Association and epistasis analyses of obesity-related genes in osteoporosis
4 affiliations
- 1Medicina Genómica, Instituto Nacional de Rehabilitación “Luis Guillermo Ibarra Ibarra”
- 2Facultad de Nutrición, Universidad Autónoma del Estado de Morelos
- 3Departamento de Embriología y Genética, Facultad de Medicina, Universidad Nacional Autónoma de México
- 4Unidad de Vigilancia Epidemiológica Hospitalaria, Instituto Nacional de Rehabilitación “Luis Guillermo Ibarra Ibarra”
Abstract
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.
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BibTeX
@article{mirandaduarte2026association,
title = {{Association and epistasis analyses of obesity-related genes in osteoporosis}},
author = {Antonio Miranda-Duarte and Erika Velázquez-Quitl and Celeste Martínez-Ramírez and Edgar Hernández-Zamora and Valeria Ponce de León-Suárez and M. Guadalupe Sánchez-Bringas and Esteban Cruz-Arenas and Karem Nieto-Martínez and Alberto Hidalgo-Bravo and Azucena Salazar-Piña and Leonora Casas-Avila},
journal = {Frontiers in Endocrinology},
year = {2026},
month = nov,
doi = {10.3389/fendo.2026.1966176},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1966176/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Association and epistasis analyses of obesity-related genes in osteoporosis
AU - Antonio Miranda-Duarte
AU - Erika Velázquez-Quitl
AU - Celeste Martínez-Ramírez
AU - Edgar Hernández-Zamora
AU - Valeria Ponce de León-Suárez
AU - M. Guadalupe Sánchez-Bringas
AU - Esteban Cruz-Arenas
AU - Karem Nieto-Martínez
AU - Alberto Hidalgo-Bravo
AU - Azucena Salazar-Piña
AU - Leonora Casas-Avila
PY - 2026
DA - 2026/11/02
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1966176
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1966176/full
AB - 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.
SN - 1664-2392
ER -