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. CONCLUSION: 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.
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. CONCLUSION: 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: B R Pober; E Wang; S Caprio; K F Petersen; C Brandt; T Stanley; L R Osborne; J Dzuria; B Gulanski Journal: Am J Med Genet C Semin Med Genet Date: 2010-05-15 Impact factor: 3.908
Authors: S Dash; C Langenberg; K A Fawcett; R K Semple; S Romeo; S Sharp; H Sano; G E Lienhard; J J Rochford; T Howlett; A F Massoud; P Hindmarsh; S J Howell; R J Wilkinson; V Lyssenko; L Groop; M G Baroni; I Barroso; N J Wareham; S O'Rahilly; D B Savage Journal: Diabetologia Date: 2010-03-27 Impact factor: 10.122
Authors: N P Tatonetti; J C Denny; S N Murphy; G H Fernald; G Krishnan; V Castro; P Yue; P S Tsao; P S Tsau; I Kohane; D M Roden; R B Altman Journal: Clin Pharmacol Ther Date: 2011-05-25 Impact factor: 6.875
Authors: Sandra C Doelken; Sebastian Köhler; Christopher J Mungall; Georgios V Gkoutos; Barbara J Ruef; Cynthia Smith; Damian Smedley; Sebastian Bauer; Eva Klopocki; Paul N Schofield; Monte Westerfield; Peter N Robinson; Suzanna E Lewis Journal: Dis Model Mech Date: 2012-10-25 Impact factor: 5.758