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Estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor alpha (ESR1) and insulin-like growth factor I (IGF1) variants influence the risk of fracture in postmenopausal women.
J Bone Miner Res. 2006 Sep; 21(9):1443-56.JB

Abstract

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.

INTRODUCTION

Osteoporosis is a complex disease with strong genetic influence, but the genes involved are ill-defined. We examined estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor alpha (ESR1) and insulin-like growth factor I (IGF1) variants in relation to the risk of osteoporotic fracture, BMD, and bone geometry.

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'-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.

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 (p(interaction) = 0.10). Such effects and interactions were stronger in women homozygous for the IGF1 192-bp allele, with 9.3-fold increased risk (p(interaction) = 0.002) for vertebral and 4.0-fold increased risk (p(interaction) = 0.01) for fragility fractures. Multilocus interaction analyses of fracture endured correction for multiple testing using Monte-Carlo simulations (p(interaction) = 0.02 for vertebral and p(interaction) = 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.

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.

Authors+Show Affiliations

Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. f.rivadeneira@erasmusmc.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16939403

Citation

Rivadeneira, Fernando, et al. "Estrogen Receptor Beta (ESR2) Polymorphisms in Interaction With Estrogen Receptor Alpha (ESR1) and Insulin-like Growth Factor I (IGF1) Variants Influence the Risk of Fracture in Postmenopausal Women." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 21, no. 9, 2006, pp. 1443-56.
Rivadeneira F, van Meurs JB, Kant J, et al. Estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor alpha (ESR1) and insulin-like growth factor I (IGF1) variants influence the risk of fracture in postmenopausal women. J Bone Miner Res. 2006;21(9):1443-56.
Rivadeneira, F., van Meurs, J. B., Kant, J., Zillikens, M. C., Stolk, L., Beck, T. J., Arp, P., Schuit, S. C., Hofman, A., Houwing-Duistermaat, J. J., van Duijn, C. M., van Leeuwen, J. P., Pols, H. A., & Uitterlinden, A. G. (2006). Estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor alpha (ESR1) and insulin-like growth factor I (IGF1) variants influence the risk of fracture in postmenopausal women. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 21(9), 1443-56.
Rivadeneira F, et al. Estrogen Receptor Beta (ESR2) Polymorphisms in Interaction With Estrogen Receptor Alpha (ESR1) and Insulin-like Growth Factor I (IGF1) Variants Influence the Risk of Fracture in Postmenopausal Women. J Bone Miner Res. 2006;21(9):1443-56. PubMed PMID: 16939403.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor alpha (ESR1) and insulin-like growth factor I (IGF1) variants influence the risk of fracture in postmenopausal women. AU - Rivadeneira,Fernando, AU - van Meurs,Joyce B J, AU - Kant,Jojanneke, AU - Zillikens,M Carola, AU - Stolk,Lisette, AU - Beck,Thomas J, AU - Arp,Pascal, AU - Schuit,Stephanie C E, AU - Hofman,Albert, AU - Houwing-Duistermaat,Jeanine J, AU - van Duijn,Cornelia M, AU - van Leeuwen,Johannes P T M, AU - Pols,Huibert A P, AU - Uitterlinden,André G, PY - 2006/8/31/pubmed PY - 2006/11/15/medline PY - 2006/8/31/entrez SP - 1443 EP - 56 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 21 IS - 9 N2 - UNLABELLED: 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. INTRODUCTION: Osteoporosis is a complex disease with strong genetic influence, but the genes involved are ill-defined. We examined estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor alpha (ESR1) and insulin-like growth factor I (IGF1) variants in relation to the risk of osteoporotic fracture, BMD, and bone geometry. 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'-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. 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 (p(interaction) = 0.10). Such effects and interactions were stronger in women homozygous for the IGF1 192-bp allele, with 9.3-fold increased risk (p(interaction) = 0.002) for vertebral and 4.0-fold increased risk (p(interaction) = 0.01) for fragility fractures. Multilocus interaction analyses of fracture endured correction for multiple testing using Monte-Carlo simulations (p(interaction) = 0.02 for vertebral and p(interaction) = 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. 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. SN - 0884-0431 UR - https://www.unboundmedicine.com/medline/citation/16939403/Estrogen_receptor_beta__ESR2__polymorphisms_in_interaction_with_estrogen_receptor_alpha__ESR1__and_insulin_like_growth_factor_I__IGF1__variants_influence_the_risk_of_fracture_in_postmenopausal_women_ L2 - https://doi.org/10.1359/jbmr.060605 DB - PRIME DP - Unbound Medicine ER -