A genome-wide association study identifies a novel major locus for glycemic control in type 1 diabetes, as measured by both A1C and glucose.
OBJECTIVE
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 individuals with type 1 diabetes. To identify such loci in type 1 diabetes, we analyzed longitudinal repeated measures of A1C from the Diabetes Control and Complications Trial.


METHODS
We performed a genome-wide association study using the mean of quarterly A1C 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 A1C levels in the conventional treatment group near SORCS1 (10q25.1, P = 7 x 10(-10)), which was also associated with mean glucose (P = 2 x 10(-5)). This was confirmed using A1C 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 and 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 Genetics of Diabetes in Kidneys (GoKinD) study control subjects (P = 0.01) and the BNC2 association with A1C in nondiabetic individuals.


CONCLUSIONS
A major locus for A1C 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.
Paterson
Andrew D
AD
Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada. andrew.paterson@utoronto.ca
Waggott
Daryl
D
Boright
Andrew P
AP
Hosseini
S Mohsen
SM
Shen
Enqing
E
Sylvestre
Marie-Pierre
MP
Wong
Isidro
I
Bharaj
Bhupinder
B
Cleary
Patricia A
PA
Lachin
John M
JM
Below
Jennifer E
JE
Nicolae
Dan
D
Cox
Nancy J
NJ
Canty
Angelo J
AJ
Sun
Lei
L
Bull
Shelley B
SB
D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002096:C-Peptide / Q000097:blood; D048909:Diabetes Complications / Q000453:epidemiology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D004334:Drug Administration Schedule; D005006:Ethnicity; D055106:Genome-Wide Association Study / Q000379:methods*; D006442:Glycated Hemoglobin / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000150:complications; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use*; D015201:Meta-Analysis as Topic; D018579:Patient Selection; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups; D011956:Receptors, Cell Surface / Q000235:genetics; D012016:Reference Values; D035781:Siblings
D001786:Blood Glucose; D002096:C-Peptide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D011956:Receptors, Cell Surface; C472780:SORCS1 protein, human