The 9p21 myocardial infarction risk locus does not associate with peripheral artery disease in patients with type 2 diabetes mellitus

Abstract

Background and aims: The chromosome 9p21 (Chr9p21) locus can be considered today the most robust genetic markers for coronary artery disease (CHD). The association between this locus and CHD has been replicated several times. Subsequent work showed associations of Chr9p21 with a number of other cardiovascular disease traits, such as carotid artery plaque, stroke, aneurysms, heart failure and cardiovascular mortality, suggesting a more general role in vascular biology. Importantly, Chr9p21 lacks associations with common cardiovascular risk factors, such as lipids and hypertension indicating that the locus exerts its effects through largely independent mechanisms. Recently, genome-wide association studies identified a significant association on Chr9p21 with ankle-brachial index (ABI), a noninvasive measure of peripheral arterial disease (PAD). Materials and methods: It was the aim of our study to investigate whether the CAD locus on Chr9p21 (as represented by SNP rs2383206) is associated with continuous ABI and PAD (ABI<0.9) in 937 unrelated type 2 diabetic patients of European ancestry (550 males, 58.7%; 387 females, 41.3%). Typing was performed by means of TaqMan assay implemented on an HT7900 Applied Biosystems platform. Linear and logistic regression models were used to test the SNP for association with ABI and PAD. Results: Patients were 59.2+/-7.5 years old with a diabetes duration (DD) of 10.4+/-9.0 years (BMI 29.4+/-5.4 kg/m2; sBP 142+/-19 mmHg, dBP 82+/-10 mmHg). HbA1c was 7.7+/-2.7% (median value 7.45%; first and third quartile thresholds 6.75 and 8.25%, respectively). Genotypes distribution was: AA (n. 146) 15.6%; GA (n. 452) 48.2%; GG (n. 339) 36.2%; 128 patients (13.7%) had PAD. The sample was in Hardy-Weinberg equilibrium as investigated by the chi-square test. Among genotypes have not been observed differences as far as age, DD, smoking, BMI, SBP, DBP, HbA1c, total-, LDL-and HDL-cholesterol, triglycerides, uric acid, fibrinogen, urinary A/C ratio and eGFR by MDRD. No association was found between the rs2383206 genotype and ABI considered as a continuous trait (AA: ; GA: ; GG: ; ANOVA oneway, p=). Furthermore, no association was found between rs2383206 and PAD prevalence (AA 15.1%; GA 13.1%; GG 13.9%: chi-square 0.399, p=0.819). No interaction was observed between rs2383206 and poor glycemic control defined as an HbA1c above the median or within the fourth quartile. No differences were observed between genders or in subjects with compared to those without family history of CHD. In a logistic stepwise regression PAD was associated with age, sBP, smoking (p<0.001 for all), dBP, male gender (p=0.001 for both) and A/C ratio (p=0.035) (model 1) or CHD (p<0.001) (model 2), but not to rs2383206 or HbA1c. Conclusion: In our cohort of type 2 diabetes patients, the rs2383206 SNP, previously related to the CAD risk mainly in presence of poor glycemic control, does not associate with continuous ABI and PAD phenotypes.