{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T10:33:45Z","timestamp":1780569225497,"version":"3.54.1"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2006,9,1]],"date-time":"2006-09-01T00:00:00Z","timestamp":1157068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>In this large population-based cohort study, variants in ESR2 were associated with increased risk of vertebral and incident fragility fracture in postmenopausal women. Interaction of ESR2 with ESR1 and IGF1 was determined and revealed a deleterious genetic combination that enhances the risk of osteoporotic fracture.<\/jats:p>\n               <jats:p>Introduction: Osteoporosis is a complex disease with strong genetic influence, but the genes involved are ill-defined. We examined estrogen receptor \u03b2 (ESR2) polymorphisms in interaction with estrogen receptor \u03b1 (ESR1) and insulin-like growth factor I (IGF1) variants in relation to the risk of osteoporotic fracture, BMD, and bone geometry.<\/jats:p>\n               <jats:p>Materials and Methods: In the Rotterdam study, a prospective population-based cohort of elderly white individuals, we studied six single nucleotide polymorphisms (SNPs) in ESR2 (n = 6343, 60% women). We analyzed the genetic variants in the form of haplotypes reconstructed by a statistical method. Results refer to the most frequent ESR2 haplotype 1 estimated from two SNPs in intron 2 and the 3\u2032-untranslated region (UTR). Outcomes included vertebral and incident nonvertebral fractures, BMD, and hip structural analysis (HSA). We also studied the interaction with (the most frequent) ESR1 haplotype 1 estimated from the PvuII and XbaI polymorphisms and an IGF1 promoter CA-repeat.<\/jats:p>\n               <jats:p>Results: Compared with ESR2 haplotype 1 noncarriers, female homozygous carriers had a 1.8- and 1.4-fold increased risk of vertebral and fragility fractures. HSA showed that ESR2 haplotype 1 homozygote women had 2.6% thinner cortices, 1.0% increased neck width, and 4.3% higher bone instability (buckling ratios). For testing the gene interaction, we assumed a recessive model of ESR2 haplotype 1. Female homozygous carriers of ESR2 haplotype 1 and noncarriers of ESR1 haplotype 1 had a 3.5- and 1.8-fold increased risk of vertebral and fragility fractures (pinteraction = 0.10). Such effects and interactions were stronger in women homozygous for the IGF1 192-bp allele, with 9.3-fold increased risk (pinteraction = 0.002) for vertebral and 4.0-fold increased risk (pinteraction = 0.01) for fragility fractures. Multilocus interaction analyses of fracture endured correction for multiple testing using Monte-Carlo simulations (pinteraction = 0.02 for vertebral and pinteraction = 0.03 for fragility fractures). Similar patterns of interaction were observed for BMD, cortical thickness, bone strength (section modulus), and instability (buckling ratio). In men, no such effects were observed.<\/jats:p>\n               <jats:p>Conclusions: Variants of ESR2 alone and in interaction with ESR1 and IGF1 influence the risk of fracture in postmenopausal women. These findings reinforce the polygenic and complex character of osteoporosis.<\/jats:p>","DOI":"10.1359\/jbmr.060605","type":"journal-article","created":{"date-parts":[[2006,8,30]],"date-time":"2006-08-30T04:29:34Z","timestamp":1156912174000},"page":"1443-1456","source":"Crossref","is-referenced-by-count":70,"title":["Estrogen Receptor \u03b2 (<i>ESR2<\/i>) Polymorphisms in Interaction With Estrogen Receptor \u03b1 (<i>ESR1)<\/i> and Insulin-Like Growth Factor I (<i>IGF1<\/i>) Variants Influence the Risk of Fracture in Postmenopausal Women"],"prefix":"10.1093","volume":"21","author":[{"given":"Fernando","family":"Rivadeneira","sequence":"first","affiliation":[{"name":"Instituto de Genetica Humana, Pontificia Universidad Javeriana, Bogota, Colombia"},{"name":"Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands"},{"name":"Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce BJ","family":"van Meurs","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jojanneke","family":"Kant","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Carola","family":"Zillikens","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisette","family":"Stolk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J","family":"Beck","sequence":"additional","affiliation":[{"name":"Department of Radiology, Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Arp","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie CE","family":"Schuit","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Hofman","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanine J","family":"Houwing-Duistermaat","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics, Leiden University Medical Centre, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia M","family":"van Duijn","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes PTM","family":"van Leeuwen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huibert AP","family":"Pols","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands"},{"name":"Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 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