G2Cdb::Human Disease report

Disease id
D00000139
Name
Diabetes mellitus
Nervous system disease
no

Genes (2)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001821 SHANK2
SH3 and multiple ankyrin repeat domains 2
N (12765847) Single nucleotide polymorphism (SNP) Y
G00001473 GNAS
GNAS complex locus
Y (15894831) Single nucleotide polymorphism (SNP) N

References

  • Association of a GNAS1 gene variant with hypertension and diabetes mellitus.

    Yamamoto M, Abe M, Jin JJ, Wu Z, Tabara Y, Mogi M, Kohara K, Miki T and Nakura J

    Department of Geriatric Medicine, School of Medicine, Ehime University, Onsen-gun, Ehime, Japan.

    Previous studies have shown that the T allele of the GNAS1 T393C polymorphism is associated with poor responsiveness to beta-blockade and that the T393C polymorphism interacts with cigarette smoking and alcohol consumption in the pathogenesis of hypertension. Thus, the T393C polymorphism is likely to interact with beta-adrenoceptor (beta-AR) stimulation in the pathogenesis of hypertension. Although this interaction might be caused by a direct effect of Gs proteins on the cardiovascular system, it could also result from an indirect effect of Gs proteins mediated by glucose metabolism. Moreover, association studies are often irreproducible. We therefore examined the possible interaction between the T393C polymorphism and gamma-glutamyl transpeptidase (GGT), which is an established biomarker of alcohol consumption, in the association with glucose metabolism as well as with hypertension in a Japanese population. Genotyping for GNAS1 was performed by using the polymerase chain reaction-restriction fragment length polymorphism method in all 821 samples. The present study showed a significant interaction between the T393C polymorphism and GGT in the association with hypertension (p =0.033). This interaction was even more significant after adjustment for all confounding factors (p =0.0025). In contrast, analysis of the possible interaction of the T393C polymorphism with GGT in the association with diabetes mellitus or fasting plasma glucose failed to show a significant result. These results did not support the hypothesis that the interaction between the T393C polymorphism and GGT in the association with hypertension could be caused by an indirect effect of Gs proteins mediated by glucose metabolism.

    Hypertension research : official journal of the Japanese Society of Hypertension 2004;27;12;919-24

  • Association of a F479L variant in the cytosolic phospholipase A2 gene (PLA2G4A) with decreased glucose turnover and oxidation rates in Pima Indians.

    Wolford JK, Konheim YL, Colligan PB and Bogardus C

    Clinical Diabetes and Nutrition Section, Phoenix Epidemiology and Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 4212 North 16th Street, AZ 85016, USA. jwolford@exchange.nih.gov

    Phospholipase A2, Group IVA (PLA2G4A) belongs to the class of cytosolic calcium-dependent phospholipases (cPLA2s) that preferentially cleave arachidonic acid (AA) from membrane glycerophospholipids. AA and AA metabolites play key roles in glucose disposal and insulin secretion. PLA2G4A is located on Chromosome 1q, where a number of groups have reported linkage to type 2 diabetes mellitus. We have screened the PLA2G4A gene and identified a C-->G variant, which predicts a phenylalanine to leucine substitution. In logistic regression analyses adjusted for age, sex, ethnicity, and birth year, we found a trend toward association between this SNP and diabetes [OR=1.53 (0.97-2.40); p=0.06]. Individuals with the variant genotype had lower mean basal endogenous glucose output (1.8+/-0.03 vs. 1.9+/-0.01 mg/kgEMBS/min; p=0.04) and lower mean basal glucose oxidation (1.2+/-0.11 vs. 1.4+/-0.03 mg/kgEMBS/min; p=0.005) compared to individuals with the wild-type genotype. During a low dose insulin infusion, non-diabetic individuals with the variant genotype had a lower mean glucose oxidation (1.9+/-0.11 vs. 2.0+/-0.03 mg/kgEMBS/min; p=0.04) and total glucose turnover rate (2.5+/-0.22 vs. 2.6+/-0.06 mg/kgEMBS/min; p=0.01) compared to subjects with the wild-type genotype. In addition, under basal conditions, individuals with the variant genotype had a higher mean lipid oxidation rate compared to individuals with the wild-type genotype (0.77+/-0.25 vs. 0.67+/-0.23 mg/kgEMBS/min; p=0.02). These results provide evidence supporting a role for the eicosanoid biosynthesis pathway in type 2 diabetes mellitus pathophysiology.

