title: Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.
abstract: BACKGROUND
  Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.
  
  
  OBJECTIVE
  To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.
  
  
  METHODS
  Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.
  
  
  METHODS
  Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.
  
  
  RESULTS
  The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.
  
  
  CONCLUSIONS
  Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
authors: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors: Joyce B J
authors: JB
authors: van Meurs
authors: Thomas A
authors: TA
authors: Trikalinos
authors: Stuart H
authors: SH
authors: Ralston
authors: Susana
authors: S
authors: Balcells
authors: Maria Luisa
authors: ML
authors: Brandi
authors: Kim
authors: K
authors: Brixen
authors: Douglas P
authors: DP
authors: Kiel
authors: Bente L
authors: BL
authors: Langdahl
authors: Paul
authors: P
authors: Lips
authors: Osten
authors: O
authors: Ljunggren
authors: Roman
authors: R
authors: Lorenc
authors: Barbara
authors: B
authors: Obermayer-Pietsch
authors: Claes
authors: C
authors: Ohlsson
authors: Ulrika
authors: U
authors: Pettersson
authors: David M
authors: DM
authors: Reid
authors: Francois
authors: F
authors: Rousseau
authors: Serena
authors: S
authors: Scollen
authors: Wim
authors: W
authors: Van Hul
authors: Lidia
authors: L
authors: Agueda
authors: Kristina
authors: K
authors: Akesson
authors: Lidia I
authors: LI
authors: Benevolenskaya
authors: Serge L
authors: SL
authors: Ferrari
authors: Göran
authors: G
authors: Hallmans
authors: Albert
authors: A
authors: Hofman
authors: Lise Bjerre
authors: LB
authors: Husted
authors: Marcin
authors: M
authors: Kruk
authors: Stephen
authors: S
authors: Kaptoge
authors: David
authors: D
authors: Karasik
authors: Magnus K
authors: MK
authors: Karlsson
authors: Mattias
authors: M
authors: Lorentzon
authors: Laura
authors: L
authors: Masi
authors: Fiona E A
authors: FE
authors: McGuigan
authors: Dan
authors: D
authors: Mellström
authors: Leif
authors: L
authors: Mosekilde
authors: Xavier
authors: X
authors: Nogues
authors: Huibert A P
authors: HA
authors: Pols
authors: Jonathan
authors: J
authors: Reeve
authors: Wilfried
authors: W
authors: Renner
authors: Fernando
authors: F
authors: Rivadeneira
authors: Natasja M
authors: NM
authors: van Schoor
authors: Kurt
authors: K
authors: Weber
authors: John P A
authors: JP
authors: Ioannidis
authors: André G
authors: AG
authors: Uitterlinden
mesh_terms: D015519:Bone Density / Q000235:genetics*; D005272:Femur Neck; D050723:Fractures, Bone / Q000453:epidemiology* / Q000235:genetics*; D005838:Genotype; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008159:Lumbar Vertebrae; D010024:Osteoporosis / Q000453:epidemiology* / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D016103:Spinal Fractures / Q000453:epidemiology / Q000235:genetics
chemical_list: D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6