青春期的年龄与哮喘风险：一项孟德尔随机化研究
2018/09/10
摘要
背景：主要在女性中进行关于青春期和哮喘的观察性研究提供了青春期早期可能与成人哮喘风险相关联的相互矛盾的结果，可能是由于残留的混杂因素。为了解决混杂问题，我们使用孟德尔随机化（MR）方法，即遗传变异被用作工具变量来评估青春期早期对女性和男性的青春期后哮喘的因果关系。
方法：MR分析在英国生物银行进行，对243,316名女性用254种月经初潮年龄基因变异，192,067名男性用46种变声期年龄基因变异。初潮年龄，以年份记录，分为早期（<12），正常（12-14）或晚期（>14）;变声期年龄分为早期（小于平均年龄），正常（约平均年龄）或晚期（大于平均年龄）。
结果：在女性中，我们发现了青春期和哮喘的因果影响的证据，早期月经初潮哮喘风险增加8％（OR值1.08; 95％CI 1.04-1.12;p=8.7×10-5）和晚期月经初潮哮喘风险减少8％（OR值 0.92; 95％CI 0.89-0.97;p=3.4×10-4），表明青春期随着年龄增加的持续保护作用。在男性中，我们发现相似的因果效应估计值，尽管置信区间更宽（早期变声期：OR 1.07; 95％CI 1.00-1.16；p=0.06；晚期变声期：OR 0.93; 95％CI 0.87-0.99;p=0.03）。我们仅适度的检测基因多效性，并且我们的研究结果表明，当应用不同的多效性方法时，它们具有稳健性。 BMI可能会引入多效性或依赖于因果途径;不包括与BMI相关变异的二级分析产生与主要分析相似的结果。我们的研究依赖于自我报告的暴露和结果，这可能影响了变声期年龄分析的可信力。
结论：这项大型MR研究提供了早期青春期和哮喘的因果不利影响的证据，并且不支持之前观察到的青春期时间与哮喘呈U形关系的观察结果。与青春期早期相关的常见生物或心理机制可能解释了我们在女性和男性中的结果的相似性，但需要进一步研究。结合其他早期青春期对健康有害影响的证据，我们的研究强调需要进一步调查和解决世界范围内观察到的早期青春期长期转变的原因。
Age at puberty and risk of asthma: A Mendelian randomisation study.
Minelli C, van der Plaat DA, Leynaert B, Granell R, Amaral AFS, Pereira M, Mahmoud O, Potts J, Sheehan NA, Bowden J, Thompson J, Jarvis D, Davey Smith G, Henderson J.
Abstract
BACKGROUND:Observational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males.
METHODS:MR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12-14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average).
RESULTS:In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10-5) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10-4), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking.
CONCLUSIONS:This large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide.
背景：主要在女性中进行关于青春期和哮喘的观察性研究提供了青春期早期可能与成人哮喘风险相关联的相互矛盾的结果，可能是由于残留的混杂因素。为了解决混杂问题，我们使用孟德尔随机化（MR）方法，即遗传变异被用作工具变量来评估青春期早期对女性和男性的青春期后哮喘的因果关系。
方法：MR分析在英国生物银行进行，对243,316名女性用254种月经初潮年龄基因变异，192,067名男性用46种变声期年龄基因变异。初潮年龄，以年份记录，分为早期（<12），正常（12-14）或晚期（>14）;变声期年龄分为早期（小于平均年龄），正常（约平均年龄）或晚期（大于平均年龄）。
结果：在女性中，我们发现了青春期和哮喘的因果影响的证据，早期月经初潮哮喘风险增加8％（OR值1.08; 95％CI 1.04-1.12;p=8.7×10-5）和晚期月经初潮哮喘风险减少8％（OR值 0.92; 95％CI 0.89-0.97;p=3.4×10-4），表明青春期随着年龄增加的持续保护作用。在男性中，我们发现相似的因果效应估计值，尽管置信区间更宽（早期变声期：OR 1.07; 95％CI 1.00-1.16；p=0.06；晚期变声期：OR 0.93; 95％CI 0.87-0.99;p=0.03）。我们仅适度的检测基因多效性，并且我们的研究结果表明，当应用不同的多效性方法时，它们具有稳健性。 BMI可能会引入多效性或依赖于因果途径;不包括与BMI相关变异的二级分析产生与主要分析相似的结果。我们的研究依赖于自我报告的暴露和结果，这可能影响了变声期年龄分析的可信力。
结论：这项大型MR研究提供了早期青春期和哮喘的因果不利影响的证据，并且不支持之前观察到的青春期时间与哮喘呈U形关系的观察结果。与青春期早期相关的常见生物或心理机制可能解释了我们在女性和男性中的结果的相似性，但需要进一步研究。结合其他早期青春期对健康有害影响的证据，我们的研究强调需要进一步调查和解决世界范围内观察到的早期青春期长期转变的原因。
(中日友好医院呼吸与危重症医学科 王瑞茵 摘译 林江涛 审校)
(PLoS Med. 2018 Aug 7;15(8):e1002634.)
(PLoS Med. 2018 Aug 7;15(8):e1002634.)
Age at puberty and risk of asthma: A Mendelian randomisation study.
Minelli C, van der Plaat DA, Leynaert B, Granell R, Amaral AFS, Pereira M, Mahmoud O, Potts J, Sheehan NA, Bowden J, Thompson J, Jarvis D, Davey Smith G, Henderson J.
Abstract
BACKGROUND:Observational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males.
METHODS:MR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12-14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average).
RESULTS:In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10-5) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10-4), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking.
CONCLUSIONS:This large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide.
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