title: Search for genetic variants of the SYNTAXIN 1A (STX1A) gene: the -352 A>T variant in the STX1A promoter associates with impaired glucose metabolism in an Italian obese population.
abstract: OBJECTIVE
  To test if sequence variations of the SYNTAXIN 1A (STX1A) gene contribute to the susceptibility to type 2 diabetes in a cohort of overweight/obese subjects.
  
  
  METHODS
  A total of 717 overweight/obese individuals underwent oral glucose tolerance test and were stratified in four groups according to fasting and 2 h glucose levels (NGT, IGT, CGI, T2DM), representing the natural history of diabetes from normal glucose tolerance to overt disease. These subjects were analysed by a two-step genetic study. Functional analysis was performed by electrophoretic mobility shift assay (EMSA) and by supershift with CCAAT/enhancer-binding protein (C/EBP)beta antibody.
  
  
  RESULTS
  Among the several sequence variations detected in the STX1A gene, the T allele of the -352 A>T single nucleotide polymorphism in the promoter was found in a lower frequency in the subset of individuals with greater impairment of insulin secretion (CGI). To confirm that a lower frequency of the T allele was associated with this condition, we genotyped a second group of 202 overweight/obese individuals with type 2 diabetes, and the frequency of the T allele was reduced in this group also (P<0.01). Logistic regression confirmed a protective odds ratio (0.49, P<0.01) for the T allele. The EMSA showed that the PRM -352 A allele binds transcription factors with lower affinity compared to the T allele, and incubation with C/EBPbeta antibody 'supershifted' the complex, indicating that C/EBPbeta had a different binding with the PRM -352T allele.
  
  
  CONCLUSIONS
  A lower frequency of the PRM -352T allele of the STX1A gene was observed in overweight/obese subjects with impaired glucose regulation, particularly among individuals with combined glucose intolerance and overt diabetes. Both these groups have a greater defect in beta-cell function compared to normal and glucose intolerant subjects, and this association together with the functional study suggests a possible role of the PRM -352 A>T variant in insulin secretion.
authors.affiliation: Department of Medical Sciences, Endocrinology and Metabolism, University of Cagliari, Cagliari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Romeo
authors.forename: F
authors.initials: F
authors.lastname: Sentinelli
authors.forename: M G
authors.initials: MG
authors.lastname: Cavallo
authors.forename: F
authors.initials: F
authors.lastname: Leonetti
authors.forename: M
authors.initials: M
authors.lastname: Fallarino
authors.forename: S
authors.initials: S
authors.lastname: Mariotti
authors.forename: M G
authors.initials: MG
authors.lastname: Baroni
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D018149:Glucose Intolerance / Q000235:genetics*; D005951:Glucose Tolerance Test; D006801:Humans; D007558:Italy; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D050177:Overweight / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D050827:Syntaxin 1 / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D050827:Syntaxin 1