Secretory granule neuroendocrine protein 1 (SGNE1) genetic variation and glucose intolerance in severe childhood and adult obesity.

BACKGROUND: 7B2 is a regulator/activator of the prohormone convertase 2 which is involved in the processing of numerous neuropeptides, including insulin, glucagon and pro-opiomelanocortin. We have previously described a suggestive genetic linkage peak with childhood obesity on chr15q12-q14, where the 7B2 encoding gene, SGNE1 is located. The aim of this study is to analyze associations of SGNE1 genetic variation with obesity and metabolism related quantitative traits. METHODS: We screened SGNE1 for genetic variants in obese children and genotyped 12 frequent single nucleotide polymorphisms (SNPs). Case control analyses were performed in 1,229 obese (534 children and 695 adults), 1,535 individuals with type 2 diabetes and 1,363 controls, all French Caucasians. We also studied 4,922 participants from the D.E.S.I.R prospective population-based cohort. RESULTS: We did not find any association between SGNE1 SNPs and childhood or adult obesity. However, the 5' region SNP -1,701A>G associated with higher area under glucose curve after oral glucose tolerance test (p = 0.0005), higher HOMA-IR (p = 0.005) and lower insulinogenic index (p = 0.0003) in obese children. Similar trends were found in obese adults. SNP -1,701A>G did not associate with risk of T2D but tends to associate with incidence of type 2 diabetes (HR = 0.75 95%CI [0.55-1.01]; p = 0.06) in the prospective cohort. CONCLUSION: SGNE1 genetic variation does not contribute to obesity and common forms of T2D but may worsen glucose intolerance and insulin resistance, especially in the background of severe and early onset obesity. Further molecular studies are required to understand the molecular bases involved in this process.

Impact of common type 2 diabetes risk polymorphisms in the DESIR prospective study.

OBJECTIVE: The emerging picture of type 2 diabetes genetics involves differently assembled gene variants, each modestly increasing risk with environmental exposure. However, the relevance of these genes for disease prediction has not been extensively tested. RESEARCH DESIGN AND METHODS: We analyzed 19 common polymorphisms of 14 known candidate genes for their contribution to prevalence and incidence of glucose intolerance in the DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) prospective study of middle-aged Caucasian subjects, including 3,877 participants (16.8% with hyperglycemia and 7.9% with diabetes after the 9-year study). RESULTS: The GCK (Glucokinase) -30A allele was associated with increased type 2 diabetes risk at the end of the follow-up study (adjusted OR 1.34 [95% CI 1.07-1.69]) under an additive model, as supported in independent French diabetic case subjects (OR 1.22, P = 0.007), with increased fasting glycemia (0.85% per A allele, P = 6 x 10(-5)) and decreased homeostasis model assessment of beta-cell function (4%, P = 0.0009). IL6 (Interleukin- 6) -174 G/C interacts with age in disease risk and modulates fasting glycemia according to age (1.36% decrease over 56 years, P = 5 x 10(-5)). These polymorphisms together with KCNJ11 (Kir6.2)-E23K and TCF7L2-rs7903146 may predict diabetes incidence in the DESIR cohort. Each additional risk allele at GCK, TCF7L2, and IL6 increased risk by 1.34 (P = 2 x 10(-6)), with an OR of 2.48 (95% CI 1.59-3.86), in carriers of at least four at-risk alleles compared with those with none or one risk allele. CONCLUSIONS: Our data confirm several at-risk polymorphisms for type 2 diabetes in a general population and demonstrate that prospective studies are valuable designs to complement classical genetic approaches.