Variants in the Calpain-10 Gene Predispose to Insulin Resistance and Elevated Free Fatty Acid Levels
Author:
Orho-Melander Marju1, Klannemark Mia1, Svensson Malin K.1, Ridderstråle Martin1, Lindgren Cecilia M.1, Groop Leif1
Affiliation:
1. Department of Endocrinology, Wallenberg Laboratory, Lund University, Malmö, Sweden
Abstract
The calpain-10 gene (CAPN10) has been associated with type 2 diabetes, but information on molecular and physiological mechanisms explaining this association is limited. Here we addressed this question by studying the role of CAPN10 for phenotypes associated with type 2 diabetes and free fatty acid (FFA) metabolism. Among 395 type 2 diabetic patients and 298 nondiabetic control subjects from Finland, the SNP-43 allele 1 (P = 0.011), SNP-63 allele 2 (P = 0.010), and the haplotype combination SNP-44/43/19/63 1121/1121 (P = 0.028) were associated with type 2 diabetes. The SNP-43 genotypes 11 and 12 were associated with higher fasting insulin and homeostasis model assessment (HOMA) insulin resistance index among control subjects (P = 0.021 and P = 0.0076) and with elevated FFA among both control subjects (P = 0.0040) and type 2 diabetic patients (P = 0.0025). Multiple regression analysis further indicated that SNP-43 is an independent predictor of FFA levels (P = 0.0037). Among 80 genotype discordant sibling pairs, the SNP-43 allele 1 was associated with elevated fasting serum insulin and HOMA index (P = 0.013 and P = 0.0068). None of the four SNPs showed distorted transmission of alleles to patients with type 2 diabetes in a qualitative transmission disequilibrium test, including 108 trios. Because FFA and insulin resistance are known to predict type 2 diabetes, the finding that variation in the CAPN10 gene influences FFA levels and insulin resistance may provide an explanation for how the CAPN10 gene increases susceptibility to type 2 diabetes.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Reference26 articles.
1. Hanis C, Boerwinkle E, Chakraborty R, Ellsworth D, Concannon P, Stirling B, Morrison V, Wapelhorst B, Spielman R, Goglin-Ewens K, Shephard J, Williams S, Risch N, Hinds D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietsch H, Schröder H-E, Schulze J, Cox N, Menzel S, Boriraj V, Chen X, Lim L, Lindner T, Mereu L, Wang Y-Q, Xiang K, Yamagata K, Yang Y, Bell G: A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 13:161–166,1996 2. Horikawa Y, Oda N, Cox N, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner T, Mashi H, Schwarz P, del Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchi I, Colilla S, Polonsky K, Wei S, Concannon P, Iwasaki N, Schulze J, Baier L, Bogardus C, Groop L, Boerwinkle E, Hanis C, Bell G: Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26:163–175,2000 3. Evans JC, Frayling TM, Cassell PG, Saker PJ, Hitman GA, Walker M, Levy JC, O’Rahilly S, Rao PV, Bennett AJ, Jones EC, Menzel S, Prestwich P, Simecek N, Wishart M, Dhillon R, Fletcher C, Millward A, Demaine A, Wilkin T, Horikawa Y, Cox NJ, Bell GI, Ellard S, McCarthy MI, Hattersley AT: Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom. Am J Hum Genet 69:544–552,2001 4. Baier L, Permana P, Yang X, Pratley R, Hanson R, Shen G, Mott D, Knowler W, Cox N, Horikawa Y, Oda N, Bell G, Bogardus C: A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 106:R69–R73,2000 5. Sorimachi H, Ishiura S, Suzuki K: A novel tissue-specific calpain species expressed predominantly in the stomach comprises two alternative splicing products with and without Ca(2+)-binding domain. J Biol Chem 268:19476–19482,1993
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