title: Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type II.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This was a genetic association study using five single-nucleotide polymorphisms and a variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Max Planck Institute for Molecular Genetics and Institute for Medical Genetics, Charité University Hospital, D-13353 Berlin, Germany. uwe.kornak@charite.de
authors.forename: U
authors.initials: U
authors.lastname: Kornak
authors.forename: A
authors.initials: A
authors.lastname: Ostertag
authors.forename: S
authors.initials: S
authors.lastname: Branger
authors.forename: O
authors.initials: O
authors.lastname: Benichou
authors.forename: M-C
authors.initials: MC
authors.lastname: de Vernejoul
mesh_terms: D000368:Aged; D015519:Bone Density / Q000235:genetics*; D018118:Chloride Channels / Q000235:genetics*; D015914:Estrogen Replacement Therapy; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008875:Middle Aged; D010022:Osteopetrosis / Q000145:classification / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic; D017698:Postmenopause / Q000502:physiology*
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels