Association of the aromatase gene alleles with BMD: epidemiological and functional evidence.
BMD has a strong heritable component. Estrogen activity depends on the aromatization of androgenic precursors in nongonadal tissues both in postmenopausal women and men. Therefore, aromatase is an appealing candidate gene to explain, in part, the genetic component of BMD. In fact, an association between aromatase polymorphisms and BMD has been previously reported in some relatively small groups. In this study, we explored the relationship between several SNPs in the aromatase region and hip BMD in 1163 postmenopausal women. We found significant differences across genotypes, particularly in older women. The BMD differences between homozygous women with opposing genotypes were 4.2% in the whole group and 7.3% in women >67 yr of age. Body weight was significantly associated with BMD also, but there was no evidence for a statistically significant interaction between body weight and aromatase polymorphisms. Electrophoretic mobility shift assays suggested the binding of the CEBPss transcription factor to the C/G rs1062033 locus, located approximately 12 kb upstream of the translation start site. Experiments of transient transfection of osteoblastic cells with luciferase reporters showed differences in the transcriptional activity of alleles C and G at this locus, with different responses to the co-transfection of a CEBPss expression vector. Furthermore, evidence for differential allelic expression was found in bone tissue samples. In conclusion, polymorphisms in a 12-kb region of the aromatase gene are associated with BMD in postmenopausal women, particularly during the late postmenopausal period. In vitro functional studies point to rs1062033 as a true regulatory polymorphism.
Riancho
José A
JA
Department of Internal Medicine, Hospital U. M. Valdecilla, University of Cantabria, Av. Valdecilla s/n, Santander 39008, Spain. rianchoj@unican.es
Sañudo
Carolina
C
Valero
Carmen
C
Pipaón
Carlos
C
Olmos
José M
JM
Mijares
Verónica
V
Fernández-Luna
José L
JL
Zarrabeitia
María T
MT
D000368:Aged; D000483:Alleles; D001141:Aromatase / Q000235:genetics*; D015992:Body Mass Index; D015519:Bone Density / Q000235:genetics* / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D016021:Epidemiologic Studies; D005260:Female; D017930:Genes, Reporter; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017698:Postmenopause / Q000235:genetics / Q000502:physiology
D022762:CCAAT-Enhancer-Binding Proteins; D008156:Luciferases; D001141:Aromatase