Decisive gene strategy on osteoporosis: a comprehensive whole-literature-based approach for conclusive candidate gene targets.

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 ß1 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.

Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Susceptibility to Osteoarthritis of the Knee: A Case-Control Study and Meta-Analysis.

BACKGROUND: Studies of angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms and the risks of knee osteoarthritis (OA) have yielded conflicting results. OBJECTIVE: To determine the association between ACE I/D and knee OA, we conducted a combined case-control study and meta-analysis. METHODS: For the case-control study, 447 knee OA cases and 423 healthy controls were recruited between March 2010 and July 2011. Knee OA cases were defined using the Kellgren-Lawrence grading system, and the ACE I/D genotype was determined using a standard polymerase chain reaction. The association between ACE I/D and knee OA was detected using allele, genotype, dominant, and recessive models. For the meta-analysis, PubMed and Embase databases were systematically searched for prospective observational studies published up until August 2015. Studies of ACE I/D and knee OA with sufficient data were selected. Pooled results were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) for the D versus I allele with regard to knee OA risk. RESULTS: We found no significant association between the D allele and knee OA [OR: 1.09 (95% CI: 0.76-1.89)] in the present case-control study, and the results of other genetic models were also nonsignificant. Five current studies were included, and there were a total of six study populations after including our case-control study (1165 cases and 1029 controls). In the meta-analysis, the allele model also yielded nonsignificant results [OR: 1.37 (95% CI: 0.95-1.99)] and a high heterogeneity (I2: 87.2%). CONCLUSIONS: The association between ACE I/D and knee OA tended to yield negative results. High heterogeneity suggests a complex, multifactorial mechanism, and an epistasis analysis of ACE I/D and knee OA should therefore be conducted.