”

“…For this polymorphism, the studies by O'Halloran et al [27] and Abu el Maaty et al [32] deviated from HWE. We did not find a statistically significant association between the Fok I polymorphism and CAD risk under the dominant model (OR = 0.91, 95% CI = 0.75-1.07), recessive model (OR = 1.08, 95% CI = 0.86-1.35), allelic model (OR = 1.05, 95% CI = 0.85-1.30), homozygote model (OR = 0.83, 95% CI = 0.58-1.08), and heterozygote contrast (TC vs. TT, OR = 1.13, 95% CI = 0.83-1.55) in the overall population (Table 3).…”

“…Four studies including 2,068 cases and 745 controls addressed this issue [27,28,29,30] (Tables 1, 2). Of these, 3 studies were performed in Caucasians (cases, 1,853; controls, 678) [27,29,30], and 1 study was performed in East-Asians (cases, 215; controls, 67) [28].…”

“…There were 6 studies [26,27,28,29,31,32] with 2,823 cases and 1,072 controls concerning the Fok I polymorphism and CAD risk; among them, 4 studies were performed in Caucasians [26,27,29,32], and 2 studies were performed in East-Asians [28,31] (Tables 1, 2). For this polymorphism, the studies by O'Halloran et al [27] and Abu el Maaty et al [32] deviated from HWE.…”

“…Of the 272 excluded studies, 44 were duplicate publications; 196 were not relevant to VDR gene polymorphisms and CAD risk; 12 were reviews, editorials, or comments; 4 were case reports; 5 were studies that reported on the association between other polymorphisms of the VDR gene and CAD risk; 4 were on patients with diabetes or kidney disorders; 2 were studies without any control group; and 8 were other irrelevant articles. A total of 8 relevant studies (cases, 5,259; controls, 1,981) were finally included based on the inclusion criteria for CAD susceptibility related to the Fok I, Bsm I, Taq I, and Apa I polymorphisms [24,25,26,27,28,29,30,31,32]. Of these, 7 studies were performed in Caucasians [24,25,26,27,29,30,32], and 2 studies [28,31] were performed in East-Asians.…”