title: Identification of an aromatase haplotype that is associated with gene expression and postmenopausal osteoporosis.
abstract: BACKGROUND
  Osteoporosis has a significant genetic component. The aromatase-dependent conversion of androgenic precursors is the main source of estrogens in postmenopausal women.
  
  
  OBJECTIVE
  The objective of the investigation was to study the relationship of a set of single nucleotide polymorphisms (SNPs) of the aromatase gene with osteoporosis and determine their functional influence on gene transcription.
  
  
  METHODS
  This was a case-control study including 135 women with vertebral fractures due to postmenopausal osteoporosis and 312 controls. Alleles at four SNPs situated between exons I.2 and 3 were determined by Taqman assays. Total aromatase RNA and differential allelic-specific expression were studied by RT-real time PCR in adipose tissue samples taken from 50 individuals.
  
  
  RESULTS
  The SNPs studied were in strong linkage disequilibrium. A common haplotype, present in about half of the population, was identified as being associated with an increased risk of fractures (odds ratio 1.8, 95% confidence interval 1.2-2.8, P = 0.006). There was evidence of differential allelic expression. In heterozygous individuals, transcripts bearing T alleles at rs700518 SNP (which were included in the risk haplotype) were less abundant than those with the alternative C alleles (P < 0.001). Total aromatase expression was four times lower in fat samples from individuals who were homozygotes for the unfavorable alleles than in the opposite homozygotes (P = 0.007).
  
  
  CONCLUSIONS
  A common haplotype of aromatase associated with gene expression is also associated with the risk of osteoporotic vertebral fractures in postmenopausal women. These data are in line with the hypothesis that the aromatase-dependent synthesis of estrogens plays an important role in bone homeostasis in postmenopausal women.
authors.affiliation: Department of Internal Medicine, Hospital U. M. Valdecilla, University of Cantabria, 39008 Santander, Spain. rianchoj@unican.es
authors.forename: José A
authors.initials: JA
authors.lastname: Riancho
authors.forename: Carmen
authors.initials: C
authors.lastname: Valero
authors.forename: Angel
authors.initials: A
authors.lastname: Naranjo
authors.forename: Dieter J
authors.initials: DJ
authors.lastname: Morales
authors.forename: Carolina
authors.initials: C
authors.lastname: Sañudo
authors.forename: María T
authors.initials: MT
authors.lastname: Zarrabeitia
mesh_terms: D000328:Adult; D000368:Aged; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005598:Fractures, Spontaneous / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D015663:Osteoporosis, Postmenopausal / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause / Q000235:genetics*; D012307:Risk Factors
chemical_list: D004967:Estrogens; D001141:Aromatase