Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.
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.
van Meurs
Joyce B J
JB
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Trikalinos
Thomas A
TA
Ralston
Stuart H
SH
Balcells
Susana
S
Brandi
Maria Luisa
ML
Brixen
Kim
K
Kiel
Douglas P
DP
Langdahl
Bente L
BL
Lips
Paul
P
Ljunggren
Osten
O
Lorenc
Roman
R
Obermayer-Pietsch
Barbara
B
Ohlsson
Claes
C
Pettersson
Ulrika
U
Reid
David M
DM
Rousseau
Francois
F
Scollen
Serena
S
Van Hul
Wim
W
Agueda
Lidia
L
Akesson
Kristina
K
Benevolenskaya
Lidia I
LI
Ferrari
Serge L
SL
Hallmans
Göran
G
Hofman
Albert
A
Husted
Lise Bjerre
LB
Kruk
Marcin
M
Kaptoge
Stephen
S
Karasik
David
D
Karlsson
Magnus K
MK
Lorentzon
Mattias
M
Masi
Laura
L
McGuigan
Fiona E A
FE
Mellström
Dan
D
Mosekilde
Leif
L
Nogues
Xavier
X
Pols
Huibert A P
HA
Reeve
Jonathan
J
Renner
Wilfried
W
Rivadeneira
Fernando
F
van Schoor
Natasja M
NM
Weber
Kurt
K
Ioannidis
John P A
JP
Uitterlinden
André G
AG
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
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