title: Association between a variation in the phosphodiesterase 4D gene and bone mineral density.
abstract: BACKGROUND
  Fragility fractures caused by osteoporosis are a major cause of morbidity and mortality in aging populations. Bone mineral density (BMD) is a useful surrogate marker for risk of fracture and is a highly heritable trait. The genetic variants underlying this genetic contribution are largely unknown.
  
  
  METHODS
  We performed a large-scale association study investigating more than 25,000 single nucleotide polymorphisms (SNPs) located within 16,000 genes. Allele frequencies were estimated in contrasting DNA pools from white females selected for low (<0.87 g/cm2, n = 319) and high (> 1.11 g/cm2, n = 321) BMD at the lumbar spine. Significant findings were verified in two additional sample collections.
  
  
  RESULTS
  Based on allele frequency differences between DNA pools and subsequent individual genotyping, one of the candidate loci indicated was the phosphodiesterase 4D (PDE4D) gene region on chromosome 5q12. We subsequently tested the marker SNP, rs1498608, in a second sample of 138 white females with low (<0.91 g/cm2) and 138 females with high (>1.04 g/cm2) lumbar spine BMD. Odds ratios were 1.5 (P = 0.035) in the original sample and 2.1 (P = 0.018) in the replication sample. Association fine mapping with 80 SNPs located within 50 kilobases of the marker SNP identified a 20 kilobase region of association containing exon 6 of PDE4D. In a second, family-based replication sample with a preponderance of females with low BMD, rs1498608 showed an opposite relationship with BMD at different sites (p = 0.00044-0.09). We also replicated the previously reported association of the Ser37Ala polymorphism in BMP2, known to interact biologically with PDE4D, with BMD.
  
  
  CONCLUSIONS
  This study indicates that variants in the gene encoding PDE4D account for some of the genetic contribution to bone mineral density variation in humans. The contrasting results from different samples indicate that the effect may be context-dependent. PDE4 inhibitors have been shown to increase bone mass in normal and osteopenic mice, but up until now there have been no reports implicating any member of the PDE4 gene family in human osteoporosis.
authors.affiliation: Sequenom, Inc, San Diego, California, USA. abraun@sequenom.com
authors.forename: Richard H
authors.initials: RH
authors.lastname: Reneland
authors.forename: Steven
authors.initials: S
authors.lastname: Mah
authors.forename: Stefan
authors.initials: S
authors.lastname: Kammerer
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Hoyal
authors.forename: George
authors.initials: G
authors.lastname: Marnellos
authors.forename: Scott G
authors.initials: SG
authors.lastname: Wilson
authors.forename: Philip N
authors.initials: PN
authors.lastname: Sambrook
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nelson
authors.forename: Andreas
authors.initials: A
authors.lastname: Braun
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics*; D000328:Adult; D000368:Aged; D001315:Australia; D015519:Bone Density / Q000235:genetics*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D002874:Chromosome Mapping; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005260:Female; D005787:Gene Frequency; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D016212:Transforming Growth Factor beta / Q000235:genetics; D006113:United Kingdom
chemical_list: C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human