Variation in the Calpain-10 Gene Affects Blood Glucose Levels in the British Population

• Published in: Diabetes (New York, N.Y.) Vol. 51; no. 1; pp. 247 - 250
• Main Authors: Lynn, Stephen, Evans, Julie C., White, Christopher, Frayling, Timothy M., Hattersley, Andrew T., Turnbull, Doug M., Horikawa, Yukio, Cox, Nancy J., Bell, Graeme I., Walker, Mark
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.01.2002
• Subjects: Adult; Aged; Biological and medical sciences; Blood Glucose - metabolism; Body Constitution; Body Mass Index; Calpain - genetics; Disease susceptibility; European Continental Ancestry Group; Female; Genetic aspects; Genetic disorders; Genetic Variation; Glucose Tolerance Test; Humans; Insulin - blood; Ireland - ethnology; Male; Middle Aged; Polymerase Chain Reaction; Type 2 diabetes; United Kingdom; United States; United Kingdom
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.51.1.247

Variation in the Calpain-10 Gene Affects Blood Glucose Levels in the British Population Stephen Lynn 1 , Julie C. Evans 2 , Christopher White 3 , Timothy M. Frayling 2 , Andrew T. Hattersley 2 , Doug M. Turnbull 3 , Yukio Horikawa 4 5 , Nancy J. Cox 6 7 , Graeme I. Bell 4 5 6 7 and Mark Walker 1 1 School of Clinical Medical Sciences, the Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, U.K. 2 Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter, U.K. 3 Department of Neurology, the Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, U.K. 4 Howard Hughes Medical Institute, the University of Chicago, Chicago, Illinois 5 Departments of Biochemistry and Molecular Biology, the University of Chicago, Chicago, Illinois 6 Department of Medicine, the University of Chicago, Chicago, Illinois 7 Department of Human Genetics, the University of Chicago, Chicago, Illinois Abstract Variation in the calpain-10 gene ( CAPN10 ) has been shown to be associated with type 2 diabetes in Mexican-Americans and in at least three Northern European populations. Studies in nondiabetic Pima Indians showed that one of the at-risk DNA polymorphisms, single-nucleotide polymorphism (SNP)-43, in CAPN10 was associated with insulin resistance, and individuals with the G/G-genotype had significantly higher fasting plasma glucose and 2-h insulin concentrations after a 75-g oral glucose tolerance test (OGTT). We have examined the effect of variation in CAPN10 on plasma glucose and insulin levels in a group of 285 nondiabetic British subjects after a 75-g OGTT. The results showed that subjects with G/G genotype at SNP-43 had higher 2-h plasma glucose levels than the combined G/A + A/A group ( P = 0.05). We also examined the SNP-43, -19, and -63 haplotype combination 112/121, which is associated with an approximately threefold increased risk of diabetes. Subjects with the 112/121 haplotype combination ( n = 29) had increased fasting ( P = 0.004) and 2-h plasma glucose levels ( P = 0.003) compared with the rest of the study population after correction for age, sex, and BMI. The 112/121 haplotype combination was also associated with a marked decrease in the insulin secretory response, adjusted for the level of insulin resistance ( P = 0.002). We conclude that genetic variation in the CAPN10 gene influences blood glucose levels in nondiabetic British subjects and that this is due, at least in part, to the effects of calpain-10 on the early insulin secretory response. Footnotes Address correspondence and reprint requests to Dr. Mark Walker, School of Clinical Medical Sciences, the Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, U.K. E-mail: mark.walker{at}ncl.ac.uk . Additional information can be found in an online appendix at http://diabetes.diabetesjournals.org . Received for publication 2 April 2001 and accepted in revised form 18 October 2001. CV, coefficient of variation; EIR, early insulin response; HOMA IR , homeostasis model assessment of insulin resistance; OGTT, oral glucose tolerance test; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism.