L-type voltage-dependent calcium channel alpha subunit 1C is a novel candidate gene associated with secondary hyperparathyroidism: an application of haplotype-based analysis for multiple linked single nucleotide polymorphisms

Nephron Clin Pract. 2010;115(4):c237-43. doi: 10.1159/000313481. Epub 2010 Apr 28.

Abstract

Background and methods: We conducted a large-scale case-control study that explored the association of 358 single nucleotide polymorphisms (SNPs) in 185 patients with end-stage renal disease. A variety of SNPs were recognized as significant in simple association studies. In addition, haplotype analysis identified the gene for the alpha 1C subunit of the voltage-dependent L-type calcium channel (CACNA1C) as having a significant association with secondary hyperparathyroidism (intact parathyroid hormone level >200 pg/ml) among 61 haplotypes. Since CACNA1C is a relatively large molecule, we examined 84 SNP markers from the CACNA1C region located on chromosome 12 by haplotype case-control association analysis.

Results: Sixteen SNPs of 14 genes were significant according to allelic and/or genotypic studies (p < 0.05 by Fisher's exact test). Three different SNPs were from the CACNA1C gene. Next, we performed haplotype-based association testing with a focus on the CACNA1C region, revealing an odds ratio (OR) of 1.63 and 95% confidence interval (CI) of 1.05-2.52. The second major haplotype with a frequency of 27% was also significant and acted as a protective haplotype (p = 0.022 by Fisher's exact test, with an OR of 0.55 and 95% CI of 0.33-0.90).

Conclusion: These results suggest that CACNA1C may be associated with secondary hyperparathyroidism. In addition, the haplotype-based approach may be useful to screen for key molecules associated with complex traits.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Channels, L-Type / genetics*
  • Female
  • Genetic Predisposition to Disease / epidemiology*
  • Genetic Predisposition to Disease / genetics*
  • Haplotypes
  • Humans
  • Hyperparathyroidism, Secondary / epidemiology*
  • Hyperparathyroidism, Secondary / genetics*
  • Japan / epidemiology
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics*
  • Prevalence
  • Risk Assessment
  • Risk Factors

Substances

  • Calcium Channels, L-Type