Background The low-density lipoprotein receptor-related protein 5 (LRP5) gene is a key regulator of bone mineral density and skeletal metabolism. The rs3736228 (Ala1330Val) polymorphism in LRP5 has been firmly established as a genome-wide significant locus for bone mineral density and fracture risk in large-scale GWAS. However, demographic and clinical subgroups that are frequently underrepresented in GWAS cohorts, such as sex, menopausal status and ethnicity, may have different impact sizes and ideal genetic models. Previous candidate-gene meta-analyses, while informative, did not systematically evaluate these subgroup-specific effects, owing to limited sample sizes and incomplete stratification. Therefore, we conducted this updated systematic review and meta-analysis to provide granular, subgroup-stratified risk estimates that complement existing GWAS evidence. Methods This systematic review was conducted in accordance with PRISMA guidelines. A comprehensive electronic search was performed across five databases: PubMed, Embase, Cochrane Library, Web of Science, and Ovid. The literature search was conducted using a combination of Medical Subject Headings(MeSH)terms, such as"osteoporosis, “fracture, “LRP5,“and"polymorphism,“along with their related synonyms. We also manually screened reference lists of retrieved articles to identify additional relevant studies. To address heterogeneity, we employed both the Cochran’s Q test and the I²statistic. A fixed-effects model was used when I²<50%and P ≥ 0.05; otherwise, a random-effects model was applied. All analyses were performed using STATA software version 17.0, and the odds ratios(ORs)and their corresponding 95%confidence interval(CI)values were calculated using fixed effects or random effects model. We carried out a subgroup analysis to explore the source of heterogeneity according to gender, race, disease, genotyping methods, control resources, female menopause, and HWE balance. Results The current meta-analysis involved 14 studies, comprising 16 independent comparisons, including 1,549 patients and 3,345 control subjects. The analyses revealed a significant association between LRP5 rs3736228 polymorphism and an increased risk of osteoporosis and fractures. Specifically,in the overall analysis, the polymorphism showed a higher likelihood of osteoporosis and fractures in the allelic model [OR=1.17, 95%CI(1.04-1.31), P=0.011], homozygous model [OR=1.47, 95%CI(1.07-2.01), P=0.018], dominant model [OR=1.44, 95%CI(1.05-2.97), P=0.023], and recessive model [OR=1.16, 95%CI(1.01-1.33), P=0.017]but not in the heterozygous model [OR=1.34, 95%CI(0.96-1.88), P=0.09]. Subgroup analyses showed that the polymorphism was associated with increased risk in males under the allelic(OR = 1.59, 95% CI 1.06–2.39, P = 0.026)and dominant models(OR = 1.74, 95% CI 1.11–2.73, P = 0.016). In females, risk was elevated in the homozygous(OR = 1.50, 95% CI 1.05–2.14, P = 0.027)and recessive models(OR = 1.48, 95% CI 1.04–2.09, P = 0.030). In population-based controls, significant associations were observed in the allelic(OR = 1.21, 95% CI 1.06–1.39, P = 0.005), homozygous(OR = 1.49, 95% CI 1.06–2.10, P = 0.021), dominant(OR = 1.22, 95% CI 1.03–1.43, P = 0.017), and recessive models(OR = 1.46, 95% CI 1.04–2.04, P = 0.027). No significant associations were found in the hospital-based subgroup. Heterogeneity was partly explained by disease type, publication year, and control source(P < 0.05 in multivariate meta-regression). Conclusion This updated meta-analysis confirms that the LRP5 rs3736228 polymorphism is significantly associated with osteoporosis and fracture risk, consistent with GWAS evidence, while further providing risk estimates stratified by sex and menopausal status, which are not readily obtainable from GWAS-level summary statistics alone.Notably, the observed associations appeared less robust in males, and premenopausal females, although these subgroup findings should be interpreted with caution owing to limited sample sizes. Nevertheless, further large-scale, prospective studies are warranted to validate these subgroup-specific estimates and to evaluate their potential utility in clinical risk stratification.

