Original Article
International Journal of Obesity (2008) 32, 413–420; doi:10.1038/sj.ijo.0803743; published online 2 October 2007
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
S Romeo1,2,5, F Sentinelli1,3,5, M G Cavallo4, F Leonetti3, M Fallarino3, S Mariotti1 and M G Baroni1
- 1Department of Medical Sciences, Endocrinology and Metabolism, University of Cagliari, Cagliari, Italy
- 2Donald W Reynolds Cardiovascular Clinical Research Center, Southwestern Medical Center, University of Texas, Dallas, TX, USA
- 3Division of Endocrinology, Department of Clinical Sciences, I Faculty of Medicine, University of Rome 'La Sapienza', Rome, Italy
- 4Department of Medical Therapy, University of Rome 'La Sapienza', Rome, Italy
Correspondence: Professor MG Baroni, Department of Medical Sciences, Endocrinology and Metabolism, University of Cagliari, Policlinico Universitario, Bivio di Sestu, 09042, Monserrato (CA), Italy. E-mail: marcobaroni@pacs.unica.it
5These authors contributed equally to this work.
Received 26 February 2007; Revised 5 July 2007; Accepted 19 August 2007; Published online 2 October 2007.
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)
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/EBP antibody 'supershifted' the complex, indicating that C/EBP 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 -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.
Keywords:
SYNTAXIN 1A, insulin secretion, diabetes mellitus, SNARE, EMSA, human insulinoma
