Influence of puberty timing on adiposity and cardiometabolic traits: A Mendelian randomisation study.
Influence of puberty timing on adiposity and cardiometabolic traits: A Mendelian randomisation study.
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DOI：
10.1371/journal.pmed.1002641
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发表时间：
2018-08
期刊：
影响因子：
15.8
通讯作者：
Davey Smith G
中科院分区：
文献类型：
--
作者：
Bell JA;Carslake D;Wade KH;Richmond RC;Langdon RJ;Vincent EE;Holmes MV;Timpson NJ;Davey Smith G
青春期提前与未来的肥胖和心脏代谢疾病有广泛联系。我们研究了青春期开始的年龄是否可能影响肥胖和心脏代谢特征，而与儿童肥胖无关。单样本孟德尔随机化（MR）分析进行了多达3,611白人欧洲女性和男性后代的雅芳纵向研究的父母和儿童（ALSPAC）队列招募在出生时通过母亲在1991年4月1日和1992年12月31日之间。对时间敏感的暴露是初潮时的年龄和变声时的年龄。在18岁时测量的结果是体重指数（BMI）、基于双能X射线吸收测定法的脂肪和瘦体重指数、血压和来自靶向代谢组学的230种心脏代谢特征（150种浓度加上80种来自核磁共振[NMR]光谱的比率，涵盖胆固醇和甘油三酯、氨基酸、炎性糖蛋白等脂蛋白亚类）。对8岁时测量的青春期前BMI进行了调整。对于阴性对照MR分析，使用8岁时（青春期前，因此不能是青春期本身的结果）测量的BMI和心脏代谢特征。对于重复分析，使用汇总全基因组关联研究数据对多达322，154名成年人进行了青春期后BMI，24，925名成年人进行了青春期后NMR心脏代谢特征，13，848名儿童进行了青春期前肥胖（阴性对照）。与观察估计值一样，ALSPAC中使用351个多态性对月经初潮年龄进行单样本MR估计（解释10.6%的方差）表明，月经初潮年龄（每年）较晚与18岁时BMI为-1.38 kg/m2（或-0.34 SD单位，95% CI-0.46，-0.23; P = 9.77 × 10−09）相关。在8岁时根据BMI调整后，该系数衰减了10倍，至-0.12kg/m2（或-0.03SD，95%CI-0.13，0.07; P = 0.55）。与血压的关联是相似的，但其他特征之间的关联很小，而且不一致。在阴性对照MR分析中，较晚的初潮年龄与8岁时测量的青春期前BMI为-0.77 kg/m2相关（或-0.39 SD，95% CI-0.50，-0.29; P = 6.28 × 10 - 13），表明影响初潮的变量也影响初潮前的BMI。心脏代谢性状协会较弱，男性和两性之间的一致性较低。在2,648名女性中，8岁时较高的BMI（每1 kg/m2使用BMI的95个多态性解释3.4%的方差）与初潮提前相关（-0.26岁，95%CI-0.37，-0.16; P = 1.16 × 10 - 06），在男性和两性中也是如此。在使用234个多态性和逆方差加权（IVW）回归的双样本MR分析中，初潮年龄每增加一年与成人BMI为-0.81 kg/m2（或-0.17 SD单位，95% CI-0.21，-0.12; P = 4.00 × 10−15）相关。与心脏代谢特征的关联较弱。使用202个多态性，月经初潮较晚与儿童肥胖的几率较低相关（基于IVW的比值比= 0.52每年后，95%CI 0.48，0.57; P = 6.64 × 10−15）。研究的局限性包括单样本MR的样本量适中，缺乏对非白人欧洲人群的推断，青春期问卷完成率适中导致的潜在选择偏倚，以及性别暴露的可能不成比例的测量误差。检查的心脏代谢特征主要集中在脂质方面，不包括胰岛素和胰岛素样生长因子等糖尿病相关特征。我们的研究结果表明，青春期时间对肥胖和心脏代谢特征的影响很小，预防干预措施应侧重于减少儿童肥胖。在一项孟德尔随机研究中，约书亚贝尔和他的同事调查了青春期年龄可能对健康的影响。在较年轻时进入青春期的人更容易在成年后患上肥胖症和心脏代谢疾病，但这是否是因为青春期本身的时间尚不清楚。儿童期肥胖（肥胖）可能会导致青春期提前，也可能会进入成年期，使儿童期肥胖成为一个重要的潜在混杂因素。大多数以前的研究青春期时间作为成人肥胖和心脏代谢功能障碍的危险因素，没有考虑儿童肥胖，并使用粗略的心脏代谢特征的措施。他们还依赖于观察方法，这些方法容易产生更广泛的混淆。我们利用自然发生的初潮年龄遗传变异来研究青春期时间本身是否可能影响肥胖和心脏代谢特征。使用来自多代英国出生队列研究的> 3，600名后代的数据，我们检查了与体重指数，客观脂肪和瘦体重指数，血压以及目标代谢组学的200多个详细特征相关的月经初潮/声音中断的遗传代理年龄。这些结果特征都是在18岁（青春期开始后）和8岁（青春期开始前）测量的，这使我们能够检查青春期时间的影响，同时考虑儿童期的结果特征水平。我们发现，当考虑到8岁时的肥胖时，18岁时较晚的青春期开始对较低的肥胖和血压的明显影响在很大程度上减弱了。对其他心脏代谢特征的影响较小且不一致。我们还发现，8岁时肥胖率较高对青春期提前的影响很大。我们的研究结果支持青春期时间是肥胖和心脏代谢特征水平的标志，而不是驱动因素。这些研究结果表明，预防成人肥胖和心脏代谢疾病的干预措施应侧重于儿童肥胖，而不是青春期时间。
Earlier puberty is widely linked with future obesity and cardiometabolic disease. We examined whether age at puberty onset likely influences adiposity and cardiometabolic traits independent of childhood adiposity. One-sample Mendelian randomisation (MR) analyses were conducted on up to 3,611 white-European female and male offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort recruited at birth via mothers between 1 April 1991 and 31 December 1992. Time-sensitive exposures were age at menarche and age at voice breaking. Outcomes measured at age 18 y were body mass index (BMI), dual-energy X-ray absorptiometry–based fat and lean mass indices, blood pressure, and 230 cardiometabolic traits derived from targeted metabolomics (150 concentrations plus 80 ratios from nuclear magnetic resonance [NMR] spectroscopy covering lipoprotein subclasses of cholesterol and triglycerides, amino acids, inflammatory glycoproteins, and others). Adjustment was made for pre-pubertal BMI measured at age 8 y. For negative control MR analyses, BMI and cardiometabolic trait measures taken at age 8 y (before puberty, and which therefore cannot be an outcome of puberty itself) were used. For replication analyses, 2-sample MR was conducted using summary genome-wide association study data on up to 322,154 adults for post-pubertal BMI, 24,925 adults for post-pubertal NMR cardiometabolic traits, and 13,848 children for pre-pubertal obesity (negative control). Like observational estimates, 1-sample MR estimates in ALSPAC using 351 polymorphisms for age at menarche (explaining 10.6% of variance) among 2,053 females suggested that later age at menarche (per year) was