Genetic and functional assessment of the role of the rs13431652-A and rs573225-A alleles in the G6PC2 promoter that are strongly associated with elevated fasting glucose levels.

Diabetes
Nabila Bouatia-NajiR M O'Brien

Abstract

Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs560887, located in a G6PC2 intron that is highly correlated with variations in fasting plasma glucose (FPG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. This study examines the contribution of two G6PC2 promoter SNPs, rs13431652 and rs573225, to the association signal. We genotyped 9,532 normal FPG participants (FPG <6.1 mmol/l) for three G6PC2 SNPs, rs13431652 (distal promoter), rs573225 (proximal promoter), rs560887 (3rd intron). We used regression analyses adjusted for age, sex, and BMI to assess the association with FPG and haplotype analyses to assess comparative SNP contributions. Fusion gene and gel retardation analyses characterized the effect of rs13431652 and rs573225 on G6PC2 promoter activity and transcription factor binding. Genetic analyses provide evidence for a strong contribution of the promoter SNPs to FPG variability at the G6PC2 locus (rs13431652: β = 0.075, P = 3.6 × 10(-35); rs573225 β = 0.073 P = 3.6 × 10(-34)), in addition to rs560887 (β = 0.071, P = 1.2 × 10(-31)). The rs13431652-A and rs573225-A alleles promote increased NF-Y and Foxa2 binding, respectively. The rs13431652-A allele is ...Continue Reading

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Citations

Sep 30, 2010·Current Diabetes Reports·Martijn van de Bunt, Anna L Gloyn
Nov 5, 2011·Critical Reviews in Biochemistry and Molecular Biology·Diletta DolfiniRoberto Mantovani
Dec 8, 2015·Genetic Epidemiology·Debashree RaySaonli Basu
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Jan 27, 2017·Journal of Molecular Endocrinology·Kayla A BoortzRichard M O'Brien
Jun 18, 2019·Journal of Diabetes Research·Ying WangZhiguang Su

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Methods Mentioned

BETA
genotyping
fluorescence-activated cell sorter
PCR
transfection
electrophoresis
immunoprecipitation

Software Mentioned

THESIAS
MatInspector
ABI HT SDS
R meta package
rmeta
R
survival

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