title: CYP19 and ESR1 gene polymorphisms: response of the bone mineral density in post-menopausal women to hormonal replacement therapy.
abstract: OBJECTIVE
  Sex steroids are important regulators of bone physiology and play an essential role in the maintenance of bone health throughout the life. Hormonal replacement therapy (HRT) is a treatment commonly used to relieve symptoms and some undesirable consequences of menopause such as osteoporosis. Osteoporosis, characterized by the loss of bone mass and deterioration of microarchitecture with a consequent higher risk of fragility fractures, is under genetic influence. A tetranucleotide (TTTA)n microsatellite repeat polymorphism, at intron 4 of the CYP19 (aromatase) gene, has been previously associated with higher lumbar spine bone mineral density (LS-BMD) and lower risk of spine fracture in postmenopausal women. Moreover, the ERα encoded by the ESR1 gene is another important candidate for the regulation of bone mass of menopause. Moreover prospective analysis from >18.000 subjects at the GENOMOS study indicated that XX homozygotes genotype had a reduced risk of fracture independently from BMD. In the present study, we investigated in postmenopausal Italian women, at baseline and after 1 year of HRT, whether ESR1 and CYP19 gene polymorphisms could affect BMD through different statistical models.
  
  
  METHODS
  This study has been performed on 100 post-menopausal Italian women, from a larger group of 250. The study group was administred HRT and LS-BMD was measured at baseline and after 1 year of therapy. Genetic analysis evaluating ESR1 and CYP19 gene polymorphisms was performed.
  
  
  RESULTS
  Generalized Linear Models (GLMs) test showed that women with normal LS-BMD at the baseline had a major statistically significant BMD increase of 0.1426 gr/cm(2) (p= 0.0001) with respect to the osteoporotic patients. In addition, subjects with genotype 1 and 2 of CYP19 gene had a lower modification in LS-BMD after 1 year of HRT (0.0837 gr/cm(2) and 0,076 g/cm(2); p=0.0470 and 0,0547 respectively) when compared to genotype 3. No influences of the aromatase genotypes were observed in the variable difference using both Anova and GLMs test. Regarding the ESR1 gene polymorphism, the LS-BMD after 1 year of HRT was influenced by the diagnosis at the baseline and height and ERα genotypes were able to influence difference with statistical significant results with both test.
  
  
  CONCLUSIONS
  In the present study, we have demonstrated that CYP19 gene polymorphism is able to influence the effect of 1 year HRT on LS-BMD with no influence on pre-/ and post-/HRT LS-BMD differences. Although ESR1 gene polymorphism is not able to influence the LS-BMD after 1 year HRT, it influences the observed modifications during the year of therapy. These data underlie the complexity of the genetics of the bone mass and its importance in influencing the response to HRT.
authors.affiliation: Metabolic Bone Diseases Unit, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Masi
authors.affiliation: Metabolic Bone Diseases Unit, University of Florence, Florence, Italy.
authors.forename: Silva
authors.initials: S
authors.lastname: Ottanelli
authors.affiliation: Department of Statistics, University of Florence, Florence, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Berni
authors.affiliation: Department of Statistics, University of Florence, Florence, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Cacudi
authors.affiliation: Metabolic Bone Diseases Unit, University of Florence, Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giusti
authors.affiliation: Metabolic Bone Diseases Unit, University of Florence, Florence, Italy.
authors.forename: Gemma
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Metabolic Bone Diseases Unit, University of Florence, Florence, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Cavalli
authors.affiliation: Metabolic Bone Diseases Unit, University of Florence, Florence, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fossi
authors.affiliation: Metabolic Bone Diseases Unit, University of Florence, Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Marini
authors.affiliation: Metabolic Bone Diseases Unit, University of Florence, Florence, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Ciuffi
authors.affiliation: Metabolic Bone Diseases Unit, University of Florence, Florence, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tanini
authors.affiliation: Metabolic Bone Diseases Unit, University of Florence, Florence, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Brandi
keywords: CYP19 gene; ESR1 gene; Hormonal Replace Therapy (HRT); polymorphism