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

Bouatia-Naji N, Vatin V, Lecoeur C, Heude B, Proença C, Veslot J, Jouret B, Tichet J, Charpentier G, Marre M, Balkau B, Froguel P, Meyre D - BMC Med. Genet. (2007)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: CNRS-8090-Institute of Biology, Pasteur Institute, Lille, France. nabila.bouatia-naji@good.ibl.fr

ABSTRACT

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.

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Plasma glucose (A and B) and plasma insulin (C and D) after OGTTs in obese children (A and C) and obese adults (B and D) according to SNP -1,701A>G (rs11635997) genotypes. Glucose and insulin levels during OGTT were compared using a general linear model ANOVA for repeated measures, adjusted for age, sex, and BMI. P values are for the dominant model (AA vs. AG+GG).
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Figure 2: Plasma glucose (A and B) and plasma insulin (C and D) after OGTTs in obese children (A and C) and obese adults (B and D) according to SNP -1,701A>G (rs11635997) genotypes. Glucose and insulin levels during OGTT were compared using a general linear model ANOVA for repeated measures, adjusted for age, sex, and BMI. P values are for the dominant model (AA vs. AG+GG).

Mentions: We then investigated associations between SGNE1 SNPs and obesity related quantitative traits in obese subjects. SNP-1,701A>G, located in intron 1 which is part of the 5' region of SGNE1 (Figure 1), showed several strong and consistent associations with glucose intolerance. In obese children, despite no significant difference for fasting glucose, SNP -1,701A>G associated with an average 0.5 mmol/l increase (p = 0.0002) in glucose levels 30 min after an OGTT (Figure 2A) suggesting that -1,701A>G might alter the early insulin response after a glucose load. Indeed, the allele -1,701A carriers showed a 27% decrease in the insulinogenic index, an estimator of insulin secretion capacity (p = 0.0003) (Figure 3). Differences in glucose levels according to -1,701A>G genotypes were still significant after 120 min (p = 0.005). Thus, -1,701A>G associated with a 6% increase in the area under the curve (AUC) for glucose after OGTT (Figure 3; p = 0.0001). On the other hand, excepting for a borderline association with fasting insulin levels (p = 0.034), no significant differences were observed according to the -1,701A>G genotype for insulin levels during the OGTT (Figure 2B). Consequently, SNP -1,701A>G did not associate with AUC for insulin (p = 0.141) (Figure 3). However, the -1,701A allele associated with higher circulating fasting levels of pro-insulin in obese children (p = 0.037, data not shown).


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

Bouatia-Naji N, Vatin V, Lecoeur C, Heude B, Proença C, Veslot J, Jouret B, Tichet J, Charpentier G, Marre M, Balkau B, Froguel P, Meyre D - BMC Med. Genet. (2007)

Plasma glucose (A and B) and plasma insulin (C and D) after OGTTs in obese children (A and C) and obese adults (B and D) according to SNP -1,701A>G (rs11635997) genotypes. Glucose and insulin levels during OGTT were compared using a general linear model ANOVA for repeated measures, adjusted for age, sex, and BMI. P values are for the dominant model (AA vs. AG+GG).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1936990&req=5

Figure 2: Plasma glucose (A and B) and plasma insulin (C and D) after OGTTs in obese children (A and C) and obese adults (B and D) according to SNP -1,701A>G (rs11635997) genotypes. Glucose and insulin levels during OGTT were compared using a general linear model ANOVA for repeated measures, adjusted for age, sex, and BMI. P values are for the dominant model (AA vs. AG+GG).
Mentions: We then investigated associations between SGNE1 SNPs and obesity related quantitative traits in obese subjects. SNP-1,701A>G, located in intron 1 which is part of the 5' region of SGNE1 (Figure 1), showed several strong and consistent associations with glucose intolerance. In obese children, despite no significant difference for fasting glucose, SNP -1,701A>G associated with an average 0.5 mmol/l increase (p = 0.0002) in glucose levels 30 min after an OGTT (Figure 2A) suggesting that -1,701A>G might alter the early insulin response after a glucose load. Indeed, the allele -1,701A carriers showed a 27% decrease in the insulinogenic index, an estimator of insulin secretion capacity (p = 0.0003) (Figure 3). Differences in glucose levels according to -1,701A>G genotypes were still significant after 120 min (p = 0.005). Thus, -1,701A>G associated with a 6% increase in the area under the curve (AUC) for glucose after OGTT (Figure 3; p = 0.0001). On the other hand, excepting for a borderline association with fasting insulin levels (p = 0.034), no significant differences were observed according to the -1,701A>G genotype for insulin levels during the OGTT (Figure 2B). Consequently, SNP -1,701A>G did not associate with AUC for insulin (p = 0.141) (Figure 3). However, the -1,701A allele associated with higher circulating fasting levels of pro-insulin in obese children (p = 0.037, data not shown).

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: CNRS-8090-Institute of Biology, Pasteur Institute, Lille, France. nabila.bouatia-naji@good.ibl.fr

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus