PDF(Pubmed)
Abstract：
BACKGROUND: Oestrone, predominantly made in fat, is the main circulating oestrogen and important for target tissue oestradiol production in women after menopause. The present study was undertaken to determine the genetic regulation of blood oestrone, measured with precision, in postmenopausal women and to explore associations between the identified genetic loci and endometrial cancer in a large, independent cohort.
METHODS: A genome-wide association study (GWAS) was undertaken in women aged at least 70 years to identify genetic associations with blood oestrone concentrations measured by liquid chromatography and tandem mass spectrometry. The GWAS included participants from the Sex Hormones in Older Women (SHOW) study, a sub-study of the longitudinal ASPREE (ASPirin in Reducing Events in the Elderly) randomised trial. Of the 6358 women providing a biobank sample at enrolment, 4951 unrelated women of European ancestry, not taking sex hormones, anti-oestrogens, anti-androgens or systemic glucocorticoids were included in the GWAS. Single nucleotide polymorphisms (SNPs) from loci identified below the genome-wide significance threshold were then tested in an independent cohort (the UK Biobank) for association with endometrial cancer risk, using logistic regression and adjusting for age, body mass index (BMI) and the top 10 genetic principal components.
RESULTS: The median age of the 4951 women included in the GWAS was 75.9 years (range 70-94.8 years). The GWAS identified four independent SNPs associated with oestrone concentrations (p < 5 × 10-8). Among them, the effect (minor) alleles rs34670419-T, rs2846729-T and rs2414098-T were associated with lower oestrone concentrations. Carrying these effect alleles was associated with lower oestrone concentrations in a dose-dependent manner. The effect allele rs56400819-A was associated with higher oestrone concentrations. When applied to UK Biobank, carrier status for rs2414098-T associated with the CYP19A1 gene which encodes the aromatase enzyme required for oestrogen synthesis was significantly associated with lower endometrial cancer risk (adjusted odd ratio [aOR] 0.87 [95% CI 0.82-0.93]; p = 6.69 × 10-5 for women across all ages and aOR 0.89 [95% CI 0.83-0.96]; p = 0.003 for postmenopausal women). None of the models that included age, body mass index (BMI), the top 10 genetic principal components, parity and diabetes mellitus explained more than 7.6% of the variation in risk.
CONCLUSIONS: We have shown genetic regulation of oestrone concentrations in postmenopausal women, and that SNPs associated with oestrone were also associated with endometrial cancer risk, independent of BMI, parity and diabetes mellitus. Although the apparent contribution was modest, the biological influence of oestrone concentrations may be greater through conversion to oestradiol in endometrial tissue.
BACKGROUND: The ASPREE trial was supported by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (Grant U01AG029824); the National Health and Medical Research Council (NHMRC) of Australia (Grant 34047, 1127060); Monash University (Australia); and the Victorian Cancer Agency (Australia). The ASPREE Healthy Ageing Biobank was funded by the CSIRO (Flagship Grant), the National Cancer Institute (Grant U01 AG029824) and Monash University. This analysis of sex hormones was funded by an NHMRC of Australia Project Grant (No. 1105305). SRD holds an NHMRC Investigator Grant (2016627). PL is supported by a National Heart Foundation Future Leader Fellowship (102604).
METHODS: A genome-wide association study (GWAS) was undertaken in women aged at least 70 years to identify genetic associations with blood oestrone concentrations measured by liquid chromatography and tandem mass spectrometry. The GWAS included participants from the Sex Hormones in Older Women (SHOW) study, a sub-study of the longitudinal ASPREE (ASPirin in Reducing Events in the Elderly) randomised trial. Of the 6358 women providing a biobank sample at enrolment, 4951 unrelated women of European ancestry, not taking sex hormones, anti-oestrogens, anti-androgens or systemic glucocorticoids were included in the GWAS. Single nucleotide polymorphisms (SNPs) from loci identified below the genome-wide significance threshold were then tested in an independent cohort (the UK Biobank) for association with endometrial cancer risk, using logistic regression and adjusting for age, body mass index (BMI) and the top 10 genetic principal components.
