A meta-analysis of VDR polymorphisms and postmenopausal osteoporosis

Literature search and inclusion criteria

Medline, Embase, Wanfang, VIP and CNKI were comprehensively searched by the authors using the below keywords: (vitamin D receptor OR VDR) AND (polymorphism OR polymorphic OR variation OR variant OR mutant OR mutation OR SNP OR genotypic OR genotype OR allelic OR allele) AND (postmenopausal OR postmenopause) AND (osteoporosis OR bone loss). Moreover, we also manually screened the references of retrieved literature to make up for the potential incompleteness of literature searching from databases.

Selection criteria of this meta-analysis were listed below: (1) studies of case–control or cohort design; (2) give genotypic frequencies of VDR polymorphisms in cases with postmenopausal osteoporosis and population-based controls; (3) the full manuscript with detailed genotypic frequencies of VDR polymorphisms is retrievable or buyable. Articles would be excluded if one of the following three criteria is satisfied: (1) studies without complete genotypic data of VDR polymorphisms in cases with postmenopausal osteoporosis and population-based controls; (2) narrative or systematic reviews, meta-analysis or comments; (3) case series of subjects with postmenopausal osteoporosis only. If duplicate reports are retrieved, we would only include the most complete one for integrated analyses.

Data extraction and quality assessment

The authors extracted the following data items from eligible studies: (1) last name of the leading author; (2) year of publication; (3) country and ethnicity of study population; (4) the number of cases with postmenopausal osteoporosis and population-based controls; (5) genotypic frequencies of VDR polymorphisms in cases with postmenopausal osteoporosis and population-based controls. We also examined Hardy–Weinberg equilibrium (HWE) by comparing the actual genotypic frequencies of investigated VDR polymorphisms to their expected distributions using the chi-square test. The significance threshold of HWE was set at 0.05, if P value > 0.05, then we considered that the genotypic distribution of the investigated polymorphism was in agreement with HWE. The quality of eligible literature was assessed by the Newcastle–Ottawa scale (NOS) (12), and these with a score of 7–9 were considered to be literature of good quality. Two authors extracted data and assessed quality of eligible literature in parallel. A thorough discussion until a consensus is reached would be endorsed in case of any discrepancy between two authors.

Statistical analyses

All statistical analyses in this meta-analysis were performed with the Cochrane Review Manager software version 5.3 (The Cochrane Collaboration, Software Update, Oxford, United Kingdom). Associations between VDR gene polymorphisms and the risk of postmenopausal osteoporosis were explored by using odds ratio and its 95 % CI. The statistically significant P value was set at 0.05. All investigated VDR polymorphisms have a major allele (M) and a minor allele (m), the dominant comparison was defined as MM vs Mm + mm, the recessive comparison was defined as mm vs MM + Mm, the over-dominant comparison was defined as Mm vs MM + mm, and the allele comparison was defined as M vs m. The authors used I² statistics to estimate heterogeneities among included studies. The authors would use DerSimonian–Laird method, which is also known as the random effect model, to integrate the results of eligible studies if I² is larger than 50%. Otherwise, the authors would use Mantel–Haenszel method, which is also known as the fixed effect model, to integrate the results of eligible studies. Meanwhile, the authors also conduct subgroup analyses by ethnic groups. Stabilities of integrated results were tested by deleting studies that violated HWE, and then integrating the results of the rest of eligible studies. Publication biases were evaluated by assessing symmetry of funnel plots.

Characteristics of included studies

Five hundred and seven papers were retrieved by the authors by using our searching strategy. One hundred and thirty-three papers were then selected to screen for eligibility after omitting unrelated and repeated items. Thirty-eight reviews and 13 case series were further excluded, and another 15 papers without complete genotypic data were further excluded by the authors. Totally 67 studies met the inclusion criteria, and were finally enrolled for integrated analyses (Fig. 1). Data extracted from eligible studies were summarized in Table 1.

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Flowchart of study selection for this meta-analysis.

Citation: Endocrine Connections 9, 9; 10.1530/EC-20-0296

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ApaI rs7975232 polymorphism and the risk of postmenopausal osteoporosis

Thirty papers assessed relationship between ApaI rs7975232 polymorphism and the risk of postmenopausal osteoporosis. The integrated analyses demonstrated that ApaI rs7975232 polymorphism was significantly associated with the risk of postmenopausal osteoporosis in overall population (recessive comparison: OR = 1.20, P = 0.004) and Caucasians (dominant comparison: OR = 0.77, P = 0.007; allele comparison: OR = 0.81, P = 0.04), but not in Asians (Table 2).

BsmI rs1544410 polymorphism and the risk of postmenopausal osteoporosis

Forty-five papers assessed relationship between BsmI rs1544410 polymorphism and the risk of postmenopausal osteoporosis. The integrated analyses demonstrated that BsmI rs1544410 polymorphism was significantly associated with the risk of postmenopausal osteoporosis in overall population (dominant comparison: OR = 0.77, P = 0.002; recessive comparison: OR = 1.28, P = 0.0001; allele comparison: OR = 0.80, P = 0.002) and Caucasians (dominant comparison: OR = 0.69, P = 0.002; allele com­parison: OR = 0.78, P = 0.008), but not in Asians (Table 2).

FokI rs10735810 polymorphism and the risk of postmenopausal osteoporosis

Twenty-six papers assessed relationship between FokI rs10735810 polymorphism and the risk of postmenopausal osteoporosis. The integrated analyses demonstrated that FokI rs10735810 polymorphism was significantly associated with the risk of osteoporosis in overall population (dominant comparison: OR = 0.76, P < 0.0001; recessive comparison: OR = 1.40, P = 0.005; allele comparison: OR = 0.86, P = 0.04) and Asians (dominant comparison: OR = 0.61, P = 0.0001; recessive comparison: OR = 2.02, P = 0.001; allele comparison: OR = 0.68, P = 0.002), but not in Caucasians (Table 2).

TaqI rs731236 polymorphism and the risk of postmenopausal osteoporosis

Twenty-five papers assessed relationship between TaqI rs731236 polymorphism and the risk of postmenopausal osteoporosis. The integrated analyses demonstrated that TaqI rs731236 polymorphism was significantly associated with the risk of postmenopausal osteoporosis in Caucasians (recessive comparison: OR = 1.32, P = 0.01), but not in Asians (Table 2).

Sensitivity analyses

The authors examined stabilities of integrated analyses results by deleting studies that violated HEW, and then integrating the results of the rest of studies. The trends of associations were not significantly altered in sensitivity analyses, which indicated that from statistical perspective, our integrated analyses results were reliable and stable.

Publication biases

The authors examined potential publication biases in this meta-analysis by assessing symmetry of funnel plots. Funnel plots were found to be generally symmetrical, which indicated that our integrated analyses results were not likely to be severely deteriorated by publication biases (Supplementary Fig. 1, see section on supplementary materials given at the end of this article).