Identification of an Aromatase Haplotype That Is Associated with Gene Expression and Postmenopausal Osteoporosis

Riancho, José A.; Valero, Carmen; Naranjo, Angel; Morales, Dieter; Sañudo, Carolina; Zarrabeitia, Marı́a T.

doi:10.1210/jc.2006-1616

Cited by 42 publications

(36 citation statements)

References 46 publications

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“…These results fit with the association data, for the CC genotype was related to a higher risk of hip fractures. They also agree with our previous data showing a relationship between aromatase genotype and gene expression in the adipose tissue [21]. Therefore, we hypothesize that women with TT alleles of the estrogen receptor are more sensitive to small changes in estrogen availability, such as those determined by aromatase allelic variants.…”

Section: Discussionsupporting

confidence: 93%

“…Thus, women with unfavorable variants of both genes are at increased risk of hip fractures. The molecular mechanism involved in the differences in aromatase RNA levels across different genotypes has not been elucidated, but it is likely to depend on differences in the ability to bind transcription factors, which in turn results in differential allelic expression [21]. Whatever the mechanism might be, women with C alleles appear to express less aromatase at the tissue level and are therefore likely to have less bioavailable estradiol after the menopause, which in the long term will have a deleterious influence on the bone mass and result in a higher risk of fractures.…”

Section: Discussionmentioning

confidence: 99%

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Association of aromatase and estrogen receptor gene polymorphisms with hip fractures

et al. 2007

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Summary Two polymorphisms of the aromatase and estrogen receptor genes appeared to interact to influence the risk of hip fractures in women. Introduction Allelic variants of the aromatase gene have been associated with bone mineral density and vertebral fractures. Our objective was to analyze the relationship between two polymorphisms of the aromatase and estrogen receptor genes and hip fractures. Methods We studied 498 women with hip fractures and 356 controls. A C/G polymorphism of the aromatase gene and a T/C polymorphism of the estrogen receptor α gene were analyzed using Taqman assays. Aromatase gene expression was determined in 43 femoral neck samples by real-time RT-PCR. Results There were no significant differences in the overall distribution of genotypes between the fracture and control groups. However, among women with a TT genotype of the estrogen receptor, the CC aromatase genotype was more frequent in women with fractures than in controls (39 vs. 23%, p=0.009). Thus, women homozygous for T alleles of estrogen receptor and C alleles of aromatase were at increased risk of fracture (odds ratio 2.0; 95% confidence interval 1.2-3.4). The aromatase polymorphism was associated with RNA levels in bone tissue, which were three times lower in samples with a CC genotype (p=0.009). Conclusions These common polymorphisms of the aromatase and estrogen receptor genes appear to interact, influencing the risk of hip fractures in women.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Association of aromatase and estrogen receptor gene polymorphisms with hip fractures

et al. 2007

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“…Previously reported single nucleotide polymorphisms (SNPs) have small individual effects and the genetic correlation with the phenotypes is low (9). Therefore, more haplotype and gene-gene interaction cohort studies should be performed for the investigation of the genetic background of OP (5,10,11).…”

Section: Introductionmentioning

confidence: 99%

Single nucleotide polymorphisms in new candidate genes are associated with bone mineral density and fracture risk

Lazáry

Kósa

Tobiás

et al. 2008

European Journal of Endocrinology

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Objective: Osteoporosis (OP) is a multifactorial disease with high heritability but its exact genetic background is still poorly understood. We examined the effect of 24 single nucleotide polymorphisms (SNPs) located in five genes -alkaline phosphatase, matrix metalloproteinase-2, tissue inhibitor of metalloproteases-2 (TIMP2), fibroblast growth factor receptor-1 (FGFR1), and fatty acid-binding protein-3 (FABP3) -previously not associated with OP. Design: We performed a genotype-phenotype association study at a university hospital. Methods: A total of 360 Hungarian postmenopausal women were involved in the study. Bone mineral density (BMD) was determined at spine, hip, and distal radius. Genomic DNA was extracted from venous blood samples and a high-throughput genotyping method based on single-based primer extension was applied for allelic discrimination. Robust statistical tools were utilized for multiplex data analysis. Results: SNP rs6996321 in FGFR1 was significantly related to spine BMD (PZ0.002) and rs10914367 in FABP3 was associated with hip BMD (PZ0.028). Non-vertebral fracture risk was significantly increased in carriers of ' A' allele of rs9900972 in TIMP2 (odds ratioZ2.06, PZ0.0187). We could also identify validated gene-gene interactions significantly affecting BMD and fracture risk. Conclusions: We identified two previously unreported SNPs in FGFR1 and FABP3 associated with BMD and a third SNP in TIMP2 related to risk for non-vertebral osteoporotic fractures. This is the first report about the association between these allelic variants and the phenotypes of postmenopausal OP. Further studies need to clarify the role of these genes and their polymorphisms in the process of bone loss.

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“…>9 , rs727479(T), rs10046(T), and rs4646(G) were associated with higher levels of estrogens (27,(35)(36)(37)(38)(39). The Val 80 (rs700518) G allele was found to be associated with elevated aromatase expression (40).…”

Section: Introductionmentioning

confidence: 90%

BRCA1 Breast Cancer Risk Is Modified by CYP19 Polymorphisms in Ashkenazi Jews

Raskin

Lejbkowicz

Barnett‐Griness

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Exposure to sex hormones is a major risk factor for breast cancer and current treatments include hormone modifying drugs, among them aromatase inhibitors. We studied the association of CYP19 ( IntroductionBreast cancer is one of the leading causes of cancer morbidity and mortality worldwide (1). In the past decade, two major genes have been shown to be related to breast (and ovarian) cancer susceptibility, BRCA1 and BRCA2 (2). Three Ashkenazi Jewish founder mutations in these genes (BRCA1: 185delAG and 5382insC and BRCA2: 6174delT) have a combined frequency of 2.5% in the Ashkenazi population and appear in f10% (3-5) of breast cancer cases in Ashkenazi Jewish women. Estimates of penetrance vary greatly across different studies, ranging from 37% to 90% (6-12). This heterogeneity in risk among women who carry BRCA1/2 mutations suggests the existence of modifying genetic and/or environmental factors. Polymorphisms in several genes have been suggested to modify breast and ovarian cancer risk in BRCA1 and BRCA2 carriers, although most have not been replicated (13-21). The only confirmed BRCA2 breast cancer risk modifier is RAD51 135G>C (22). No studies have, as yet, evaluated the association between polymorphisms in the genes involved in estrogen metabolism and breast cancer risk in BRCA mutation carriers.Because estrogens play an important role in carcinogenesis and progression of breast cancer (23, 24), genes encoding for enzymes involved in estrogen biosynthesis and metabolism are plausible candidates as breast cancer susceptibility genes. One such candidate is CYP19 (p450arom), which encodes for aromatase, an enzyme that converts androgens to estrogens. The association of polymorphisms in the CYP19 with breast cancer risk has previously been studied, with particular focus on the [TTTA] n repeats polymorphism (25)(26)(27)(28)(29)(30)(31) Estrogen receptor (ER) status is an important prognostic factor of breast tumors. A higher prevalence of ER-negative breast tumors in BRCA1 carriers was described (41). It has been shown that this association is neither a consequence of the young age at onset nor high grade but is an intrinsic property of BRCA1-related cancers (42). Recent studies found a significant association of the CYP19 [TTTA] 7 (delTCT) allele with ERpositive and CYP19 Trp 39 Arg (TC/CC) genotypes with ER-negative breast tumors (32, 43).Previous genotyping efforts established the LD haplotype block structure of CYP19 (44). In block 4, which spans the entire coding region of CYP19, four common haplotypes cover 88% of haplotype diversity in Caucasians and can be distinguished by only three single nucleotide polymorphisms (SNP; rs727479, rs10046, and rs4646). None of these haplotypes was found to be significantly associated with breast cancer risk in a large multiethnic case-control study (44), but individual alleles rs727479(T), rs10046(T), and rs4646(G) were shown to be in association with elevated estrogen levels in postmenopausal women (39).The present study investigates the causality of breast ca...

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Identification of an Aromatase Haplotype That Is Associated with Gene Expression and Postmenopausal Osteoporosis

Cited by 42 publications

References 46 publications

Association of aromatase and estrogen receptor gene polymorphisms with hip fractures

Association of aromatase and estrogen receptor gene polymorphisms with hip fractures

Single nucleotide polymorphisms in new candidate genes are associated with bone mineral density and fracture risk

BRCA1 Breast Cancer Risk Is Modified by CYP19 Polymorphisms in Ashkenazi Jews

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