Time of onset of coronary artery disease in diabetic patients depends on genetic polymorphism in region 9p21 but not in 1p25

Introduction. Type 2 diabetes (T2DM) is an important risk factor for development of coronary artery disease (CAD) and its complications. Recent genetic studies revealed possible association between those two conditions on the genome level. In our study we analysed whether polymorphisms in loci 1q25 and 9p21, previously characterized as risk factors of CVD, have an influence on early-onset CAD in T2DM patients. Materials and methods. Our case-control study included 338 patients suffering from T2DM and CAD. For the study purpose the cohort was divided into two groups based on the age of CAD onset: case group with earlyonset CAD (< 55 for males and < 65 years for females, n = 180) and control group ( >= 55 and >= 65 years respectively, n = 158). Epidemiological data was taken from medical history and retrospective questionnaire; blood samples were collected. The rs2383206, rs1333049 and rs10911021 were genotyped using method of fluorescently labelled allele specific oligonucleotides. Results. Statistical analysis did not reveal any significant differences between two groups in the mean duration of diabetes, metabolic parameters (weight, waist circumference, frequency of obesity according to BMI, mean blood pressure or lipids levels) and smoking history. There were statistical differences between groups in family incidence of CAD (70.0% patients in cases vs. 45.6% in controls; p < 0.005), hypertension (77.1% vs. 47.8%; p < 0.005) and obesity (61.2% vs. 49.0%; p < 0.05). Genetic analysis revealed that frequency of the G allele of rs2383206 in 9p21 region was significantly higher in cases than in controls (62.4% vs 44.0% p < 0.00001). Homozygotes GG were 39.4% of cases and 18.8% in controls (p = 0.0001). The OR for increased risk of early CAD in GG homozygotes was 2.81, 95% CI: 2.39-3.24, after adjustment for conventional risk factors it was reduced to 2.58. There was statistically significantly higher frequency of GG homozygotes among patients with poor glycaemic control (HbA(1c) >= 7%; 41.3% vs. 15.9; p = 0.0011) and non-obese subjects (BMI < 30 kg/m(2); 39.7% vs. 18.2%, p = 0.0002). Similar association between genotype and risk of early CAD was found for another polymorphism rs1333049 in 9p21 region. Frequency of allele C was significantly higher in cases than in controls (56.3% vs 43.4, p = 0.0036) and homozygotes CC were 31.6% in cases and 17.4% in controls (p = 0.0083). OR for this association was 2.2 (95% CI: 1.83-2.56); after adjustments 1.96. We didn't find any association between genotypes distribution of rs10911021 and early onset of CAD. Conclusions. Our findings clearly suggest that polymorphisms in 9p21 region have an influence on development of early-onset CAD in T2DM, especially in non-obese patients and subjects with poor glycaemic control.