title: Functional variants of the HMGA1 gene and type 2 diabetes mellitus.
abstract: BACKGROUND
  High-mobility group A1 (HMGA1) protein is a key regulator of insulin receptor (INSR) gene expression. We previously identified a functional HMGA1 gene variant in 2 insulin-resistant patients with decreased INSR expression and type 2 diabetes mellitus (DM).
  
  
  OBJECTIVE
  To examine the association of HMGA1 gene variants with type 2 DM.
  
  
  METHODS
  Case-control study that analyzed the HMGA1 gene in patients with type 2 DM and controls from 3 populations of white European ancestry. Italian patients with type 2 DM (n = 3278) and 2 groups of controls (n = 3328) were attending the University of Catanzaro outpatient clinics and other health care sites in Calabria, Italy, during 2003-2009; US patients with type 2 DM (n = 970) were recruited in Northern California clinics between 1994 and 2005 and controls (n = 958) were senior athletes without DM collected in 2004 and 2009; and French patients with type 2 DM (n = 354) and healthy controls (n = 50) were enrolled at the University of Reims in 1992. Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and controls.
  
  
  METHODS
  The frequency of HMGA1 gene variants among cases and controls. Odds ratios (ORs) for type 2 DM were estimated by logistic regression analysis.
  
  
  RESULTS
  The most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of patients with type 2 DM in all 3 populations. The prevalence of IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group; OR, 15.77 [95% confidence interval {CI}, 8.57-29.03]; P < .001 and 7.23% vs 3.32% in the other control group; OR, 2.03 [95% CI, 1.51-3.43]; P < .001). In the US population, the prevalence of IVS5-13insC variant was 7.7% among patients with type 2 DM vs 4.7% among controls (OR, 1.64 [95% CI, 1.05-2.57]; P = .03). In the French population, the prevalence of IVS5-13insC variant was 7.6% among patients with type 2 DM and 0% among controls (P = .046). In the Italian population, 3 other functional variants were observed. When all 4 variants were analyzed, HMGA1 defects were present in 9.8% of Italian patients with type 2 DM and 0.6% of controls. In addition to the IVS5 C-insertion, the c.310G>T (p.E104X) variant was found in 14 patients and no controls (Bonferroni-adjusted P = .01); the c.*82G>A variant (rs2780219) was found in 46 patients and 5 controls (Bonferroni-adjusted P < .001); the c.*369del variant was found in 24 patients and no controls (Bonferroni-adjusted P < .001). In circulating monocytes and Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and the IVS5-13insC variant, the messenger RNA levels and protein content of both HMGA1 and the INSR were decreased by 40% to 50%, and these defects were corrected by transfection with HMGA1 complementary DNA.
  
  
  CONCLUSIONS
  Compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with type 2 DM.
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università di Catanzaro Magna Græcia, Viale Europa, Germaneto Catanzaro, 88100 Italy.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Chiefari
authors.forename: Sinan
authors.initials: S
authors.lastname: Tanyolaç
authors.forename: Francesco
authors.initials: F
authors.lastname: Paonessa
authors.forename: Clive R
authors.initials: CR
authors.lastname: Pullinger
authors.forename: Carmelo
authors.initials: C
authors.lastname: Capula
authors.forename: Stefania
authors.initials: S
authors.lastname: Iiritano
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mazza
authors.forename: Michele
authors.initials: M
authors.lastname: Forlin
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Vincent
authors.initials: V
authors.lastname: Durlach
authors.forename: Anne
authors.initials: A
authors.lastname: Durlach
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Malloy
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
authors.forename: Steven W
authors.initials: SW
authors.lastname: Heiner
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
authors.forename: Daniela P
authors.initials: DP
authors.lastname: Foti
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
authors.forename: Antonio
authors.initials: A
authors.lastname: Brunetti
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D024003:HMGA Proteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011401:Promoter Regions, Genetic / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D024003:HMGA Proteins; D022821:RNA Splice Sites