    Molecular genetics and metabolism 2003;79;1;61-6

Literature (2)

Pubmed - human_disease

  • Association of a GNAS1 gene variant with hypertension and diabetes mellitus.

    Yamamoto M, Abe M, Jin JJ, Wu Z, Tabara Y, Mogi M, Kohara K, Miki T and Nakura J

    Department of Geriatric Medicine, School of Medicine, Ehime University, Onsen-gun, Ehime, Japan.

    Previous studies have shown that the T allele of the GNAS1 T393C polymorphism is associated with poor responsiveness to beta-blockade and that the T393C polymorphism interacts with cigarette smoking and alcohol consumption in the pathogenesis of hypertension. Thus, the T393C polymorphism is likely to interact with beta-adrenoceptor (beta-AR) stimulation in the pathogenesis of hypertension. Although this interaction might be caused by a direct effect of Gs proteins on the cardiovascular system, it could also result from an indirect effect of Gs proteins mediated by glucose metabolism. Moreover, association studies are often irreproducible. We therefore examined the possible interaction between the T393C polymorphism and gamma-glutamyl transpeptidase (GGT), which is an established biomarker of alcohol consumption, in the association with glucose metabolism as well as with hypertension in a Japanese population. Genotyping for GNAS1 was performed by using the polymerase chain reaction-restriction fragment length polymorphism method in all 821 samples. The present study showed a significant interaction between the T393C polymorphism and GGT in the association with hypertension (p =0.033). This interaction was even more significant after adjustment for all confounding factors (p =0.0025). In contrast, analysis of the possible interaction of the T393C polymorphism with GGT in the association with diabetes mellitus or fasting plasma glucose failed to show a significant result. These results did not support the hypothesis that the interaction between the T393C polymorphism and GGT in the association with hypertension could be caused by an indirect effect of Gs proteins mediated by glucose metabolism.

    Hypertension research : official journal of the Japanese Society of Hypertension 2004;27;12;919-24

Pubmed - other

  • Association of a F479L variant in the cytosolic phospholipase A2 gene (PLA2G4A) with decreased glucose turnover and oxidation rates in Pima Indians.

    Wolford JK, Konheim YL, Colligan PB and Bogardus C

    Clinical Diabetes and Nutrition Section, Phoenix Epidemiology and Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 4212 North 16th Street, AZ 85016, USA. jwolford@exchange.nih.gov

    Phospholipase A2, Group IVA (PLA2G4A) belongs to the class of cytosolic calcium-dependent phospholipases (cPLA2s) that preferentially cleave arachidonic acid (AA) from membrane glycerophospholipids. AA and AA metabolites play key roles in glucose disposal and insulin secretion. PLA2G4A is located on Chromosome 1q, where a number of groups have reported linkage to type 2 diabetes mellitus. We have screened the PLA2G4A gene and identified a C-->G variant, which predicts a phenylalanine to leucine substitution. In logistic regression analyses adjusted for age, sex, ethnicity, and birth year, we found a trend toward association between this SNP and diabetes [OR=1.53 (0.97-2.40); p=0.06]. Individuals with the variant genotype had lower mean basal endogenous glucose output (1.8+/-0.03 vs. 1.9+/-0.01 mg/kgEMBS/min; p=0.04) and lower mean basal glucose oxidation (1.2+/-0.11 vs. 1.4+/-0.03 mg/kgEMBS/min; p=0.005) compared to individuals with the wild-type genotype. During a low dose insulin infusion, non-diabetic individuals with the variant genotype had a lower mean glucose oxidation (1.9+/-0.11 vs. 2.0+/-0.03 mg/kgEMBS/min; p=0.04) and total glucose turnover rate (2.5+/-0.22 vs. 2.6+/-0.06 mg/kgEMBS/min; p=0.01) compared to subjects with the wild-type genotype. In addition, under basal conditions, individuals with the variant genotype had a higher mean lipid oxidation rate compared to individuals with the wild-type genotype (0.77+/-0.25 vs. 0.67+/-0.23 mg/kgEMBS/min; p=0.02). These results provide evidence supporting a role for the eicosanoid biosynthesis pathway in type 2 diabetes mellitus pathophysiology.

    Molecular genetics and metabolism 2003;79;1;61-6

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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