Estrogen Receptor β (ESR2) Polymorphisms in Interaction With Estrogen Receptor α (ESR1) and Insulin‐Like Growth Factor I (IGF1) Variants Influence the Risk of Fracture in Postmenopausal Women

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 osteo...

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Published in:Journal of bone and mineral research 2006-09, Vol.21 (9), p.1443-1456
Main Authors: Rivadeneira, Fernando, van Meurs, Joyce BJ, Kant, Jojanneke, Zillikens, M Carola, Stolk, Lisette, Beck, Thomas J, Arp, Pascal, Schuit, Stephanie CE, Hofman, Albert, Houwing‐Duistermaat, Jeanine J, van Duijn, Cornelia M, van Leeuwen, Johannes PTM, Pols, Huibert AP, Uitterlinden, André G
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
association
Cohort Studies
estrogen receptor
Estrogen Receptor alpha - genetics
Estrogen Receptor beta - genetics
Female
Fractures, Bone - epidemiology
Genetic Predisposition to Disease - epidemiology
growth factors
Haplotypes
Hip - anatomy & histology
Humans
Insulin-Like Growth Factor I - genetics
Linkage Disequilibrium
Middle Aged
osteoporosis
Osteoporosis - genetics
Osteoporosis, Postmenopausal - etiology
Osteoporosis, Postmenopausal - genetics
Polymorphism, Genetic
Postmenopause
Risk Factors
single nucleotide polymorphisms
Spine - anatomy & histology
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Summary: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 β (ESR2) polymorphisms in interaction with estrogen receptor α (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 (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 m
ISSN:0884-0431
1523-4681
DOI:10.1359/jbmr.060605