title: Infrequent TRIB3 coding variants and coronary artery disease in type 2 diabetes.
abstract: OBJECTIVE
  Genes that modulate insulin sensitivity may also be involved in shaping the risk of coronary artery disease (CAD). The relatively common TRIB3 Q84R polymorphism (rs2295490) has been associated with abnormal insulin signaling, endothelial dysfunction, insulin resistance, and pro-atherogenic phenotypes. The aim of our study was to investigate the association between low-frequency TRIB3 coding variants and CAD in patients with type 2 diabetes (T2D).
  
  
  METHODS
  Three case-control studies for CAD from Italy and US were analyzed, for a total of 1565 individuals, all with type 2 diabetes. Infrequent variants were identified by re-sequencing TRIB3 exons in 140 "extreme cases" and 140 "super-controls" and then genotyped in all study subjects.
  
  
  RESULTS
  TRIB3 infrequent variants (n = 8), considered according to a collapsing rare variants framework, were significantly associated with CAD in diabetic patients from Italy (n = 700, OR = 0.43, 95% CI 0.20-0.91; p = 0.027), but not from the US (n = 865, OR = 1.22, 95% CI 0.69-2.18; p = 0.49). In the Italian sets, the association was especially strong among individuals who also carried the common R84 variant.
  
  
  CONCLUSIONS
  Although preliminary, our finding suggests a role of TRIB3 low-frequency variants on CAD among Italian patients with T2D. Further studies are needed to address the role of TRIB3 infrequent variants in other populations of both European and non-European ancestries.
authors.affiliation: IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy. Electronic address: s.prudente@css-mendel.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Prudente
authors.affiliation: IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy; Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Bailetti
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Mendonca
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA, USA; Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy.
authors.forename: Gaia Chiara
authors.initials: GC
authors.lastname: Mannino
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Unit of Biostatistics, San Giovanni Rotondo, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fontana
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreozzi
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hastings
authors.affiliation: IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Mercuri
authors.affiliation: IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Alberico
authors.affiliation: IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy; Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Basile
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Unit of Biostatistics, San Giovanni Rotondo, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Copetti
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sesti
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.affiliation: IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy; Department of Experimental Medicine, Sapienza University, Rome, Italy; IRCSS Casa Sollievo della Sofferenza, Research Unit of Diabetes and Endocrine Diseases, San Giovanni Rotondo, Italy. Electronic address: vincenzo.trischitta@uniroma1.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Trischitta
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007558:Italy; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D018797:Cell Cycle Proteins; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Coronary artery disease; Infrequent variants; Insulin sensitivity; Insulin signaling; Type 2 diabetes mellitus