Gene–Gene and Gene–Environment Interactions among CYP19A1, ESR1, IL6, IL6R, IL1β, RANK and RANKL variants associated with Osteoporosis and Hip Fracture in Mexican Women

Antonio Miranda-Duarte¹Valeria Ponce de León-Suárez¹Alberto Hidalgo Bravo¹Rafael Velazquez-Cruz²Esperanza Ramírez-Pérez¹O. Celeste Martínez-Ramírez³Clementina Castro-Hernández⁴Blanca Barredo-Prieto¹LEONORA CASAS-AVILA^1*

• ¹INSTITUTO NACIONAL DE REHABILITACIÓN LUIS GUILLERMO IBARRA IBARRA, Mexico, Mexico
• ²Instituto Nacional de Medicina Genomica, Mexico City, Mexico
• ³Universidad Autonoma del Estado de Morelos, Cuernavaca, Mexico
• ⁴Universidad Nacional Autonoma de Mexico Instituto de Investigaciones Biomedicas, Mexico City, Mexico

Background: Osteoporosis is a complex disease influenced by genetic variants, environmental factors, and comorbidities. While individual single-nucleotide variants (SNVs) have been associated with disease risk, limited data are available on how gene–gene and gene–environment interactions contribute to osteoporosis and fracture susceptibility in Mexican women. Method: In this case–control study, we evaluated the association of SNVs in estrogen receptor alpha (ESR1), aromatase (CYP19A1), interleukin 6 (IL6) and its receptor (IL6R), interleukin 1 beta (IL1β), Receptor activator of nuclear factor κ B (RANK) and its ligand (RANKL) genes, with the risk of osteoporosis and hip fracture, as well as their gene-gene and gene-environment interactions, in 609 Mexican women (169 with osteoporosis, 205 with hip fracture, and 235 controls), by real time PCR with TaqMan probes. In addition, multifactor dimensionality reduction (MDR) software was used to detect gene–gene interactions and gene-environment interactions. Results: The GA and AA genotypes of RANK rs3018362 were significantly associated with increased osteoporosis risk (OR = 2.08 [1.08–3.98] and 2.76 [1.21–6.30], respectively) while the CC genotype of ESR1 rs2234693 was associated with reduced risk (OR = 0.28 [0.11–0.69]). For hip fracture, ESR1 rs2234693 (CC genotype) was protective (OR = 0.30 [0.12–0.75]), whereas RANK rs3018362 (AA genotype) increased risk (OR = 2.4 [1.01–6.06]). A significant gene–gene interaction between ESR1 (rs2228480) and RANK (rs3018362) increased osteoporosis risk (OR = 2.1 [1.4–3.2], CVC = 10/10), and a gene–gene model involving ESR1, IL6R, IL1β, and RANKL was identified for hip fracture (CVC = 8/10). In osteoporosis, a gene–environment interaction was observed between CYP19A1 SNVs (rs700518, rs1062033, rs4775936, rs767199), IL1β rs16944, and 10-year probability of major fracture (CVC = 10/10). This is a provisional file, not the final typeset article Conclusion: Our findings suggest that RANK and ESR1 variants are independently and interactively associated with osteoporosis and fracture risk, and that gene–gene and gene–environment interactions play a critical role in disease susceptibility among Mexican women.