title: TRIB3 R84 variant affects glucose homeostasis by altering the interplay between insulin sensitivity and secretion.
abstract: OBJECTIVE
  The results of studies on the genetics of complex traits need to be replicated and to reach robust statistical significance before they can be considered as established. We here tried to replicate the previously reported association between the TRIB3 Q84R polymorphism (rs2295490) and glucose homeostasis.
  
  
  METHODS
  Three samples of Europeans with fasting glucose <7.0 mmol/l were studied. In sample 1 (n=791), the association between TRIB3 Q84R and impaired glucose regulation (IGR; defined as impaired fasting glucose and/or impaired glucose tolerance and/or type 2 diabetes by OGTT) and insulin sensitivity (ISI), and its interplay with early-phase insulin secretion (i.e. disposition index [DI]) were analysed. Sample 2 (n=374) and sample 3 (n=394) were used to replicate the association with IGR and insulin sensitivity (by glucose clamp), respectively. Genotyping was performed by TaqMan allele discrimination.
  
  
  RESULTS
  R84 carriers were at higher risk of IGR: OR for the additive model 1.54, p=0.004, and 1.63, p=0.027, in samples 1 and 2, respectively. In sample 1, both ISI (p=0.005) and DI (p=0.043) were progressively lower from QQ to QR and RR individuals. A 'triangulation approach' indicated that the association with IGR was mostly mediated by DI rather than by ISI changes (i.e. being the expected ORs 1.51 and 1.25, respectively). In sample 3, glucose disposal was 38.8+/-17.7, 33.8+/-14.4, and 31.6+/-13.3 micromol min(-1)kg(-1), p=0.022, in QQ, QR and RR individuals, respectively.
  
  
  CONCLUSIONS
  Our data confirm that the TRIB3 R84 variant affects glucose homeostasis and suggest this effect is due to an alteration of the interplay between insulin sensitivity and secretion.
authors.affiliation: IRCCS Casa Sollievo della Sofferenza Mendel Institute, Viale Regina Margherita 261, 00198 Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Prudente
authors.forename: R
authors.initials: R
authors.lastname: Baratta
authors.forename: F
authors.initials: F
authors.lastname: Andreozzi
authors.forename: E
authors.initials: E
authors.lastname: Morini
authors.forename: M G
authors.initials: MG
authors.lastname: Farina
authors.forename: A
authors.initials: A
authors.lastname: Nigro
authors.forename: M
authors.initials: M
authors.lastname: Copetti
authors.forename: F
authors.initials: F
authors.lastname: Pellegrini
authors.forename: E
authors.initials: E
authors.lastname: Succurro
authors.forename: L
authors.initials: L
authors.lastname: Di Pietrantonio
authors.forename: C
authors.initials: C
authors.lastname: Brufani
authors.forename: F
authors.initials: F
authors.lastname: Barbetti
authors.forename: B
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: G
authors.initials: G
authors.lastname: Sesti
authors.forename: V
authors.initials: V
authors.lastname: Trischitta
authors.forename: L
authors.initials: L
authors.lastname: Frittitta
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; D007328:Insulin; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D017346:Protein Serine-Threonine Kinases; D005947:Glucose
references.citation: Diabetes. 2002 May;51(5):1419-24
references.pmid: 11978638
references.citation: Lancet. 1992 Oct 17;340(8825):925-9
references.pmid: 1357346
references.citation: Diabetes. 1999 Sep;48(9):1881-4
references.pmid: 10480624
references.citation: Diabetes. 1994 Aug;43(8):1066-84
references.pmid: 8039601
references.citation: Diabetes Care. 2007 Jun;30(6):1544-8
references.pmid: 17384342
references.citation: Diabetes. 2008 Apr;57(4):1125-30
references.pmid: 18071025
references.citation: Am J Physiol. 1979 Sep;237(3):E214-23
references.pmid: 382871
references.citation: Lancet. 1995 Aug 12;346(8972):397-402
references.pmid: 7623569
references.citation: J Clin Invest. 1999 Sep;104(6):787-94
references.pmid: 10491414
references.citation: Diabetes. 2001 Apr;50(4):882-5
references.pmid: 11289056
references.citation: Nat Genet. 2008 May;40(5):638-45
references.pmid: 18372903
references.citation: Biometrics. 1994 Dec;50(4):1088-101
references.pmid: 7786990
references.citation: J Clin Endocrinol Metab. 2009 Jan;94(1):190-6
references.pmid: 18984671
references.citation: Diabetes. 2005 Sep;54(9):2807-11
references.pmid: 16123373
references.citation: Stat Med. 2008 Feb 28;27(5):651-69
references.pmid: 17514698
references.citation: Stat Med. 2001 Aug 15;20(15):2219-41
references.pmid: 11468761
references.citation: Diabetes. 2008 May;57(5):1419-26
references.pmid: 18346983
references.citation: Science. 2003 Jun 6;300(5625):1574-7
references.pmid: 12791994
references.citation: Arterioscler Thromb Vasc Biol. 2008 Jul;28(7):1355-60
references.pmid: 18436806
references.citation: Am J Epidemiol. 2002 Aug 1;156(3):204-10
references.pmid: 12142254
references.citation: Annu Rev Physiol. 2006;68:123-58
references.pmid: 16460269
references.citation: Science. 2007 Jun 1;316(5829):1331-6
references.pmid: 17463246
references.citation: BMJ. 1997 Sep 13;315(7109):629-34
references.pmid: 9310563
references.citation: Diabetes Care. 2009 Jul;32(7):1311-3
references.pmid: 19389818
references.citation: Am J Hum Genet. 2005 May;76(5):887-93
references.pmid: 15789306
references.citation: Diabetes. 2005 Jan;54(1):166-74
references.pmid: 15616025
references.citation: Diabetes. 2008 Dec;57(12):3360-4
references.pmid: 18776139
references.citation: Diabetes. 1988 Dec;37(12):1595-607
references.pmid: 3056758
references.citation: Diabetologia. 1985 Jul;28(7):412-9
references.pmid: 3899825