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.
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).


CONCLUSIONS
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.
Yokoyama
Keitaro
K
Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. keitaro @ jikei.ac.jp
Urashima
Mitsuyoshi
M
Ohkido
Ichiro
I
Kono
Takashi
T
Yoshida
Toyohiko
T
Muramatsu
Masaaki
M
Niu
Tianhua
T
Hosoya
Tatsuo
T
D020746:Calcium Channels, L-Type / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000453:epidemiology* / Q000235:genetics*; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D018570:Risk Assessment; D012307:Risk Factors
D020746:Calcium Channels, L-Type