Determinants of HbA1c in nondiabetic Dutch adults: genetic loci and clinical and lifestyle parameters, and their interactions in the Lifelines Cohort Study

J Intern Med. 2013 Mar;273(3):283-93. doi: 10.1111/joim.12010. Epub 2012 Dec 5.


Objectives: 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.

Design: Population-based cohort study.

Setting: Three northern provinces of the Netherlands.

Subjects: A total of 2921 nondiabetic adults participating in the population-based LifeLines Cohort Study.

Measurements: 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.

MeSH terms

  • Adult
  • Alcohol Drinking
  • Cohort Studies
  • Erythrocyte Indices
  • European Continental Ancestry Group / genetics*
  • Female
  • Genetic Loci*
  • Genome-Wide Association Study
  • Glycated Hemoglobin A / analysis*
  • Glycated Hemoglobin A / genetics
  • Humans
  • Life Style
  • Male
  • Middle Aged
  • Netherlands
  • Polymorphism, Single Nucleotide
  • Quality Control
  • Risk Assessment


  • Glycated Hemoglobin A