Association between estrogen receptor α gene (ESR1) PvuII (C/T) and XbaI (A/G) polymorphisms and hip fracture risk: evidence from a meta-analysis

Abstract

Background and objective: Genetic factors are important in the pathogenesis of fractures. Notably, estrogen receptor α (ESR1) has been suggested as a possible candidate gene for hip fractures; however, published studies of ESR1 gene polymorphisms have been hampered by small sample sizes and inconclusive or ambiguous results. The aim of this meta-analysis is to investigate the associations between two novel common ESR1 polymorphisms (intron 1 polymorphisms PvuII-rs2234693: C>T and XbaI-rs9340799: A>G) and hip fracture.

Methods: Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the association.

Results: Five case-control and three cohort studies were assessed, including a total of 1,838 hip fracture cases and 14,972 healthy controls. This meta-analysis revealed that the PvuII T allele is a highly significant risk factor for hip fracture susceptibility, with an effect magnitude similar in male and pre-menopausal and post-menopausal female patients. In stratified analysis based on ethnicity, the PvuII T allele remained significantly correlated with increased risk of hip fracture in Caucasian populations; this correlation, however, was not found in Asian populations. Unlike the PvuII polymorphism, we did not find significant differences in the XbaI (A>G) polymorphism allele or genotype distributions of hip fracture patients and controls. We also found no obvious association between the XbaI polymorphism and hip fracture in any of the racial or gender subgroups.

Conclusion: Our findings show that the ESR1 PvuII T allele may increase the risk of hip fracture and that the XbaI polymorphism is not associated with hip fracture.

Figure 1. Flow diagram of selection of studies and specific reasons for exclusion from the present meta-analysis.

Figure 2. Forest plot of ORs for the association between PvuII (C>T) polymorphism and susceptibility to hip fracture in subgroup analysis based on ethnicity (A), gender (B), and menopausal status (C) under the allele model.

Figure 3. Forest plot of ORs for the association of XbaI (A>G) polymorphism and susceptibility to hip fracture in subgroup analysis based on ethnicity (A) and gender (B) under the allele model.

Figure 4. Sensitivity analysis of the summary odds ratio coefficients of PvuII (C>T) and XbaI (A>G) polymorphisms are illustrated under the allele model.

Results were computed by omitting each study in turn. The two ends of the dotted lines represent the 95% CI (A: PvuII; B: XbaI).

Figure 5. Begger’s funnel plot of publication bias in the selection of studies for PvuII (C>T) and XbaI (A>G) polymorphisms are illustrated (A: PvuII; B: XbaI).

Each point represents a separate study by the indicated association. Log[OR], natural logarithm of OR. Horizontal line, mean magnitude of the effect.