title: Polymorphisms of the CLCN7 gene are associated with BMD in women.
abstract: Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects.
  
  
  BACKGROUND
  The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population.
  
  
  METHODS
  We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age.
  
  
  RESULTS
  We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of >5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001-0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site.
  
  
  CONCLUSIONS
  Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects.
authors.affiliation: Bone Research Group, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Pettersson
authors.forename: Omar M E
authors.initials: OM
authors.lastname: Albagha
authors.forename: Max
authors.initials: M
authors.lastname: Mirolo
authors.forename: Anna
authors.initials: A
authors.lastname: Taranta
authors.forename: Annalisa
authors.initials: A
authors.lastname: Frattini
authors.forename: Fiona E A
authors.initials: FE
authors.lastname: McGuigan
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzoni
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
authors.forename: Wim
authors.initials: W
authors.lastname: van Hul
authors.forename: David M
authors.initials: DM
authors.lastname: Reid
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
mesh_terms: D000328:Adult; D015519:Bone Density / Q000235:genetics*; D018118:Chloride Channels / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005272:Femur Neck / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium; D008159:Lumbar Vertebrae / Q000378:metabolism; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels