A common polymorphism in the 5'-untranslated region of the aromatase gene influences bone mass and fracture risk

Abstract

Objective: The aromatization of androgenic precursors in peripheral tissues, including bone, is the main source of estrogens after the menopause. CYP19, the gene encoding aromatase, has a long 5 0 -untranslated region with several variants of exon I and specific promoters. The aim of this study was to investigate the possible relationship between a common biallelic (C/G) polymorphism located on exon I.2 and bone mineral density (BMD). Design: This was designed to be an association study between CYP19 polymorphism and BMD and the risk of vertebral fractures in women. Methods: DNA was extracted from the peripheral blood of 299 women (116 premenopausal and 183 postmenopausal). CYP19 alleles were identified by a method based on the exonuclease activity of Taq-polymerase. BMD was determined by dual-energy absorptiometry. Results: In premenopausal women there were no genotype-related differences in BMD. However, postmenopausal women with the CC genotype had lower spine and hip BMD than those with the GG genotype. The association between CYP19 genotypes and BMD was independent of other variables, such as age, height, body weight, calcium intake or years since menopause. The CC genotype was also associated with an increased risk of osteoporotic vertebral fractures (odds ratio 2.0; P ¼ 0.03). Serum levels of estrone and estradiol were similar in women with CC and GG alleles. Conclusions: A common biallelic polymorphism in the 5 0 -untranslated region of the CYP19-aromatase gene was associated with significant differences in bone mass and the risk of vertebral fractures in postmenopausal women. Given the frequency of allelic variants, genotype-related differences appear to be important from the perspective of the individual as well as the general population. Further studies are needed to elucidate underlying mechanisms that may be dependent on differences in estrogen bioactivity at the bone tissue level.European Journal of Endocrinology 150 699-704

Association of aromatase and estrogen receptor gene polymorphisms with hip fractures

“…This 5′ region contains regulatory sequences and several variants of the first exon, whose transcription is driven by different tissuespecific promoters. Several investigators have reported an association between some common polymorphisms of the aromatase gene and BMD [8][9][10]. We have previously shown that a gene-gene interaction between aromatase and estrogen receptor α appears to influence BMD in postmenopausal women [11].…”

“…A C/G SNP located in the I.2 region of the aromatase gene (rs1062033) and a T/C SNP located in the first intron of the estrogen receptor (rs2234693) were typed using Taqman assays (Applied Biosystems), as previously reported [10,11].…”

CYP19 gene polymorphisms and the susceptibility to breast cancer in Xinjiang Uigur women

“…Estrogen levels have a close relationship with breast cancer. Zarrabeitia et al (2004) showed that the variant contributing to P450 19 gene polymorphism had relationship with estrone synthesis, and revealed that there was relationship between this polymorphism and the susceptibility to breast cancer. Moreover, Rhiem et al (2003) found that metastasis and the recurrence of breast cancer patients was higher than primary breast cancer significantly (57.6 vs 8.9%, P < 0.01) in CYP19 gene polymorphism.…”

Aromatase inhibitors and osteoporosis: Comment on the review by Felson and Cummings

“…Subjects carrying the G allele (GA and GG genotypes) compared with those carrying the AA genotype had significantly lower estradiol levels and an increased risk of osteoporosis and fractures (8). A C-to-G polymorphism in the 5Ј-untranslated region on exon 1.2 has been described (9). Individuals homozygous for the C allele had lower spine and hip BMD and increased vertebral fractures compared with those carrying the G allele (9).…”

“…A C-to-G polymorphism in the 5Ј-untranslated region on exon 1.2 has been described (9). Individuals homozygous for the C allele had lower spine and hip BMD and increased vertebral fractures compared with those carrying the G allele (9). Finally, the C1558T polymorphism in exon 10 in the 3Ј-untranslated region of the CYP19 gene appears to influence response to therapy (10).…”