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  • Title: A novel functional polymorphism (-336A/G) in the promoter of the partitioning-defective protein-6alpha gene is associated with increased glucose tolerance and lower concentrations of serum non-esterified fatty acids.
    Author: Weyrich P, Lammers R, Fritsche A, Machicao F, Häring HU, Stefan N.
    Journal: Diabetologia; 2005 Apr; 48(4):669-74. PubMed ID: 15744531.
    Abstract:
    AIMS/HYPOTHESIS: Partitioning-defective protein-6alpha (Par6alpha) has recently been demonstrated to negatively regulate insulin signalling in murine myoblasts. To address whether Par6alpha plays a role in human physiology, the present study investigated whether mutations exist in the Par6alpha gene and whether these mutations, if present, are associated with pre-diabetic phenotypes in non-diabetic subjects. METHODS: The complete gene (part of the promoter [2.1 kb], all exons/introns and the 3' untranslated region) encoding Par6alpha was analysed in 664 non-diabetic subjects. We investigated possible associations between single nucleotide polymorphisms and percentage of body fat, glucose tolerance (as determined by OGTT), serum NEFA concentrations and whole-body insulin sensitivity (estimated during the OGTT, and for a subgroup of 242 subjects determined by the euglycaemic-hyperinsulinaemic clamp). RESULTS: A rare A/G polymorphism was found 336-bp upstream of the translational start codon (allele frequency 0.03). The data for subjects homozygous and heterozygous for -336G (R/G, n=43) were combined and compared with those for subjects homozygous for -336A (A/A, n=621). Subjects with the R/G genotype had lower fasting (4.84+/-0.09 mmol/l, means+/-SEM, p=0.049) and 2-h (5.50+/-0.02 mmol/l, p=0.050) plasma glucose concentrations than subjects with the A/A genotype (5.02+/-0.02 and 5.94+/-0.06 mmol/l, respectively). Subjects with the R/G genotype also had lower fasting (448+/-31 micromol/l, p=0.018) and 2-h serum NEFA concentrations (61+/-7 micromol/l, p=0.015) than subjects with the A/A genotype (529+/-9 and 75+/-2 micromol/l, respectively), adjusted for age, sex and percentage of body fat. There were no differences in adiposity or whole-body insulin sensitivity between the two genotype groups (all p>0.36). A luciferase reporter gene assay revealed that the -336G promoter variant had a significantly lower (-22.8%, p=0.006) transcriptional activity in transfected C2C12 murine myoblasts than the -336A promoter variant. CONCLUSIONS/INTERPRETATION: A novel functional variant in the promoter of the Par6alpha gene is associated with reduced fasting glycaemia, increased glucose tolerance and reduced serum NEFA concentrations.
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