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Association of Protein Tyrosine Phosphatase-N1 Polymorphisms With Coronary Calcified Plaque in the Diabetes Heart Study

¹ Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
² Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
³ Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
⁴ Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
⁵ Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Address correspondence and reprint requests to Donald W. Bowden, PhD, Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: dbowden{at}wfubmc.edu

Abbreviations: CarCP, carotid calcified plaque; CorCP, coronary calcified plaque; CVD, cardiovascular disease; DHS, Diabetes Heart Study; IMT, intima-media thickness; LD, linkage disequilibrium; SNP, single nucleotide polymorphism

Individuals with type 2 diabetes are at increased risk of cardiovascular disease (CVD) mortality and display increased levels of subclinical CVD. Genetic variation in PTPN1, a diabetes susceptibility gene, was investigated for a role in diabetic atherosclerosis. The PTPN1 gene encodes protein tyrosine phosphatase-1B, which is ubiquitously expressed and plays a role in the regulation of several signaling pathways. Subclinical atherosclerosis was assessed in 590 Caucasian participants with type 2 diabetes in the Diabetes Heart Study using B-mode ultrasound measurement of carotid intima-media thickness (IMT) and computed tomography measurement of carotid calcified plaque (CarCP) and coronary calcified plaque (CorCP). Twenty-three single nucleotide polymorphisms (SNPs) in PTPN1 were genotyped and assessed for association with IMT, CarCP, and CorCP. A total of 12 SNPs within a block of linkage disequilibrium encompassing the coding sequence of PTPN1 were significantly associated with CorCP (P values from <0.0001 to 0.043) and 3 SNPs also within the block approached significance (P values from 0.058 to 0.066). In addition, a nine-SNP haplotype (GACTTCAGO) was also associated with increased CorCP under a dominant model (P = 0.01). No association was detected with IMT or CarCP. The associated SNPs and haplotype are the same as those observed to be associated with type 2 diabetes, insulin resistance, and fasting glucose in previous studies. With the inclusion of the most likely haplo-genotype for each individual, the heritability estimate of CorCP increased from 0.53 ± 0.1 to 0.57 ± 0.1 (P = 8.1 x 10^–10), suggesting a modest but detectable effect of this gene on the phenotype of CorCP in type 2 diabetic patients.

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