Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis

Abstract

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 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.

Figure 1

Differences in Bone Mineral Density at the Lumbar Spine Between Individuals, per Copy of the Risk Allele Results based on inverse-variance random-effects analysis of individual-level data. The size of the data markers is proportional to the weight (inverse of the variance) of each study. AUSTRIOS-B did not have available data on bone mineral density measurements and therefore is not included in this analysis. BMD indicates bone mineral density; CI, confidence interval. ^aEstimates for UFO (men) could not be obtained for LRP5 Val667Met and LRP6 Ile1062Val because all analyzed individuals had the same genotype. For LRP5 Ala1330Val, mean difference in BMD was 163 mg/cm² (95% CI, −537 to 862).

Figure 2

Differences in Bone Mineral Density at the Femoral Neck Between Individuals, per Copy of the Risk Allele Results based on inverse-variance random-effects analysis of individual-level data. The size of the data markers is proportional to the weight (inverse of the variance) of each study. AUSTRIOS-B did not have available data on bone mineral density measurements and therefore is not included in this analysis. BMD indicates bone mineral density; CI, confidence interval. Estimates for UFO (men) could not be obtained for LRP5 Val667Met and LRP6 Ile1062Val because all analyzed individuals had the same genotype.

Figure 3

Odds of Any Fracture, per Copy of the Risk Allele Results based on inverse-variance random-effects analysis of individual-level data. Summary estimates of the odds ratios and their 95% confidence intervals (CIs) are given. The size of the data markers is proportional to the weight (inverse of the variance) of each study. AOS did not have available data on any fracture and therefore is not included in this analysis.

Figure 4

Odds of Vertebral Fracture, per Copy of the Risk Allele Results based on inverse-variance random-effects analysis of individual-level data. Summary estimates of the odds ratios and their 95% confidence intervals (CIs) are given. The size of the data markers is proportional to the weight (inverse of the variance) of each study. AOS, FOS, GOOD, MrOS, and UFO did not have available data on vertebral fracture and therefore are not included in this analysis.