RESULTS: The median age of the 4951 women included in the GWAS was 75.9 years (range 70-94.8 years). The GWAS identified four independent SNPs associated with oestrone concentrations (p < 5 × 10-8). Among them, the effect (minor) alleles rs34670419-T, rs2846729-T and rs2414098-T were associated with lower oestrone concentrations. Carrying these effect alleles was associated with lower oestrone concentrations in a dose-dependent manner. The effect allele rs56400819-A was associated with higher oestrone concentrations. When applied to UK Biobank, carrier status for rs2414098-T associated with the CYP19A1 gene which encodes the aromatase enzyme required for oestrogen synthesis was significantly associated with lower endometrial cancer risk (adjusted odd ratio [aOR] 0.87 [95% CI 0.82-0.93]; p = 6.69 × 10-5 for women across all ages and aOR 0.89 [95% CI 0.83-0.96]; p = 0.003 for postmenopausal women). None of the models that included age, body mass index (BMI), the top 10 genetic principal components, parity and diabetes mellitus explained more than 7.6% of the variation in risk.
CONCLUSIONS: We have shown genetic regulation of oestrone concentrations in postmenopausal women, and that SNPs associated with oestrone were also associated with endometrial cancer risk, independent of BMI, parity and diabetes mellitus. Although the apparent contribution was modest, the biological influence of oestrone concentrations may be greater through conversion to oestradiol in endometrial tissue.
BACKGROUND: The ASPREE trial was supported by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (Grant U01AG029824); the National Health and Medical Research Council (NHMRC) of Australia (Grant 34047, 1127060); Monash University (Australia); and the Victorian Cancer Agency (Australia). The ASPREE Healthy Ageing Biobank was funded by the CSIRO (Flagship Grant), the National Cancer Institute (Grant U01 AG029824) and Monash University. This analysis of sex hormones was funded by an NHMRC of Australia Project Grant (No. 1105305). SRD holds an NHMRC Investigator Grant (2016627). PL is supported by a National Heart Foundation Future Leader Fellowship (102604).
摘要：
