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Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant
U Kornak1, A Ostertag, S Branger
1Max Planck Institute for Molecular Genetics and Institute for Medical Genetics, Charité University Hospital, D-13353 Berlin, Germany. uwe.kornak@charite.de
Context:
Genetic factors are important determinants of bone mineral density (BMD). The fact that mutations in the ClC-7 chloride channel cause autosomal dominant osteopetrosis (ADOII) make the CLCN7 gene an attractive candidate for the regulation of bone density.
Objective:
The objective of the study was to investigate the association between polymorphisms in the CLCN7 gene and BMD in postmenopausal women and with clinical variability in ADOII.
Design:
This was a genetic association study using five single-nucleotide polymorphisms and a variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene.
Participants:
A total of 425 postmenopausal women aged 64 +/- 7 yr participated in the study. We also investigated an ADOII family with low penetrance comprising 18 mutation carriers.
Main Outcome Measure(S):
In our postmenopausal cohort, individual single-nucleotide polymorphism genotypes and haplotypes were analyzed for association with BMD at the lumbar spine and the femoral neck and with the bone resorption marker deoxypyridinoline (D-Pyr/Crea). The same polymorphisms on the nonmutated CLCN7 allele were investigated for association with the variability of the ADOII phenotype.
Results:
Analysis by multiple linear regression revealed a significant association between the ss genotype of the VNTR and higher Z-score values (P = 0.029). The haplotype 4, which comprises the long allele of the VNTR, was found to be significantly associated with lower femoral neck Z-score values (P = 0.011). Furthermore, we found an association of the ss genotype of the VNTR with lower levels of the bone resorption marker D-Pyr/Crea (P = 0.015), whereas haplotype 4 was associated with higher D-Pyr/Crea levels (P = 0.039). In the ADOII family, we could demonstrate that haplotype 3, which contains the s-allele of the VNTR, is associated with a slightly higher probability that mutation carriers develop osteopetrosis (P = 0.029). In both cases the association seems largely to be driven by the VNTR genotype but is further strengthened if surrounding polymorphisms are added to the analysis.
Conclusion:
We observed a significant association of CLCN7 polymorphisms with the variance of BMD and bone resorption marker levels in postmenopausal women and with the variability of the ADOII phenotype.
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