The protein tyrosine phosphatase receptor type f (PTPRF) locus is associated with coronary artery disease in type 2 diabetes

Dear Sir, Insulin resistance is pathogenic for coronary artery disease particularly amongst patients with type 2 diabetes [1]. Protein Tyrosine Phosphatase Receptor Type F (PTPRF), also know as Leukocyte Antigen-Related (LAR), an inhibitor of insulin signalling, is overexpressed in tissues of insulin resistance subjects [2, 3]. Transgenic mice overexpressing PTPRF are insulin resistant [4]. Furthermore, PTPRF gene variability is associated with insulin resistance [5]. All these data suggest that PTPRF may contribute to the pathogenesis of insulin resistance related conditions. Aim of this study was to verify whether variability at the PTPRF locus is associated with coronary artery disease in patients with type 2 diabetes consecutively recruited at the Scientific Institute CSS-San Giovanni Rotondo, Italy, according to the following criteria: type 2 diabetes diagnosed after age 30 years; insulin treatment not required for at least 2 years after type 2 diabetes diagnosis; absence of clinically evident autoimmune disease, as previously described [6]. Of these, 248 were cases (>50% stenosis at coronary angiography and ⁄or previous myocardial infarction) and 344 controls (asymptomatic patients with no signs of myocardial ischaemia at stress ECG or with stenosis £50% at coronary angiography) for coronary artery disease. Clinical features for cases and controls, respectively, were: male ⁄ female ratio: 155 ⁄73 and 140 ⁄193; age: 64 ± 8 and 60 ± 8 years; BMI: 30 ± 4 and 31 ± 5 kg m; HbA1c: 8.6 ± 2 and 8.5 ± 2%; diabetes duration: 14.7 ± 9 and 11.8 ± 8 years; hypertension: 78% and 74%; dyslipidaemia: 90% and 88%; smokers: 44% and 25%. Four polymorphisms (rs11590627, rs2782641, rs10890257 and rs516790), tagging three linkage disequilibrium (LD) blocks and covering the entire PTPRF gene were genotyped. Coronary artery disease was significantly associated with rs2782641 (+A2518G, minor allele frequency = 0.202 in cases vs. 0.137 in controls, P = 0.035). The association was consistent with a recessive model of inheritance, with GG homozigotes having a 50% increased risk of coronary artery disease than major allele carriers (either AA or AG carriers) after adjusting for age, sex and smoking status (Table 1). The association was still significant after adjusting also for other known risk factors such as BMI, hypertension and dyslipidaemia (OR = 1.96, 95% CI = 1.13–3.28, P = 0.016). As rs2782641 resides within intron 3, its biological relevance is questionable. Looking for possible variants in LD with rs2782641, we genotyped six additional polymorphisms (rs6695915, rs651740, rs2842187, rs2819339, rs2842185, rs11580074) in a range of about 14 kb around it. Of an 8 kb area of high LD (r > 0.8), embedding rs2782641, a 450 bp DNA segment, including exons 4 and 5, were, then, re-sequenced in 100 individuals. No additional variants were found, leaving unanswered the question whether rs2782641 is in LD with other an yet unidentified variants. Unfortunately, we didn’t have the opportunity to replicate our positive association in a second sample of type 2 diabetic patients. However, we took advantage from a recently published genomewide-association case–control study for coronary artery disease in the general population performed by the Wellcome Trust Case Control Consortium (WTCCC) [7] whose results are widely accessible at http://www.wtccc. org.uk/summary_stats. shtml. In this study minor allele at rs2782641 was associated with coronary artery disease in sex-differentiated analyses with P-values of either 0.05 or 0.028 when 2000 coronary artery disease cases were compared with either 3000 or 12 000 controls respectively. Thus, despite data obtained in the general population from the WTCCC study do not represent a formal replication,