背景：雌雄同体，主要由脂肪制成，是女性绝经后产生雌二醇的主要循环雌激素和重要靶组织。本研究是为了确定血液雌酮的遗传调节，精密测量，在绝经后妇女中，探索已确定的遗传位点与子宫内膜癌之间的关联，独立队列。
方法：对年龄在70岁以上的女性进行了全基因组关联研究（GWAS），以确定通过液相色谱和串联质谱测量的血液雌酮浓度与遗传关联。GWAS包括来自老年女性性激素（SHOW）研究的参与者，纵向ASPREE（ASPirin减少老年人事件）随机试验的子研究。在注册时提供生物样本的6358名妇女中，4951名欧洲血统的无关女性，不服用性激素,抗雌激素,抗雄激素或全身性糖皮质激素纳入GWAS.然后在一个独立的队列（英国生物银行）中测试了来自低于全基因组显著性阈值的基因座的单核苷酸多态性（SNP）与子宫内膜癌风险的关联。使用逻辑回归和调整年龄，体重指数(BMI)和前10个遗传主成分。
结果：纳入GWAS的4951名女性的中位年龄为75.9岁（范围70-94.8岁）。GWAS鉴定了与雌酮浓度相关的四个独立SNP(p<5×10-8)。其中,效应(次要)等位基因rs34670419-T，rs2846729-T和rs2414098-T与较低的雌酮浓度相关。携带这些效应等位基因与较低的雌酮浓度呈剂量依赖性。效应等位基因rs56400819-A与更高的雌酮浓度相关。当应用于英国生物银行时，与编码雌激素合成所需芳香化酶的CYP19A1基因相关的rs2414098-T的携带者状态与较低的子宫内膜癌风险显著相关(调整后的奇数比[aOR]0.87[95%CI0.82-0.93];所有年龄段的女性p=6.69×10-5,aOR为0.89[95%CI0.83-0.96];绝经后女性p=0.003).没有包括年龄的模型，体重指数（BMI），十大遗传主成分，产次和糖尿病解释了超过7.6%的风险变化。
结论：我们已经显示了绝经后女性雌酮浓度的遗传调控，与雌酮相关的SNP也与子宫内膜癌风险相关，独立于BMI，胎次和糖尿病。尽管明显的贡献是微不足道的，通过子宫内膜组织中转化为雌二醇，雌酮浓度的生物学影响可能更大。
背景：ASPREE试验得到了国家老龄化研究所和美国国立卫生研究院国家癌症研究所（GrantU01AG029824）；澳大利亚国家健康与医学研究委员会（NHMRC）（Grant34047，1127060）；莫纳什大学（澳大利亚）和维多利亚癌症局（澳大利亚）的支持。ASPREE健康老龄化生物银行由CSIRO（旗舰赠款）资助，国家癌症研究所（GrantU01AG029824）和莫纳什大学。这项性激素分析是由澳大利亚NHMRC项目赠款资助的（编号1105305).SRD持有NHMRC调查员补助金（2016627）。PL由国家心脏基金会未来领袖奖学金（102604）支持。
方法：对年龄在70岁以上的女性进行了全基因组关联研究（GWAS），以确定通过液相色谱和串联质谱测量的血液雌酮浓度与遗传关联。GWAS包括来自老年女性性激素（SHOW）研究的参与者，纵向ASPREE（ASPirin减少老年人事件）随机试验的子研究。在注册时提供生物样本的6358名妇女中，4951名欧洲血统的无关女性，不服用性激素,抗雌激素,抗雄激素或全身性糖皮质激素纳入GWAS.然后在一个独立的队列（英国生物银行）中测试了来自低于全基因组显著性阈值的基因座的单核苷酸多态性（SNP）与子宫内膜癌风险的关联。使用逻辑回归和调整年龄，体重指数(BMI)和前10个遗传主成分。
结果：纳入GWAS的4951名女性的中位年龄为75.9岁（范围70-94.8岁）。GWAS鉴定了与雌酮浓度相关的四个独立SNP(p<5×10-8)。其中,效应(次要)等位基因rs34670419-T，rs2846729-T和rs2414098-T与较低的雌酮浓度相关。携带这些效应等位基因与较低的雌酮浓度呈剂量依赖性。效应等位基因rs56400819-A与更高的雌酮浓度相关。当应用于英国生物银行时，与编码雌激素合成所需芳香化酶的CYP19A1基因相关的rs2414098-T的携带者状态与较低的子宫内膜癌风险显著相关(调整后的奇数比[aOR]0.87[95%CI0.82-0.93];所有年龄段的女性p=6.69×10-5,aOR为0.89[95%CI0.83-0.96];绝经后女性p=0.003).没有包括年龄的模型，体重指数（BMI），十大遗传主成分，产次和糖尿病解释了超过7.6%的风险变化。
结论：我们已经显示了绝经后女性雌酮浓度的遗传调控，与雌酮相关的SNP也与子宫内膜癌风险相关，独立于BMI，胎次和糖尿病。尽管明显的贡献是微不足道的，通过子宫内膜组织中转化为雌二醇，雌酮浓度的生物学影响可能更大。
背景：ASPREE试验得到了国家老龄化研究所和美国国立卫生研究院国家癌症研究所（GrantU01AG029824）；澳大利亚国家健康与医学研究委员会（NHMRC）（Grant34047，1127060）；莫纳什大学（澳大利亚）和维多利亚癌症局（澳大利亚）的支持。ASPREE健康老龄化生物银行由CSIRO（旗舰赠款）资助，国家癌症研究所（GrantU01AG029824）和莫纳什大学。这项性激素分析是由澳大利亚NHMRC项目赠款资助的（编号1105305).SRD持有NHMRC调查员补助金（2016627）。PL由国家心脏基金会未来领袖奖学金（102604）支持。
