{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T16:42:00Z","timestamp":1782751320121,"version":"3.54.5"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging"],"abstract":"\n Background<\/jats:title>\n 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\u2013gene and gene\u2013environment interactions contribute to osteoporosis and fracture susceptibility in Mexican women.<\/jats:p>\n <\/jats:sec>\n \n Method<\/jats:title>\n \n In this case\u2013control study, we evaluated the association of SNVs in estrogen receptor alpha (\n ESR1<\/jats:italic>\n ), aromatase (\n CYP19A1<\/jats:italic>\n ), interleukin 6 (\n IL6<\/jats:italic>\n ) and its receptor (\n IL6R<\/jats:italic>\n ), interleukin 1 beta (\n IL1\u03b2<\/jats:italic>\n ), Receptor activator of nuclear factor \u03ba B (\n RANK<\/jats:italic>\n ) and its ligand (\n RANKL<\/jats:italic>\n ) 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\u2013gene interactions and gene-environment interactions.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The GA and AA genotypes of\n RANK<\/jats:italic>\n rs3018362 were significantly associated with increased osteoporosis risk (OR = 2.08 [1.08\u20133.98] and 2.76 [1.21\u20136.30], respectively) while the CC genotype of ESR1 rs2234693 was associated with reduced risk (OR = 0.28 [0.11\u20130.69]). For hip fracture,\n ESR1<\/jats:italic>\n rs2234693 (CC genotype) was protective (OR = 0.30 [0.12\u20130.75]), whereas\n RANK<\/jats:italic>\n rs3018362 (AA genotype) increased risk (OR = 2.4 [1.01\u20136.06]). A significant gene\u2013gene interaction between\n ESR1<\/jats:italic>\n (rs2228480) and\n RANK<\/jats:italic>\n (rs3018362) increased osteoporosis risk (OR = 2.1 [1.4\u20133.2], CVC = 10\/10), and a gene\u2013gene model involving\n ESR1<\/jats:italic>\n ,\n IL6R<\/jats:italic>\n ,\n IL1\u03b2<\/jats:italic>\n , and\n RANKL<\/jats:italic>\n was identified for hip fracture (CVC = 8\/10). In osteoporosis, a gene\u2013environment interaction was observed between\n CYP19A1<\/jats:italic>\n SNVs (rs700518, rs1062033, rs4775936, rs767199),\n IL1\u03b2<\/jats:italic>\n rs16944, and 10-year probability of major fracture (CVC = 10\/10).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Our findings suggest that\n RANK<\/jats:italic>\n and\n ESR1<\/jats:italic>\n variants are independently and interactively associated with osteoporosis and fracture risk, and that gene\u2013gene and gene\u2013environment interactions play a critical role in disease susceptibility among Mexican women.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fragi.2026.1769306","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T10:26:42Z","timestamp":1773829602000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Gene-gene and gene-environment interactions of CYP19A1, ESR1, IL6, IL6R, IL1\u03b2, RANK, and RANKL variants in relation to osteoporosis and hip fracture risk in Mexican women"],"prefix":"10.3389","volume":"7","author":[{"given":"Antonio","family":"Miranda-Duarte","sequence":"first","affiliation":[{"name":"Medicina Gen\u00f3mica, Instituto Nacional de Rehabilitaci\u00f3n","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Ponce de Le\u00f3n-Su\u00e1rez","sequence":"additional","affiliation":[{"name":"Medicina Gen\u00f3mica, Instituto Nacional de Rehabilitaci\u00f3n","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Hidalgo-Bravo","sequence":"additional","affiliation":[{"name":"Medicina Gen\u00f3mica, Instituto Nacional de Rehabilitaci\u00f3n","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Vel\u00e1zquez-Cruz","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00f3mica del Metabolismo \u00d3seo, Instituto Nacional de Medicina Gen\u00f3mica (INMEGEN)","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esperanza","family":"Ram\u00edrez-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Medicina Gen\u00f3mica, Instituto Nacional de Rehabilitaci\u00f3n","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O. Celeste","family":"Mart\u00ednez-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Facultad de Nutrici\u00f3n, Universidad Aut\u00f3noma del Estado de Morelos, Cuernavaca","place":["Morelos, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clementina","family":"Castro-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Medicina Gen\u00f3mica y Toxicolog\u00eda Ambiental, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Barredo-Prieto","sequence":"additional","affiliation":[{"name":"Medicina Gen\u00f3mica, Instituto Nacional de Rehabilitaci\u00f3n","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonora","family":"Casas-Avila","sequence":"additional","affiliation":[{"name":"Medicina Gen\u00f3mica, Instituto Nacional de Rehabilitaci\u00f3n","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"B2","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1007\/s00296-011-1890-2","article-title":"Analysis of estrogen receptor alpha gene haplotype in Mexican mestizo patients with primary osteoarthritis of the knee","volume":"32","author":"Borgonio-Cuadra","year":"2012","journal-title":"Rheumatol. 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