associated with −1.38 kg/m2 of BMI at age 18 y (or −0.34 SD units, 95% CI −0.46, −0.23; P = 9.77 × 10−09). This coefficient attenuated 10-fold upon adjustment for BMI at age 8 y, to −0.12 kg/m2 (or −0.03 SDs, 95% CI −0.13, 0.07; P = 0.55). Associations with blood pressure were similar, but associations across other traits were small and inconsistent. In negative control MR analyses, later age at menarche was associated with −0.77 kg/m2 of pre-pubertal BMI measured at age 8 y (or −0.39 SDs, 95% CI −0.50, −0.29; P = 6.28 × 10−13), indicating that variants influencing menarche also influence BMI before menarche. Cardiometabolic trait associations were weaker and less consistent among males and both sexes combined. Higher BMI at age 8 y (per 1 kg/m2 using 95 polymorphisms for BMI explaining 3.4% of variance) was associated with earlier menarche among 2,648 females (by −0.26 y, 95% CI −0.37, −0.16; P = 1.16 × 10−06), likewise among males and both sexes combined. In 2-sample MR analyses using 234 polymorphisms and inverse variance weighted (IVW) regression, each year later age at menarche was associated with −0.81 kg/m2 of adult BMI (or −0.17 SD units, 95% CI −0.21, −0.12; P = 4.00 × 10−15). Associations were weaker with cardiometabolic traits. Using 202 polymorphisms, later menarche was associated with lower odds of childhood obesity (IVW-based odds ratio = 0.52 per year later, 95% CI 0.48, 0.57; P = 6.64 × 10−15). Study limitations include modest sample sizes for 1-sample MR, lack of inference to non-white-European populations, potential selection bias through modest completion rates of puberty questionnaires, and likely disproportionate measurement error of exposures by sex. The cardiometabolic traits examined were heavily lipid-focused and did not include hormone-related traits such as insulin and insulin-like growth factors. Our results suggest that puberty timing has a small influence on adiposity and cardiometabolic traits and that preventive interventions should instead focus on reducing childhood adiposity. In a mendelian randomization study, Joshua Bell and colleagues investigate possible health implications of the age of puberty. People who enter puberty at younger ages are more likely to develop obesity and cardiometabolic diseases in adulthood, but whether this is because of puberty timing itself is unknown. Childhood adiposity (fatness) may induce earlier puberty and may also track forward into adulthood, making childhood adiposity an important potential confounder. Most prior studies of puberty timing as a risk factor for adult obesity and cardiometabolic dysfunction did not consider childhood adiposity and used crude measures of cardiometabolic traits. They also relied upon observational methods, which are prone to wider confounding. We used naturally occurring genetic variation in age at menarche to examine whether puberty timing itself is likely to influence adiposity and cardiometabolic traits. Using data from >3,600 offspring from a multigenerational British birth cohort study, we examined genetically proxied age at menarche/voice breaking in relation to body mass index, objective fat and lean mass indices, blood pressure, and over 200 detailed traits from targeted metabolomics. These outcome traits were all measured at age 18 y (after puberty onset) and at age 8 y (before puberty onset), which allowed us to examine the effects of puberty timing while accounting for outcome trait levels in childhood. We found that apparent effects of later puberty onset on lower adiposity and blood pressure at age 18 y were largely attenuated when accounting for adiposity at age 8 y. Effects on other cardiometabolic traits were small and inconsistent. We also found a strong effect of higher adiposity at age 8 y on earlier puberty onset. Our findings support puberty timing as a marker, not a driver, of adiposity and cardiometabolic trait levels. These findings suggest that interventions to prevent adult obesity and cardiometabolic disease should focus on childhood adiposity, not puberty timing.
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