Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, 38152-0001, USA.
College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
Respir Res. 2022 Jul 29;23(1):194. doi: 10.1186/s12931-022-02089-4.
Body mass index (BMI) has been shown to be associated with lung function. Recent findings showed that DNA methylation (DNAm) variation is likely to be a consequence of changes in BMI. However, whether DNAm mediates the association of BMI with lung function is unknown. We examined the mediating role of DNAm on the association of pre-adolescent BMI trajectories with post-adolescent and adulthood lung function (forced expiratory volume (FEV), forced vital capacity (FVC), and FEV/FVC).
Analyses were undertaken in the Isle of Wight birth cohort (IOWBC). Group-based trajectory modelling was applied to infer latent BMI trajectories from age 1 to 10 years. An R package, ttscreening, was applied to identify CpGs at 10 years potentially associated with BMI trajectories for each sex. Linear regressions were implemented to further screen CpGs for their association with lung function at 18 years. Path analysis, stratified by sex, was applied to each screened CpG to assess its role of mediation. Internal validation was applied to further examine the mediation consistency of the detected CpGs based on lung function at 26 years. Mendelian randomization (MR-base) was used to test possible causal effects of the identified CpGs.
Two BMI trajectories (high vs. low) were identified. Of the 442,475 CpG sites, 18 CpGs in males and 33 in females passed screening. Eight CpGs in males and 16 CpGs in females (none overlapping) were identified as mediators. For subjects with high BMI trajectory, high DNAm at all CpGs in males were associated with decreased lung function, while 8 CpGs in females were associated with increased lung function at 18 years. At 26 years, 6 CpGs in males and 14 CpGs in females showed the same direction of indirect effects as those at 18 years. DNAm at CpGs cg19088553 (GRIK2) and cg00612625 (HPSE2) showed a potential causal effect on FEV.
The effects of BMI trajectory in early childhood on post-adolescence lung function were likely to be mediated by pre-adolescence DNAm in both males and females, but such mediation effects were likely to diminish over time.
体重指数（BMI）与肺功能有关。最近的研究结果表明，DNA 甲基化（DNAm）的变化可能是 BMI 变化的结果。然而，DNAm 是否介导 BMI 与肺功能之间的关联尚不清楚。我们研究了 DNAm 在青少年前 BMI 轨迹与青少年后和成年期肺功能（用力呼气量（FEV）、用力肺活量（FVC）和 FEV/FVC）之间的关联中的中介作用。
在怀特岛出生队列（IOWBC）中进行了分析。应用基于群组的轨迹建模从 1 岁到 10 岁推断潜在的 BMI 轨迹。应用 R 包 ttscreening 为每个性别识别 10 岁时可能与 BMI 轨迹相关的 CpG。实施线性回归进一步筛选与 18 岁时肺功能相关的 CpG。基于性别，对每个筛选的 CpG 进行路径分析，以评估其在中介中的作用。基于 26 岁时的肺功能，应用内部验证进一步检查检测到的 CpG 的中介一致性。使用 Mendelian 随机化（MR-base）测试确定的 CpG 可能的因果效应。
确定了两种 BMI 轨迹（高 vs. 低）。在 442475 个 CpG 位点中，有 18 个 CpG 在男性中通过筛选，有 33 个 CpG 在女性中通过筛选。在男性中发现了 8 个 CpG，在女性中发现了 16 个 CpG（没有重叠），这些 CpG 被鉴定为中介。对于 BMI 轨迹较高的受试者，男性中所有 CpG 的高 DNAm 与肺功能下降有关，而女性中 8 个 CpG 与肺功能在 18 岁时的增加有关。在 26 岁时，男性中的 6 个 CpG 和女性中的 14 个 CpG 显示出与 18 岁时相同方向的间接效应。CpG cg19088553（GRIK2）和 cg00612625（HPSE2）的 DNAm 显示出对 FEV 的潜在因果效应。
儿童早期 BMI 轨迹对青少年后肺功能的影响可能是由男性和女性青少年前的 DNAm 介导的，但这种中介作用可能会随着时间的推移而减弱。
