A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion.
OBJECTIVE
Two independent genome-wide association studies for type 2 diabetes in Japanese subjects have recently identified common variants in the KCNQ1 gene that are strongly associated with type 2 diabetes. Here we studied whether a common variant in KCNQ1 would influence BMI as well as insulin secretion and action and predict future type 2 diabetes in subjects from Sweden and Finland.


METHODS
Risk of type 2 diabetes conferred by KCNQ1 rs2237895 was studied in 2,830 type 2 diabetic case subjects and 3,550 control subjects from Sweden (Malmö Case-Control) and prospectively in 16,061 individuals from the Malmö Preventive Project (MPP). Association between genotype and insulin secretion/action was assessed cross- sectionally in 3,298 nondiabetic subjects from the Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia Study and longitudinally in 2,328 nondiabetic subjects from the Botnia Prospective Study (BPS). KCNQ1 expression (n = 18) and glucose-stimulated insulin secretion (n = 19) were measured in human islets from nondiabetic cadaver donors.


RESULTS
The C-allele of KCNQ1 rs2237895 was associated with increased risk of type 2 diabetes in both the Malmö Case-Control (odds ratio 1.23 [95% CI 1.12-1.34]; P = 5.6 x 10(-6)) and the prospective (1.14 [1.06-1.22]; P = 4.8 x 10(-4)) studies. Furthermore, the C-allele was associated with decreased insulin secretion (corrected insulin response [CIR] P = 0.013; disposition index [DI] P = 0.013) in the PPP-Botnia Study and in the BPS at baseline (CIR P = 3.6 x 10(-4); DI P = 0.0058) and after follow-up (CIR P = 0.0018; DI P = 0.0030). C-allele carriers showed reduced glucose-stimulated insulin secretion in human islets (P = 2.5 x 10(-6)).


CONCLUSIONS
A common variant in the KCNQ1 gene is associated with increased risk of future type 2 diabetes in Scandinavians, which partially can be explained by an effect on insulin secretion.
Jonsson
Anna
A
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, and Lund University Diabetes Centre, Malmö, Sweden. anna.jonsson@med.lu.se
Isomaa
Bo
B
Tuomi
Tiinamaija
T
Taneera
Jalal
J
Salehi
Albert
A
Nilsson
Peter
P
Groop
Leif
L
Lyssenko
Valeriya
V
D015992:Body Mass Index; D002102:Cadaver; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005387:Finland; D014644:Genetic Variation; D005838:Genotype; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D007564:Japan; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D011237:Predictive Value of Tests; D012016:Reference Values; D013548:Sweden
D007328:Insulin; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D005947:Glucose