Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development.
Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development.
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DOI：
10.1371/journal.pgen.1001307
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发表时间：
2011-02
期刊：
影响因子：
4.5
通讯作者：
Early Growth Genetics Consortium
中科院分区：
文献类型：
--
作者：
Sovio U;Mook-Kanamori DO;Warrington NM;Lawrence R;Briollais L;Palmer CN;Cecil J;Sandling JK;Syvänen AC;Kaakinen M;Beilin LJ;Millwood IY;Bennett AJ;Laitinen J;Pouta A;Molitor J;Davey Smith G;Ben-Shlomo Y;Jaddoe VW;Palmer LJ;Pennell CE;Cole TJ;McCarthy MI;Järvelin MR;Timpson NJ;Early Growth Genetics Consortium
FTO位点变异与儿童BMI之间存在年龄依赖性关联。我们荟萃分析了来自8个欧洲血统队列的样本中FTO位点（rs9939609）与BMI之间的关系，这些样本年龄从婴儿期早期到13岁。我们发现，从5.5岁开始，额外的次要(a)等位基因与BMI呈正相关，但在2.5岁以下呈负相关。使用LMS方法对每种基因型的BMI曲线中位数进行建模，我们发现，携带少量等位基因的人在婴儿期BMI较低，肥胖反弹（AR）较早，儿童期BMI较高。等位基因的差异与两个独立的过程相一致：每个等位基因的早期AR相当于将发育年龄加快2.37% (95% CI 1.87, 2.87, p = 10−20)；基因型相互作用的阳性年龄使得BMI随年龄增长更快（p = 10−23）。我们还拟合了一个线性混合效应模型，将基因型与婴儿和AR时的BMI曲线拐点肥胖峰值（AP）联系起来。携带rs9939609两个小等位基因与AP时较低的BMI (- 0.40% (95% CI: - 0.74, - 0.06), p = 0.02)， AR时较高的BMI （0.93% (95% CI: 0.22, 1.64), p = 0.01）和较早的AR （- 4.72% (- 5.81, - 3.63), p = 10 - 17）相关，支持横断面结果。总的来说，我们证实了rs9939609变异与儿童期BMI之间的预期关联，但这只是在相同变异与婴儿期BMI之间的负相关之后。这种模式与发育规模的转变是一致的，这反映在AR的时间上，而不仅仅是BMI的全球增加。结果为纵向基因效应和FTO在肥胖中的作用提供了重要信息。在已知的AR与晚年BMI和代谢性疾病风险之间的关系方面，发育时间的相关变化具有临床重要性。FTO位点的变异确实与BMI和肥胖相关的特征相关，但对于该基因变异的影响，特别是对儿童的影响，我们所知甚少。我们检查了大量的样本，其中rs9939609基因型和多种BMI测量值都是可用的。我们观察到rs9939609的小等位基因(a)与儿童期出现的BMI呈正相关，具有年龄尺度变化的特征，同时导致婴儿期BMI降低，儿童期BMI升高。通过横断面和纵向评估，我们发现rs9939609位点的变异与AR发生的时间以及BMI曲线变化所预期的事件一致有关。重要的是，小等位基因(A)与早期生活中的BMI之间明显的负相关，随后是早期的AR和儿童时期更高的BMI，这是一种已知与成人BMI和代谢性疾病（如2型糖尿病）风险相关的模式。这些发现对我们理解FTO对肥胖的贡献很重要，而且也有助于在生命过程中理解遗传效应。
An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10−20) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10−23). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (−0.40% (95% CI: −0.74, −0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (−4.72% (−5.81, −3.63), p = 10−17), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk. Variation at the FTO locus is reliably associated with BMI and adiposity-related traits, but little is still known about the effects of variation at this gene, particularly in children. We have examined a large collection of samples for which both genotypes at rs9939609 and multiple measurements of BMI are available. We observe a positive association between the minor allele (A) at rs9939609 and BMI emerging in childhood that has the characteristics of a shift in the age scale leading simultaneously to lower BMI during infancy and higher BMI in childhood. Assessed in cross section and longitudinally, we find evidence of variation at rs9939609 being associated with the timing of AR and the concert of events expected with such a change to the BMI curve. Importantly, the apparently negative association between the minor allele (A) and BMI in early life, which is then followed by an earlier AR and greater BMI in childhood, is a pattern known to be associated with both the risk of adult BMI and metabolic disorders such as type 2 diabetes (T2D). These findings are important in our understanding of the contribution of FTO to adiposity, but also in light of efforts to appreciate genetic effects in a lifecourse context.
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