Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? A Mendelian randomization study.
Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? A Mendelian randomization study.
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DOI：
10.1371/journal.pgen.1009887
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发表时间：
2022-01
期刊：
影响因子：
4.5
通讯作者：
Richmond RC
中科院分区：
文献类型：
--
作者：
Hayes BL;Robinson T;Kar S;Ruth KS;Tsilidis KK;Frayling T;Murray A;Martin RM;Lawlor DA;Richmond RC
早睡型的人被发现可以预防乳腺癌和前列腺癌。性激素与生物钟类型和两种癌症的发展有关。本研究旨在使用孟德尔随机化（MR）框架评估性激素是否混淆或调节生物钟对乳腺癌和前列腺癌的影响。从已发表的全基因组关联研究（n≤244,207名女性和n≤205,527名男性）中获得了与时间型和性激素（总睾酮、生物可利用睾酮、性激素结合球蛋白和雌二醇）相关的遗传变异（p<5×10−8）。使用单变量、双向和多变量mr研究这些变异与乳腺癌（nCases/ n对照= 133,384/113,789）和前列腺癌（nCases/ n对照= 79,148/61,106）的因果关系。在女性中，我们发现了以下证据：1)每一类乳腺癌风险降低，晨起偏好增加(OR = 0.93, 95% CI:0。88年,1.00);II)每SD生物可利用睾酮（OR = 1.10, 95% CI: 1.01, 1.19）和总睾酮（OR = 1.15, 95% CI:1.07, 1.23）增加乳腺癌风险；III)晨起偏好与生物可利用睾酮和总睾酮之间的双向效应（例如，晨起偏好增加的生物可利用睾酮的平均SD差= -0.08,95% CI:-0.12, -0.05；晨起偏好增加的生物可利用睾酮的平均SD差= -0.04,95% CI: -0.08, 0.00）。在男性中，我们发现了以下证据：1)每增加晨起偏好类别，前列腺癌风险降低（OR = 0.90, 95% CI: 0.83, 0.97）； 2)每增加生物可利用睾酮类别，前列腺癌风险增加（OR = 1.22, 95% CI: 1.08, 1.37）。男性的早晨偏好和睾丸激素之间没有发现双向影响。虽然睾酮水平与生物钟和癌症都有因果关系，但睾酮作为两者关系的中介的证据并不一致。早晨偏好对乳腺癌和前列腺癌的保护作用在临床上很有趣，尽管可能很难有效地改变睡眠类型。需要进一步的研究来调查其他潜在的可修饰的中间体。虽然之前的研究已经证明，早晨偏好的睡眠类型与降低乳腺癌和前列腺癌的风险有关，但性激素在这一关系中的作用尚未得到阐明。在这项研究中，我们使用与早晨偏好的时间类型、总睾酮、生物可利用睾酮、性激素结合球蛋白和雌二醇密切相关的遗传变异来探索这些性激素作为这种关系的中介或混杂因素的潜力。这项研究的结果暗示睾酮是生物钟与前列腺癌和乳腺癌风险之间关系的潜在中介，尽管不同方法的结果不一致。因此，需要进一步的研究来更好地理解这种关系背后的机制，以便为基于睡眠的干预研究的发展提供信息，这些研究可能有助于降低高危人群患乳腺癌和前列腺癌的风险。
Morning-preference chronotype has been found to be protective against breast and prostate cancer. Sex hormones have been implicated in relation to chronotype and the development of both cancers. This study aimed to assess whether sex hormones confound or mediate the effect of chronotype on breast and prostate cancer using a Mendelian Randomization (MR) framework. Genetic variants associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin, and oestradiol) (p<5×10−8) were obtained from published genome-wide association studies (n≤244,207 females and n≤205,527 males). These variants were used to investigate causal relationships with breast (nCases/nControls = 133,384/113,789) and prostate (nCases/nControls = 79,148/61,106) cancer using univariable, bidirectional and multivariable MR. In females, we found evidence for: I) Reduced risk of breast cancer per category increase in morning-preference (OR = 0.93, 95% CI:0. 88, 1.00); II) Increased risk of breast cancer per SD increase in bioavailable testosterone (OR = 1.10, 95% CI: 1.01, 1.19) and total testosterone (OR = 1.15, 95% CI:1.07, 1.23); III) Bidirectional effects between morning-preference and both bioavailable and total testosterone (e.g. mean SD difference in bioavailable testosterone = -0.08, 95% CI:-0.12, -0.05 per category increase in morning-preference vs difference in morning-preference category = -0.04, 95% CI: -0.08, 0.00 per SD increase in bioavailable testosterone). In males, we found evidence for: I) Reduced risk of prostate cancer per category increase in morning-preference (OR = 0.90, 95% CI: 0.83, 0.97) and II) Increased risk of prostate cancer per SD increase in bioavailable testosterone (OR = 1.22, 95% CI: 1.08, 1.37). No bidirectional effects were found between morning-preference and testosterone in males. While testosterone levels were causally implicated with both chronotype and cancer, there was inconsistent evidence for testosterone as a mediator of the relationship. The protective effect of morning-preference on both breast and prostate cancer is clinically interesting, although it may be difficult to effectively modify chronotype. Further studies are needed to investigate other potentially modifiable intermediates. Although previous studies have demonstrated that morning-preference chronotype is associated with reduced breast and prostate cancer risk, the role of sex hormones in this relationship has yet to be elucidated. In this study we use genetic variants strongly associated with morning-preference chronotype, total testosterone, bioavailable testosterone, sex-hormone binding globulin and oestradiol to explore the potential of these sex hormones to act as either mediators or confounders of this relationship. The findings of this study implicate testosterone as a potential mediator of the relationship between chronotype and both prostate and breast cancer risk, although results were inconsistent between methods. As such, further studies are warranted to better understand the mechanisms underlying this relationship in order to inform the development of sleep-based intervention studies that may help to reduce breast and prostate cancer risk in high-risk populations.
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影响因子：
7.7
作者：
Bowden J;Del Greco M F;Minelli C;Davey Smith G;Sheehan NA;Thompson JR
通讯作者：
Thompson JR
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
7.7
作者：
Burgess, Stephen;Thompson, Simon G.
通讯作者：
Thompson, Simon G.
DOI：
10.1136/bmj.k601
发表时间：
2018-07-12
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Davies NM;Holmes MV;Davey Smith G
通讯作者：
Davey Smith G
影响因子：
2
作者：
Del Greco, Fabiola M.;Minelli, Cosetta;Thompsonc, John R.
通讯作者：
Thompsonc, John R.