title: Is common genetic variation at IRS1, ENPP1 and TRIB3 loci associated with cardiometabolic phenotypes in type 2 diabetes? An exploratory analysis of the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 5.
abstract: OBJECTIVE
  Insulin resistance is a hallmark of type 2 diabetes (T2DM), it is often accompanied by defective beta-cell function (BF) and is involved in the pathophysiology of cardiovascular disease (CVD). Commonalities among these traits may recognize a genetic background, possibly involving the genetic variation of insulin signaling pathway genes. We conducted an exploratory analysis by testing whether common genetic variability at IRS1, ENPP1 and TRIB3 loci is associated with cardiovascular risk traits and metabolic phenotypes in T2DM.
  
  
  RESULTS
  In 597 drug-naïve, GADA-negative, newly-diagnosed T2DM patients we performed: 1) genotyping of 10 independent single-nucleotide polymorphisms covering ∼ 90% of common variability at IRS1, ENPP1 and TRIB3 loci; 2) carotid artery ultrasound; 3) standard ECG (n = 450); 4) euglycaemic insulin clamp to assess insulin sensitivity; 5) 75 g-OGTT to estimate BF (derivative and proportional control) by mathematical modeling. False discovery rate of multiple comparisons was set at 0.20. After adjustment for age, sex and smoking status, rs4675095-T (IRS1) and rs4897549-A (ENPP1) were significantly associated with carotid atherosclerosis severity, whilst rs7265169-A (TRIB3) was associated with ECG abnormalities. Rs858340-G (ENPP1) was significantly associated with decreased insulin sensitivity, independently of age, sex and body-mass-index. No consistent relationships were found with BF.
  
  
  CONCLUSIONS
  Some associations were found between intermediate phenotypes of CVD and common genetic variation of gatekeepers along the insulin signaling pathway. These results need be replicated to support the concept that in T2DM the CVD genetic risk clock may start ticking long before hyperglycemia appears. ClinicalTrials.gov Identifier: NCT01526720.
authors: Department of Medicine, University of Verona, Verona, Italy; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital Trust of Verona, Verona, Italy.
authors: M
authors: M
authors: Trombetta
authors: Department of Medicine, University of Verona, Verona, Italy; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital Trust of Verona, Verona, Italy.
authors: M
authors: M
authors: Dauriz
authors: Department of Medicine, University of Verona, Verona, Italy.
authors: S
authors: S
authors: Bonetti
authors: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital Trust of Verona, Verona, Italy.
authors: D
authors: D
authors: Travia
authors: Department of Medicine, University of Verona, Verona, Italy.
authors: L
authors: L
authors: Boselli
authors: Department of Medicine, University of Verona, Verona, Italy.
authors: L
authors: L
authors: Santi
authors: Department of Medicine, University of Verona, Verona, Italy; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital Trust of Verona, Verona, Italy.
authors: E
authors: E
authors: Bonora
authors: Department of Clinical and Experimental Medicine, University of Parma School of Medicine, Italy; Division of Endocrinology, Azienda Ospedaliera Universitaria, Parma, Italy. Electronic address: riccardo.bonadonna@unipr.it.
authors: R C
authors: RC
authors: Bonadonna
mesh_terms: D000368:Aged; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D007333:Insulin Resistance; D016015:Logistic Models; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000235:genetics*; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction; D055105:Waist Circumference
chemical_list: D018797:Cell Cycle Proteins; D006442:Glycated Hemoglobin; D055504:Insulin Receptor Substrate Proteins; D010727:Phosphoric Diester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011755:Pyrophosphatases; D012097:Repressor Proteins; C526292:IRS1 protein, human; C474831:TRIB3 protein, human; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1
keywords: Cardiovascular disease risk; Genetic association; Insulin resistance; Subclinical atherosclerosis; Type 2 diabetes