Association and epistasis analyses of obesity-related genes in osteoporosis

Background Osteoporosis is a skeletal disease characterized by reduced bone mineral density, increased susceptibility to fracture. Obesity-related genes such as LEP , LEPR , ADIPOQ , and FTO play important roles in osteoporosis and both diseases are linked through metabolic processes. Nevertheless, the risk associated with obesity-related genes in osteoporosis and their gene-gene and gene-environment interactions have not been extensively studied. The objective of this study was to investigate the associations and interactions between single nucleotide variants in the LEP, LEPR, ADIPOQ , and FTO genes, along with body mass index and other participant factors, and their involvement in osteoporosis risk. Methods This case-control study included 365 patients (195 controls and 170 with osteoporosis) who were classified according to WHO criteria based on densitometric measurements of the lumbar spine and femoral neck. Eight single nucleotide variants of LEP, LEPR, ADIPOQ , and FTO genes were genotyped using real-time PCR with TaqMan probes. Association analyses were performed under the codominant, dominant, and recessive inheritance models using unconditional logistic regression. Gene-gene and gene-environment interactions were explored using multifactor dimensionality reduction. Results Women with OP were older and had lower body mass index than controls (p = 0.00001 for both) and obesity (BMI ≥ 30 kg/m²) was associated with reduced OP risk (p = 0.0001). Age, age at menarche, hypertension, diabetes, and arthritis increased the risk of osteoporosis, whereas higher BMI and coffee intake were protective factors. No significant associations were found for individual variants in any genetic model. However, two gene–gene interaction models suggest the synergistic contribution of some analyzed SNVs within a multilocus model with OP risk: (1) ADIPOQ rs1501299 and FTO rs9939609; and (2) LEPR rs1805134, ADIPOQ rs1501299, ADIPOQ rs17300539, and FTO rs9939609; nevertheless, there were not significant (p>0.05). A significant gene–environment interaction involving LEP rs2167270, BMI, age at menarche, age at menopause, and number of pregnancies was also identified (p = 0.002). Conclusion Our exploratory findings suggest that LEP, LEPR, ADIPOQ, and FTO obesity-related genes may contribute to increased OP risk through complex gene–gene and gene–environment interactions rather than individual effects. These preliminary results provide further hypothesis-generating evidence that OP and obesity share underlying biological connections and metabolic pathways.