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

• Published in: International Journal of Obesity Vol. 32; no. 3; pp. 413 - 420
• Main Authors: Romeo, S, Sentinelli, F, Cavallo, M.G, Leonetti, F, Fallarino, M, Mariotti, S, Baroni, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2008; Nature Publishing; Nature Publishing Group
• Subjects: Adult; Aged; Biological and medical sciences; Blood Glucose; Blood Glucose - metabolism; cohort studies; Diabetes; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; disease resistance; Electrophoretic Mobility Shift Assay; Endocrine pancreas. Apud cells (diseases); Endocrinology; Endocrinopathies; Epidemiology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Evaluation; Female; Gene Frequency; genes; Genetic aspects; Genetic Predisposition to Disease; Genetic variance; Genetic Variation; genetics; genotype; Glucose; Glucose Intolerance; Glucose Intolerance - genetics; Glucose metabolism; glucose tolerance; Glucose Tolerance Test; Health aspects; Health Promotion and Disease Prevention; Humans; Insulin resistance; insulin secretion; Internal Medicine; Italy; Logistic Models; Male; Medical sciences; Medicine; Medicine & Public Health; men; Metabolic Diseases; Metabolism; Middle Aged; molecular sequence data; Obesity; Obesity - genetics; original-article; Overweight; Overweight - genetics; Overweight persons; Polymorphism; promoter regions; Promoter Regions, Genetic; Promoter Regions, Genetic - genetics; Proteins; Public Health; Risk factors; single nucleotide polymorphism; Syntaxin 1; Syntaxin 1 - genetics; Tumors. Hypoglycemia; Type 2 diabetes; White people; women; Italy; Europe; Rome Italy; SYNTAXIN 1A; diabetes mellitus; insulin secretion; human insulinoma; EMSA; SNARE; Endocrinopathy; Pancreatic hormone; Genetic variability; SNARE protein; Insulinoma; Glucose; Secretory tumor; Promoter; Gene; Genetics; Benign neoplasm; Nutritional status; Pancreatic disease; Human; Obesity; Nutrition; Secretion; Diabetes mellitus; Genetic variant; Nutrition disorder; Genotype; Metabolic diseases; Metabolism; Insulin; Syntaxin; Digestive diseases; Endocrine pancreatic diseases
• ISSN: 0307-0565; 1476-5497; 1476-5497
• DOI: 10.1038/sj.ijo.0803743

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)β 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/EBPβ antibody ‘supershifted’ the complex, indicating that C/EBPβ 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 β-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.