title: Influence of LRP5 polymorphisms on normal variation in BMD.
abstract: Genetic studies based on cohorts with rare and extreme bone phenotypes have shown that the LRP5 gene is an important genetic modulator of BMD. Using family-based and case-control approaches, this study examines the role of the LRP5 gene in determining normal population variation of BMD and describes significant association and suggestive linkage between LRP5 gene polymorphisms and BMD in >900 individuals with a broad range of BMD.
  
  
  BACKGROUND
  Osteoporosis is a common, highly heritable condition determined by complex interactions of genetic and environmental etiologies. Genetic factors alone can account for 50-80% of the interindividual variation in BMD. Mutations in the LRP5 gene on chromosome 11q12-13 have been associated with rare syndromes characterized by extremely low or high BMD, but little is known about the contribution of this gene to the development of osteoporosis and determination of BMD in a normal population.
  
  
  METHODS
  To examine the entire spectrum of low to high BMD, 152 osteoporotic probands, their families (597 individuals), and 160 women with elevated BMD (T score > 2.5) were recruited. BMD at the lumbar spine, femoral neck, and hip were measured in each subject using DXA.
  
  
  RESULTS
  PAGE sequencing of the LRP5 gene revealed 10 single nucleotide polymorphisms (SNPs), 8 of which had allele frequencies of >5%, in exons 8, 9, 10, 15, and 18 and in introns 6, 7, and 21. Within families, a strong association was observed between an SNP at nucleotide C171346A in intron 21 and total hip BMD (p < 1 x 10(-5) in men only, p = 0.0019 in both men and women). This association was also observed in comparisons of osteoporotic probands and unrelated elevated BMD in women (p = 0.03), along with associations with markers in exons 8 (C135242T, p = 0.007) and 9 (C141759T, p = 0.02). Haplotypes composed of two to three of the SNPs G121513A, C135242T, G138351A, and C141759T were strongly associated with BMD when comparing osteoporotic probands and high BMD cases (p < 0.003). An SNP at nucleotide C165215T in exon 18 was linked to BMD at the lumbar spine, femoral neck, and total hip (parametric LOD scores = 2.8, 2.5, and 2.2 and nonparametric LOD scores = 0.3, 1.1, and 2.2, respectively) but was not genetically associated with BMD variation.
  
  
  CONCLUSIONS
  These results show that common LRP5 polymorphisms contribute to the determination of BMD in the general population.
authors.affiliation: Institute of Musculoskeletal Sciences, University of Oxford, The Botnar Research Centre, Nuffield Orthopaedic Centre, Headington, Oxford, UK.
authors.forename: M Audrey
authors.initials: MA
authors.lastname: Koay
authors.forename: Peng Y
authors.initials: PY
authors.lastname: Woon
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Miles
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.forename: Juliet E
authors.initials: JE
authors.lastname: Compston
authors.forename: Cyrus
authors.initials: C
authors.lastname: Cooper
authors.forename: Richard
authors.initials: R
authors.lastname: Keen
authors.forename: Bente L
authors.initials: BL
authors.lastname: Langdahl
authors.forename: Alasdair
authors.initials: A
authors.lastname: MacLelland
authors.forename: Jeffrey
authors.initials: J
authors.lastname: O'Riordan
authors.forename: Huibert A
authors.initials: HA
authors.lastname: Pols
authors.forename: David M
authors.initials: DM
authors.lastname: Reid
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: John A H
authors.initials: JA
authors.lastname: Wass
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density; D015331:Cohort Studies; D005091:Exons; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007438:Introns; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011973:Receptors, LDL