Research Article Synaptosomal Protein of 25 kDa (Snap25) Polymorphisms Associated with Glycemic Parameters in Type 2 Diabetes Patients Nasser M. Al-Daghri, 1,2 Andrea S. Costa, 3 Majed S. Alokail, 1,2 Milena Zanzottera, 3 Amal M. Alenad, 4 Abdul Khader Mohammed, 1,2 Mario Clerici, 3,5 and Franca R. Guerini 3 1 Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia 2 Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia 3 Fondazione Don C Gnocchi, IRCCS, 20148 Milano, Italy 4 School of Biological Sciences, University of Southampton, Southampton SO17 1 BJ, UK 5 Universit` a degli Studi di Milano, 20122 Milano, Italy Correspondence should be addressed to Nasser M. Al-Daghri; aldaghri2011@gmail.com Received 16 June 2015; Revised 24 July 2015; Accepted 28 July 2015 Academic Editor: Bernard Portha Copyright © 2016 Nasser M. Al-Daghri et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A possible role of Snap25 polymorphisms in type 2 diabetes mellitus (T2DM) was evaluated by analyzing three SNPs within intron 1 in a region known to afect the gene expression in vitro. Genomic DNA from 1019 Saudi individuals (489 confrmed T2DM and 530 controls) was genotyped for SNPs rs363039, rs363043, and rs363050 in Snap25 using the TaqMan Genotyping Assay. Signifcantly higher levels of fasting glucose and HbA1c were detected in T2DM patients carrying the rs363050 (AG/GG) genotypes compared to the (AA) genotype ( = 4.41, =1, and  = 0.03 and  = 5.31, =1, and  = 0.03, resp.). In these same patients, insulin levels were signifcantly decreased compared to the (AA) individuals ( = 7.29, =1, and  = 0.009). Signifcant associations were detected between rs363050 (AG/GG) genotypes and increasing fasting glucose levels ( = 0.01 and OR: 1.05), HbA1c levels (OR: 5.06 and  = 0.02), and lower insulinemia ( = 0.03 and OR: 0.95) in T2DM patients. Te minor Snap25 rs363050 (G) allele, which results in a reduced expression of Snap25, is associated with altered glycemic parameters in T2DM possibly because of reduced functionality in the exocytotic machinery leading to suboptimal release of insulin. 1. Introduction Blood glucose levels are regulated by insulin release from pancreatic -cells via exocytosis, a fne-tuned mechanism mediated by complex machinery. During the exocytotic process secretory granules (SG) of insulin fuse with the plasma membrane; this process is mediated by a number of key players including the soluble N-ethylmaleimide- sensitive factor attachment protein receptor (SNARE) proteins. Te SNARE-complex includes the two t-SNARE proteins, synaptosomal protein of 25 kDa (Snap25) and syntaxin 1A, as well as the v-SNARE protein VAMP2. To allow exocytosis the amino terminal of Snap25 binds to syntaxin 1A and the carboxy-terminal binds to VAMP2, forming the four-helical bundle that brings SG in close contact with the plasma membrane, thus enabling fusion to occur. Snap25 is contained in insulin-secreting cells [1] and is known to modulate several processes apart from the actual fusion event, including the activity of potassium voltage gated (Kv)2.1 channels [2]. Notably, Kv2.1 is the prevalent Kv channel in neuroendocrine and endocrine cells, and the Kv2.1 current repolarizes -cell action potentials upon exposure to glucose to limit Ca 2+ entry and insulin secretion. Because of the pivotal role of Snap25 in insulin release [2–6] we evaluated a possible role of three Snap25 polymor- phisms (rs363039, rs363043, and rs363050) that are localized Hindawi Publishing Corporation Journal of Diabetes Research Volume 2016, Article ID 8943092, 4 pages http://dx.doi.org/10.1155/2016/8943092