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 (ADO II) 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 (SNPs) and a variable number tandem repeat polymorphism (VNTR) 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 SNP genotypes and haplotypes were analyzed for association with BMD at the lumbar spine and at the femoral neck and with the bone resorption marker deoxypyridinoline. The same polymorphisms on the non-mutated 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 l 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 deoxypyridinoline (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.