A genome-wide association study identifies a novel major locus for glycemic control in type 1 diabetes, as measured by both HbA1c and glucose.

  1. Andrew D. Paterson (andrew.paterson{at}utoronto.ca)(1)(4),
  2. Daryl Waggott(2),
  3. Andrew P. Boright(3),
  4. S. Mohsen Hosseini(1),
  5. Enqing Shen(2),
  6. Marie-Pierre Sylvestre(2),
  7. Isidro Wong(1),
  8. Bhupinder Bharaj(1),
  9. Patricia A. Cleary(5),
  10. John M. Lachin(5),
  11. MAGIC,
  12. Jennifer E. Below(8),
  13. Dan Nicolae(8),
  14. Nancy J. Cox(8),
  15. Angelo J. Canty(6),
  16. Lei Sun(4)(7),
  17. Shelley B. Bull(2)(4) and
  18. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group
  1. 1. Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada
  2. 2. Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, Toronto, Canada
  3. 3. Department of Medicine, University Health Network, University of Toronto, Toronto, Canada
  4. 4. Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
  5. 5. The Biostatistics Center, The George Washington University, Rockville, Maryland
  6. 6. Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada
  7. 7. Department of Statistics, University of Toronto, Canada
  8. 8. Department of Genetics, University of Chicago, IL


    Background: Glycemia is a major risk factor for the development of long-term complications in type 1 diabetes, however no specific genetic loci have been identified for glycemic control in persons with type 1 diabetes. To identify such loci in type 1 diabetes, we analyzed longitudinal repeated measures of HbA1c from the Diabetes Control and Complications Trial (DCCT).

    Methods: We performed a genome-wide association study using the mean of quarterly HbA1c values measured over 6.5 years, separately in the conventional (n=667) and intensive (n=637) treatment groups of the DCCT. At loci of interest, linear mixed models were used to take advantage of all the repeated measures. We then assessed the association of these loci with capillary glucose, and repeated measures of multiple complications of diabetes.

    Results: We identified a major locus for HbA1c levels in the conventional treatment group near SORCS1 (10q25.1, p=7×10−10) which was also associated with mean glucose (p=2×10−5). This was confirmed using HbA1c in the intensive treatment group (p=0.01). Other loci achieved evidence close to genome-wide significance: 14q32.13 (GSC) and 9p22 (BNC2) in the combined treatment groups; 15q21.3 (WDR72) in the intensive group. Further, these loci gave evidence for association with diabetic complications, specifically SORCS1 with hypoglycemia, and BNC2 with renal and retinal complications. We replicated the SORCS1 association in GoKinD controls (p=0.01), and the BNC2 association with HbA1c in non-diabetic individuals.

    Conclusions: A major locus for HbA1c and glucose in individuals with diabetes is near SORCS1. This may influence the design and analysis of genetic studies attempting to identify risk factors for long-term diabetic complications.


      • Received May 1, 2009.
      • Accepted October 20, 2009.

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