The CAG Repeat Polymorphism At Androgen Receptor Gene Exon 1 Is Associated With The Severity Of Coronary Artery Disease

It has been suggested that the difference in the incidence of ischemic heart disease between men and women is closely correlated with sex steroids. The role of androgens in the pathogenesis of coronary artery disease (CAD) remains controversial. But ordinarily the balance between androgen and the other steroid hormones is believed to play an important role in the pathogenesis and development of CAD, which deserves to be studied further. Androgen receptor (AR) is responsible for the genomic effects of androgens at the histological level. The AR has a polymorphic region with a varying number of polyglutamines encoded by a stretch of CAG short tandem repeats (CAG-STR) in exon 1. It has been reported that the length of the repeats affects the transactivation function of the receptor, and shows some correlation with androgenic action. The AR exists in cardiovascular system, in recent years, it has been proved that CAG-STR polymorphism in AR exon 1 region correlated with many diseases, such as the male infertility, benign prostate hyperplasia, prostate cancer and the syndrome of bulbar muscular atrophy or Kennedy's disease. The peripheral blood AR gene CAG-STR polymorphism has also proved to be one of the heredity index of the pathogenesis of CAD in old man and a race difference exist in this polymorphism. Recently, it was reported that several factors possibly affecting the predisposition to cardiovascular disease may beaffected by the polyglutamine length of the AR. That is, both the endothelium dependent vasodilatation is impaired and the high-density lipoprotein (HDL) levels are lower in men carrying the shorter repeats.For the possible important effects of androgens and AR in the occurrence and development of CAD, we designed and carried this study. The aim is to explore the association between the AR gene CAG-STR polymorphism in exon 1 and the severity of CAD appraised by angiography, several factors possibly affecting the predisposition to cardiovascular disease were also studied; at the same time, we can further understand the real effects of AR gene polymorphism in the pathogenesis of CAD.125 proved or suspected continual male CAD patients (35-84 years old) undergoing coronary angiography were included in this study, Ordinary information was collected and biochemical parameters were measured. The severity of CAD was assessed by the number (0-3) of coronary vessels with > 50% reduction in the luminal diameter, the Gensini score (GS) of each was calculated. The length of CAG repeats in the peripheral blood AR gene examined by PCR.The studies show:1. The CAG repeats length ranged from 13 to 30, with their mean value 21.8. the CAG-STR was defined as the long AR (LAR) group with their repeats number >24; accordingly those with which <24 were defined as the short AR (SAR) group.2. The correlation of the CAG-STR and the risk factors of CAD: The mean body mass index (BMI) of patients with SAR group was significantly lower than in men with LAR group(t=-3.024, P=0.005); but HDL in LAR group is significantly higher than the SAR group (t =-2.610, P =0.010). Partial correlation analysis show the numbers of CAG-STR significantly correlated with serum levels of HDL cholesterol. Which independent of the influence of BMI, age, smoking index (SI)and blood glucose(partial r =0.246, P =0.003). The uric acid was higher in LAR group, but with no significant when BMI was taken into account. No inter-relationship was noted betweenthe AR gene CAG repeat length and age, the presence of diabetes, the presence of family history for diabetes or CAD at an early age (< 50 years), or smoking.3. The effect of the AR gene CAG repeat length on the extent of CAD was examined. Men with LAR belonged more frequently to the group without coronary artery stenosis: no arteries: 55.6% SAR, 44.4% LAR; one artery: 83.7% SAR, 16.3% LAR; two arteries, 73.5% SAR, 26.5% LAR; three arteries:80% SAR, 20% LAR, but the difference was below statistical significance (x2 =5.91, P =0.116) . The patients were then grouped according to the presence of significant stenosis (one to three arteries involved) or the absence of significant stenosis (no arteries involved). Men with SAR had significant CAD more frequently than men with LAR: one to three arteries: 79.4% SAR, 20.4% LAR vs. no arteries: 55.6% SAR, 44.4% LAR 6c2 =4.82, P=0.028) .4. Then the effect of the AR gene CAG repeat length on the severity of CAD is valued by Gensini's scoring (GS) system. The GS is significantly higher in LAR group(M-W ^k^lk,z=-2.644,P =0.008). Stepwise multiple linear regression analysis shows the CAG-STR (P =0.006) , uric acid (P =0.019), LDL (P=0.011) and HDL (P =0.038) have significant effects on GS. Moreover, there was significant negative correlation between the CAG repeat length and GS according to the spearman correlation analysis (r= -0.230, P =0.010) , which independent of age, BMI, LDL, UA and HDL (parfia/r= -0.250, P =0.006) .In the study, we have approved that the CAG-STR at AR gene exists polymorphism. We have found that the CAG-STR polymorphism at the AR gene exon 1 plays some role in the development or progression of CAD. The individualswith the LAR alleles may be more predisposed to the more severe CAD, accordingly the shorter CAG repeat of the AR gene is associated with less severe CAD, which suggests the increased expression and activity of AR might be one of reasons in the increased frequency of CAD in males.