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Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes

J. Pihlajamäki^{1, 2}, U. Salmenniemi¹, M. Vänttinen¹, E. Ruotsalainen¹, J. Kuusisto¹, I. Vauhkonen¹, S. Kainulainen³, M. C. Y. Ng⁴, N. J. Cox⁴, G. I. Bell⁴ and M. Laakso¹

(1)	University of Kuopio, Department of Medicine, Kuopio, Finland

(2)	Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA

(3)	University of Kuopio, Department of Clinical Radiology, Kuopio, Finland

(4)	Departments of Medicine and Human Genetics, University of Chicago, Chicago, IL, USA

Received: 23 January 2006 Accepted: 9 March 2006 Published online: 12 May 2006

Abstract

Aims/hypothesis The mechanisms by which the calpain-10 gene (CAPN10) affects the risk of type 2 diabetes are unclear. Therefore, we investigated the effects of four polymorphisms in CAPN10 (single nucleotide polymorphism [SNP]-43, SNP-44, Insertion/Deletion [Indel]-19 and SNP-63) on insulin secretion, insulin action and abdominal fat distribution in offspring of patients with type 2 diabetes.

Subjects and methods Insulin secretion was determined by an IVGTT, insulin action by the hyperinsulinaemic–euglycaemic clamp and abdominal fat distribution by computed tomography in 158 non-diabetic offspring (age 34.9±6.3 years [mean±SD], BMI 26.2±4.9 kg/m²) of type 2 diabetic patients.

Results SNP-43 (p=0.009 over the three genotypes, adjusted for age, sex, BMI and family relationship) and haplotypes carrying the A allele of SNP-43 were associated with intra-abdominal fat area. The A allele of SNP-43 was associated with intra-abdominal fat area in men (p=0.014) but not in women. SNP-44, InDel-19 and SNP-63 were not associated with intra-abdominal fat area or insulin action. Furthermore, we demonstrated in a separate sample of middle-aged men (n=234) who had a history of type 2 diabetes in first-degree relatives that the A allele of SNP-43 was associated with a large waist circumference, and high insulin levels in an OGTT.

Conclusions/interpretation SNP-43 of CAPN10 may contribute to the risk of diabetes by regulating abdominal obesity in subjects with high risk of type 2 diabetes.

Keywords Calpain-10 - Insulin resistance - Insulin secretion - Type 2 diabetes - Visceral obesity

J. Pihlajamäki
Email: Jussi.Pihlajamaki@joslin.harvard.edu
Phone: +1-617-2642773
Fax: +1-617-7322593

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