title: HbA1c-based diabetes diagnosis among patients with glucokinase mutation (GCK-MODY) is affected by a genetic variant of glucose-6-phosphatase (G6PC2).
abstract: OBJECTIVE
  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 HbA(1c) 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 HbA(1c) levels were evaluated separately within both cohorts. Following that, a meta-analysis of rs560887 genotype-HbA(1c) 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 HbA(1c) 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 HbA(1c) levels higher by 2.4 mmol/mol (0.24%), 95% CI 0.5-4.4 mmol/mol (0.05-0.44%) 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 1.07-3.36; 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 HbA(1c) level.
authors.affiliation: Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Borowiec
authors.forename: W
authors.initials: W
authors.lastname: Fendler
authors.forename: P
authors.initials: P
authors.lastname: Dusatkova
authors.forename: K
authors.initials: K
authors.lastname: Antosik
authors.forename: S
authors.initials: S
authors.lastname: Pruhova
authors.forename: O
authors.initials: O
authors.lastname: Cinek
authors.forename: M
authors.initials: M
authors.lastname: Mysliwiec
authors.forename: P
authors.initials: P
authors.lastname: Jarosz-Chobot
authors.forename: M T
authors.initials: MT
authors.lastname: Malecki
authors.forename: W
authors.initials: W
authors.lastname: Mlynarski
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000235:genetics* / Q000378:metabolism; D002648:Child; D018153:Czech Republic / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D005215:Fasting / Q000097:blood; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D008297:Male; D009154:Mutation; D011044:Poland / Q000453:epidemiology; D044465:White People
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D005952:Glucose-6-Phosphatase; D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human; C492194:G6PC2 protein, human