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Original Contribution
March 19, 2008

Large-Scale Analysis of Association Between LRP5 and LRP6 Variants and Osteoporosis

Author Affiliations

Author Affiliations: Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands (Drs van Meurs, Pols, Rivadeneira, and Uitterlinden); Center for Clinical Evidence Synthesis (Drs Trikalinos and Ioannidis) and Center for Genetic Epidemio logy and Modeling (Dr Trikalinos), Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece (Drs Trikalinos and Ioannidis); Rheumatic Diseases Unit, University of Edinburgh, Edinburgh, UK (Dr Ralston); Department of Genetics, University of Barcelona, CIBERER, IBUB, Barcelona, Spain (Dr Balcells and Ms Agueda); Department of Internal Medicine, University of Florence, Florence, Italy (Drs Brandi and Masi); Department of Endocrinology, Odense University Hospital, Odense, Denmark (Dr Brixen); Center for Bone Research at the Shlgrenska Academy, Department of Internal Medicine, Göteborg, Sweden (Drs Ohlsson, Lorentzon, and Mellström); Institute for Aging Research, Hebrew SeniorLife and Harvard Medical School, Boston, Massachusetts (Drs Kiel and Karasik); Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark (Drs Langdahl, Husted, and Moskilde); EMGO Institute, VU University Medical Center, Amsterdam, the Netherlands (Drs Lips and van Schoor); Department of Medical Sciences, University of Uppsala, Uppsala, Sweden (Dr Ljunggren); Department of Biochemistry and Experimental Medicine, Children's Memorial Health Institute, Warsaw, Poland (Drs Lorenc and Kruk); Department of Internal Medicine, Medical University, Graz, Austria (Drs Obermayer-Pietsch and Renner); Departments of Pharmacology and Neuroscience and Sports Medicine (Dr Pettersson) and Public Health and Clinical Medicine (Dr Hallmans), Umeå University, Umeå, Sweden; Department of Medicine and Therapeutics, University of Aberdeen Medical School, Aberdeen, UK (Drs Reid and McGuigan); Unite de Recherche en Genetique Humaine et Moleculaire, Center de Recherche de l’Hopital St-Francois d’Assise du Center Hospitalier Universitaire de Quebec, Quebec, Canada (Dr Rousseau); Strangeways Research Laboratory, Cambridge University, Cambridge, UK (Ms Scollen and Drs Kaptoge and Reeve); Department of Medical Genetics, University of Antwerp, Antwerp, Belgium (Dr Van Hul); Department of Orthopedics, Malmö University Hospital, Lund University, Lund, Sweden (Drs Åkesson and Karlsson); Institute of Rheumatology, Moscow, Russia (Dr Benevolenskaya); Division of Bone Diseases, University Hospital of Geneva, Geneva, Switzerland (Dr Ferrari); Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, the Netherlands (Drs Hofman, Pols, Rivadeneira, and Uitterlinden); Hospital del Mar-IMIM, UAB, Barcelona, Spain (Dr Nogues); and Department of Medicine, University Hospital, Graz, Austria (Dr Weber).

JAMA. 2008;299(11):1277-1290. doi:10.1001/jama.299.11.1277

Context 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.

Design and Setting 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.

Main Outcome Measures 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 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 × 10−5) and 8 mg/cm2 (P = 5.0 × 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.