title: Determinants of HbA1c in nondiabetic Dutch adults: genetic loci and clinical and lifestyle parameters, and their interactions in the Lifelines Cohort Study.
abstract: OBJECTIVE
  Glycated haemoglobin (HbA1c) is associated with cardiovascular disease risk in individuals without diabetes, and its use has been recommended for diagnosing diabetes. Therefore, it is important to gain further understanding of the determinants of HbA1c. The aim of this study was to investigate the effects of genetic loci and clinical and lifestyle parameters, and their interactions, on HbA1c in nondiabetic adults.
  
  
  METHODS
  Population-based cohort study.
  
  
  METHODS
  Three northern provinces of the Netherlands.
  
  
  METHODS
  A total of 2921 nondiabetic adults participating in the population-based LifeLines Cohort Study.
  
  
  METHODS
  Body mass index (BMI), waist circumference, HbA1c, fasting plasma glucose (FPG) and erythrocyte indices were measured. Data on current smoking and alcohol consumption were collected through questionnaires. Genome-wide genotyping was performed, and 12 previously identified single-nucleotide polymorphisms (SNPs) were selected for replication and categorized as 'glycaemic' and 'nonglycaemic' SNPs according to their presumed mechanism(s) of action on HbA1c. Genetic risk scores (GRSs) were calculated as the sum of the weighted effect of HbA1c-increasing alleles.
  
  
  RESULTS
  Age, gender, BMI, FPG, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, current smoking and alcohol consumption were independent predictors of HbA1c, together explaining 26.2% of the variance in HbA1c, with FPG contributing 10.9%. We replicated three of the previously identified SNPs and the GRSs were also found to be independently associated with HbA1c. We found a smaller effect of the 'nonglycaemic GRS' in females compared with males and an attenuation of the effect of the GRS of all 12 SNPs with increasing BMI.
  
  
  CONCLUSIONS
  Our results suggest that a substantial portion of HbA1c is determined by nonglycaemic factors. This should be taken into account when considering the use of HbA1c as a diagnostic test for diabetes.
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands. hannekejansen@gmail.com
authors.forename: H
authors.initials: H
authors.lastname: Jansen
authors.forename: R P
authors.initials: RP
authors.lastname: Stolk
authors.forename: I M
authors.initials: IM
authors.lastname: Nolte
authors.forename: I P
authors.initials: IP
authors.lastname: Kema
authors.forename: B H R
authors.initials: BH
authors.lastname: Wolffenbuttel
authors.forename: H
authors.initials: H
authors.lastname: Snieder
mesh_terms: D000328:Adult; D000428:Alcohol Drinking; D015331:Cohort Studies; D004909:Erythrocyte Indices; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006442:Glycated Hemoglobin / Q000032:analysis* / Q000235:genetics; D006801:Humans; D008019:Life Style; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D018570:Risk Assessment; D044465:White People / Q000235:genetics*
chemical_list: D006442:Glycated Hemoglobin