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Diabetes Care 24:1498-1499, 2001
© 2001 by the American Diabetes Association, Inc.

Letters: Observations
Letter

Absence of Association of Type 2 Diabetes With CAPN10 and PC-1 Polymorphisms in Oji-Cree

Robert A. Hegele, MD1, Stewart B. Harris, MD2, Bernard Zinman, MD3, Anthony J.G. Hanley, PHD3 and Henian Cao, MD1

1 John P. Robarts Research Institute
2 Centre for Studies in Family Medicine, University of Western Ontario, London
3 Samuel Lunenfeld Research Institute and Department of Medicine, Mount Sinai Hospital, University of Toronto, Ontario, Canada. E-mail: robert.hegele{at}rri.on.ca.

In the Oji-Cree of Northern Ontario, we previously demonstrated that the private HNF1A S319 allele was strongly associated with type 2 diabetes (1), and that the PPARG Q12 allele was associated with both the earlier onset and presence of type 2 diabetes (2). However, HNF1A S319 and PPARG Q12 were present in only ~60% of Oji-Cree subjects with type 2 diabetes, suggesting that other genetic determinants exist in this population. Recent reports have implicated CAPN10 (3), specifically the UCSNP-43 G allele (also called g.4852G) (4), and PC-1, specifically the Q121 allele (5,6), as possible genetic determinants for type 2 diabetes. We thus evaluated the association of these alleles with type 2 diabetes in the Oji-Cree.

The attributes of this Oji-Cree sample have been previously reported (1,2). We used published methods to determine genotypes of CAPN10 (4) and PC-1 (5) in 121 subjects with type 2 diabetes and 468 subjects without type 2 diabetes. The overall allele frequencies of the CAPN10 g.4852G and PC-1 Q121 were 0.504 and 0.266, with no deviation of genotype frequencies from Hardy-Weinberg expectations. The relative risk for type 2 diabetes for the CAPN10 g.4852G and PC-1 Q121 alleles, under a recessive model for each allele, are shown in Table 1. There was no difference when dominant and codominant models were evaluated (data not shown). Post-hoc analyses showed no associations when subjects with impaired glucose tolerance were included or when subjects with HNF1A S319 and PPARG Q12 were excluded.


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  		Table 1— Relative risk for type 2 diabetes (with 95% CIs)

 
The results suggest that the CAPN10 g.4852G and PC-1 Q121 alleles were not significant determinants of type 2 diabetes in this sample of Oji-Cree. However, these alleles both tended (albeit nonsignificantly) to be associated with type 2 diabetes, which raises the issue of statistical power afforded by the present sample size. It should be noted that the HNF1A S319 allele (1) had a lower overall frequency than both the CAPN10 g.4852G and PC-1 Q121 alleles in this sample and was very strongly associated with type 2 diabetes (heterozygote relative risk 1.97, 95% CI 1.44–2.70, P < 0.0001). This suggests that a sufficiently strong genetic association with diabetes can be detected in this Oji-Cree sample. The smaller magnitude of a possible genetic effect of both the CAPN10 g.4852G and PC-1 Q121 alleles might require a larger sample of this population to be detected. However, the results are also consistent with the absence of an association of these particular alleles with diabetes in Oji-Cree, indicating that such associations can be context dependent and population specific. The strong association of PPARG Q12 with diabetes in Oji-Cree (2) is in conflict with the resistance from diabetes among carriers of PPARG A12 in other populations (7), and confirms that interesting challenges can arise in human genetic studies of type 2 diabetes.

ACKNOWLEDGMENTS

This work was supported by grants from the Canadian Institutes of Health Research, the Canadian Diabetes Association (in honor of Rheta Maude Gilbert), the Canadian Genetic Diseases Network, and the Blackburn Group. R.A.H. is a Career Investigator of the Heart and Stroke Foundation of Ontario and holds a Canada Research Chair in Human Genetics.

The authors acknowledge the chief and council of the community of Sandy Lake, the Sandy Lake surveyors and nurses, the staff of the University of Toronto Sioux Lookout Program, and the Department of Clinical Epidemiology of the Samuel Lunenfeld Research Institute.

FOOTNOTES

Address correspondence to Robert A. Hegele, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406-100 Perth Dr., London, Ontario, Canada N6A 5K8.

References

  1. Hegele RA, Cao H, Harris SB, Hanley AJ, Zinman B: The hepatic nuclear factor-1{alpha} G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab 84:1077–1082, 1999[Abstract/Free Full Text]
  2. Hegele RA, Cao H, Harris SB, Zinman B, Hanley AJ, Anderson CM: Peroxisome proliferator-activated receptor-{gamma}2 P12A and type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab 85:2014–2019, 2000[Abstract/Free Full Text]
  3. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE, del Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI: Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26:163–175, 2000[Medline]
  4. Baier LJ, Permana PA, Yang X, Pratley RE, Hanson RL, Shen GQ, Mott D, Knowler WC, Cox NJ, Horikawa Y, Oda N, Bell GI, Bogardus C: A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 106:R69–73, 2000
  5. Pizzuti A, Frittitta L, Argiolas A, Baratta R, Goldfine ID, Bozzali M, Ercolino T, Scarlato G, Iacoviello L, Vigneri R, Tassi V, Trischitta V: A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance. Diabetes 48:1881–1884, 1999[Abstract]
  6. Gu HF, Almgren P, Lindholm E, Frittitta L, Pizzuti A, Trischitta V, Groop LC: Association between the human glycoprotein PC-1 gene and elevated glucose and insulin levels in a paired-sibling analysis. Diabetes 49:1601–1603, 2000[Abstract]
  7. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPAR{gamma} Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76–80, 2000[Medline]

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