Research Paper Volume 14, Issue 8 pp 3484—3528
Decisive gene strategy on osteoporosis: a comprehensive whole-literature-based approach for conclusive candidate gene targets
- 1 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C
- 2 School of Public Health, National Defense Medical Center, Taipei, Taiwan, R.O.C
- 3 Department of Orthopedics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C
- 4 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C
- 5 Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan, R.O.C
Received: October 18, 2021 Accepted: April 12, 2022 Published: April 22, 2022https://doi.org/10.18632/aging.204026
How to Cite
Copyright: © 2022 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Purpose: Previous meta-analyses only examined the association between single gene polymorphisms and osteoporosis; there is no compilation of all gene loci that correlate with osteoporosis in the literature. In this study, we develop a new literature-based approach, a decisive gene strategy (DGS), to examine the sufficiency of the cumulative sample size for each gene locus and to assess whether a definite conclusion of the association between the gene locus and osteoporosis can be drawn.
Methods: The DGS was used to search PubMed, Embase, and Cochrane databases for all meta-analyses that correlated gene polymorphisms with osteoporosis. Trial sequential analysis was employed to examine the sufficiency of the cumulative sample size. Finally, we assessed the importance of gene loci in osteoporosis based on whether there were enough sample sizes and the heterogeneity of the literature with the I2 value.
Results: After excluding 169 irrelevant publications, 39 meta-analysis papers were obtained. Among Caucasians, in 17 gene loci, there were eight gene loci (e.g., vitamin D Receptor ApaI rs7975232) with sufficient cumulative sample size to confirm that they were unrelated to the disease. Among Asians, in 15 gene loci, four gene loci that had sufficient sample sizes were risk factors: VDR FokI rs2228570 (odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.22–1.70), TGF β1 rs1800470 (OR = 1.35, 95% CI = 1.10–1.65), IGF1 rs2288377 (OR = 1.44, 95% CI = 1.28–1.62), and IGF1 rs35767 (OR = 1.20, 95% CI = 1.06–1.36), respectively, whereas one gene locus, ESR2 RsaI rs1256049 (OR = 0.69, 95% CI = 0.59–0.81), was a protective factor.
Conclusions: The DGS successfully identified five gene loci in osteoporosis that will apply to other diseases to find causal genes, which may contribute to further genetic therapy.
BMD: Bone mineral density; CI: Confidence interval; DGS: Decisive gene strategy; GTEx: Genotype-tissue expression; GWAS: Genome-wide association studies; MAF: Minor allele frequency; OR: Odds ratio; PI3K: Phosphoinositide 3-kinase; PMOP: Postmenopausal osteoporosis; rs: refSNP; RIS: Required information size; SMD: Standard mean deviation; SNP: Single-nucleotide polymorphism; TSA: Trial sequential analysis.