Variation in the Calpain-10 Gene Affects Blood Glucose Levels in the British Population
- Stephen Lynn1,
- Julie C. Evans2,
- Christopher White3,
- Timothy M. Frayling2,
- Andrew T. Hattersley2,
- Doug M. Turnbull3,
- Yukio Horikawa45,
- Nancy J. Cox67,
- Graeme I. Bell4567 and
- Mark Walker1
- 1School of Clinical Medical Sciences, the Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, U.K.
- 2Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter, U.K.
- 3Department of Neurology, the Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, U.K.
- 4Howard Hughes Medical Institute, the University of Chicago, Chicago, Illinois
- 5Departments of Biochemistry and Molecular Biology, the University of Chicago, Chicago, Illinois
- 6Department of Medicine, the University of Chicago, Chicago, Illinois
- 7Department 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
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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; HOMAIR, homeostasis model assessment of insulin resistance; OGTT, oral glucose tolerance test; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism.
