Polymorphisms in the CLCN7 Gene Modulate Bone Density in Postmenopausal Women and in Patients with Autosomal Dominant Osteopetrosis Type II

• Published in: The journal of clinical endocrinology and metabolism 2006-03, Vol.91 (3), p.995-1000
• Main Authors: Kornak, U., Ostertag, A., Branger, S., Benichou, O., de Vernejoul, M.-C.
• Format: Article
• Language: English
• Subjects: Aged; Biological and medical sciences; Bone Density - genetics; Chloride Channels - genetics; Endocrinopathies; Estrogen Replacement Therapy; Female; Fundamental and applied biological sciences. Psychology; Genes, Dominant; Humans; Male; Medical sciences; Middle Aged; Osteopetrosis - classification; Osteopetrosis - genetics; Pedigree; Polymorphism, Genetic; Postmenopause - physiology; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2005-2017

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.