HbA1c-based diabetes diagnosis among patients with glucokinase mutation (GCK-MODY) is affected by a genetic variant of glucose-6-phosphatase (G6PC2)
Abstract
Aims Genetic variation at the rs560887 locus of the glucose-6-phosphatase, catalytic 2 gene (G6PC2) is known to affect regulation of fasting glycaemia. We determined the rs560887 genotype of patients with monogenic diabetes and glucokinase gene mutations (GCK-MODY) and correlated the genotypes with HbA1c levels.
Methods Patients from families with GCK-MODY were recruited from two large cohorts from Poland (n = 128) and the Czech Republic (n = 154). Genotypes at the rs560887 polymorphic site in G6PC2 were examined using real-time quantitative polymerase chain reaction.
The effect of rs560887 genotype on age at diagnosis of GCK-MODY and initial HbA1c levels were evaluated separately within both cohorts. Following that, a meta-analysis of rs560887 genotypeHbA1c associations of both Polish and Czech cohorts was performed to confirm homogeneity of findings and validate cohort-specific results.
Results GG homozygosity at rs560887 was associated with marginally elevated HbA1c levels (P = 0.07 in both cohorts). The effects observed in both groups were very homogeneous (Q = 0.18; P = 0.68).
Meta-analysis showed that GG homozygosity at rs560887 was associated with mean HbA1c levels higher by 2.4 mmol/mol (0.24%), 95% CI 0.54.4 mmol/mol (0.050.44%) than in individuals with other genotypes. Additionally, meta-analysis of both cohorts showed that GG homozygous individuals had higher odds of reaching the 48 mmol/mol (6.5%) diagnostic threshold of diabetes; (odds ratio 1.90; 95% CI 1.073.36; P = 0.03).
No such effects were observed for age at diagnosis of diabetes. Conclusions Variation at the rs560887 locus of G6PC2 is associated with worse glycated haemoglobin levels in individuals with GCK mutations; GG homozygotes are more likely to meet diagnostic criteria for diabetes based on HbA1c level.