title: 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.
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.
  
  
  BACKGROUND
  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.
  
  
  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.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. f.rivadeneira@erasmusmc.nl
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.forename: Jojanneke
authors.initials: J
authors.lastname: Kant
authors.forename: M Carola
authors.initials: MC
authors.lastname: Zillikens
authors.forename: Lisette
authors.initials: L
authors.lastname: Stolk
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Beck
authors.forename: Pascal
authors.initials: P
authors.lastname: Arp
authors.forename: Stephanie C E
authors.initials: SC
authors.lastname: Schuit
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Johannes P T M
authors.initials: JP
authors.lastname: van Leeuwen
authors.forename: Huibert A P
authors.initials: HA
authors.lastname: Pols
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D005260:Female; D050723:Fractures, Bone / Q000453:epidemiology*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006239:Haplotypes; D006615:Hip / Q000033:anatomy & histology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D015810:Linkage Disequilibrium; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics; D015663:Osteoporosis, Postmenopausal / Q000209:etiology / Q000235:genetics; D011110:Polymorphism, Genetic; D017698:Postmenopause; D012307:Risk Factors; D013131:Spine / Q000033:anatomy & histology
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007334:Insulin-Like Growth Factor I