Glucocorticoid Receptor Gene Polymorphisms and Femoral Head Osteonecrosis

Background and Objectives: Non-traumatic osteonecrosis of the femoral head (ONFH) is a multifactorial disorder influenced by both environmental and genetic factors. The nuclear receptor subfamily 3 group C member 1 (NR3C1) gene encodes the glucocorticoid receptor, which plays a key role in bone metabolism, vascular regulation, and stress response. This study aimed to investigate the association between NR3C1 polymorphisms and susceptibility to ONFH, with particular emphasis on age-related genetic effects. Materials and Methods: A hospital-based case-control study was conducted using genotyping data from the Taiwan Biobank version 2 (TWBv2) custom array. A total of 609 patients with ONFH and 2436 age- and sex-matched controls were included. Forty-nine single-nucleotide polymorphisms (SNPs) within or near the NR3C1 gene with a minor allele frequency greater than 5% were analyzed. Logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) under multiple genetic inheritance models. Age-stratified analyses were also performed. Results: Among the analyzed SNPs, rs28593206 and rs315199 demonstrated nominally significant differences in allele distributions between cases and controls (p = 0.024 and p = 0.009, respectively), with minor alleles showing nominal associations with increased odds of ONFH. Additional exploratory analyses under different genetic models identified several SNPs with nominal associations with ONFH susceptibility, while rs7709864 showed a possible nominal protective association. In age-stratified analyses, several SNPs showed nominal associations with ONFH risk among individuals older than 40 years, whereas no nominally significant associations were observed in younger individuals. Conclusions: This exploratory study suggests that NR3C1 polymorphisms may be nominally associated with susceptibility to ONFH, particularly among individuals older than 40 years. However, because no formal correction for multiple comparisons was performed and detailed etiological data were unavailable, these findings should be interpreted cautiously and regarded as hypothesis-generating rather than clinically applicable evidence. Further studies incorporating larger cohorts, etiological stratification, multiple-testing correction, replication analyses, and functional validation are required to confirm these observations and clarify the underlying biological mechanisms.