Association of rs3736228 polymorphism in LRP5 gene with bone fracture and osteoporosis: a systematic review and updated meta-analysis

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2026年7月27日

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Chi Zhang,
Wuhua Liu,
Youhua Wang,
Yuyi Peng

摘要

Background

The low-density lipoprotein receptor-related protein 5 (LRP5) gene is a key regulator of bone mineral density and skeletal metabolism. The rs3736228 (Ala1330Val) polymorphism in LRP5 has been firmly established as a genome-wide significant locus for bone mineral density and fracture risk in large-scale GWAS. However, demographic and clinical subgroups that are frequently underrepresented in GWAS cohorts, such as sex, menopausal status and ethnicity, may have different impact sizes and ideal genetic models. Previous candidate-gene meta-analyses, while informative, did not systematically evaluate these subgroup-specific effects, owing to limited sample sizes and incomplete stratification. Therefore, we conducted this updated systematic review and meta-analysis to provide granular, subgroup-stratified risk estimates that complement existing GWAS evidence.

Methods

This systematic review was conducted in accordance with PRISMA guidelines. A comprehensive electronic search was performed across five databases: PubMed, Embase, Cochrane Library, Web of Science, and Ovid. The literature search was conducted using a combination of Medical Subject Headings(MeSH)terms, such as"osteoporosis, “fracture, “LRP5,“and"polymorphism,“along with their related synonyms. We also manually screened reference lists of retrieved articles to identify additional relevant studies. To address heterogeneity, we employed both the Cochran’s Q test and the I²statistic. A fixed-effects model was used when I²<50%and P ≥ 0.05; otherwise, a random-effects model was applied. All analyses were performed using STATA software version 17.0, and the odds ratios(ORs)and their corresponding 95%confidence interval(CI)values were calculated using fixed effects or random effects model. We carried out a subgroup analysis to explore the source of heterogeneity according to gender, race, disease, genotyping methods, control resources, female menopause, and HWE balance.

Results

The current meta-analysis involved 14 studies, comprising 16 independent comparisons, including 1,549 patients and 3,345 control subjects. The analyses revealed a significant association between LRP5 rs3736228 polymorphism and an increased risk of osteoporosis and fractures. Specifically,in the overall analysis, the polymorphism showed a higher likelihood of osteoporosis and fractures in the allelic model [OR=1.17, 95%CI(1.04-1.31), P=0.011], homozygous model [OR=1.47, 95%CI(1.07-2.01), P=0.018], dominant model [OR=1.44, 95%CI(1.05-2.97), P=0.023], and recessive model [OR=1.16, 95%CI(1.01-1.33), P=0.017]but not in the heterozygous model [OR=1.34, 95%CI(0.96-1.88), P=0.09]. Subgroup analyses showed that the polymorphism was associated with increased risk in males under the allelic(OR = 1.59, 95% CI 1.06–2.39, P = 0.026)and dominant models(OR = 1.74, 95% CI 1.11–2.73, P = 0.016). In females, risk was elevated in the homozygous(OR = 1.50, 95% CI 1.05–2.14, P = 0.027)and recessive models(OR = 1.48, 95% CI 1.04–2.09, P = 0.030). In population-based controls, significant associations were observed in the allelic(OR = 1.21, 95% CI 1.06–1.39, P = 0.005), homozygous(OR = 1.49, 95% CI 1.06–2.10, P = 0.021), dominant(OR = 1.22, 95% CI 1.03–1.43, P = 0.017), and recessive models(OR = 1.46, 95% CI 1.04–2.04, P = 0.027). No significant associations were found in the hospital-based subgroup. Heterogeneity was partly explained by disease type, publication year, and control source(P < 0.05 in multivariate meta-regression).

Conclusion

This updated meta-analysis confirms that the LRP5 rs3736228 polymorphism is significantly associated with osteoporosis and fracture risk, consistent with GWAS evidence, while further providing risk estimates stratified by sex and menopausal status, which are not readily obtainable from GWAS-level summary statistics alone.Notably, the observed associations appeared less robust in males, and premenopausal females, although these subgroup findings should be interpreted with caution owing to limited sample sizes. Nevertheless, further large-scale, prospective studies are warranted to validate these subgroup-specific estimates and to evaluate their potential utility in clinical risk stratification.