Tinworth Alexander C, Iona Andri, Yao Pang, Millwood Iona Y, Fry Hannah, Clarke Jonathan, Wang Baihan, Mazidi Mohsen, Kartsonaki Christiana, Walters Robin G, Du Huaidong, Yu Canqing, Chen Yiping, Sun Dianjianyi, Yang Ling, Schmidt Dan Valle, Lv Jun, Avery Daniel, Li Liming, Bennett Derrick A, Peto Richard, Clarke Robert, Bragg Fiona, Chen Zhengming
Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China.
EBioMedicine. 2025 Jun 16;117:105806. doi: 10.1016/j.ebiom.2025.105806.
Smokers have lower body weight than non-smokers, while smoking cessation results in weight gain. Understanding the mechanisms involved can help identify potential therapeutic targets to enhance smoking cessation.
We measured plasma levels of growth/differentiation factor 15 (GDF15), a stress-responsive protein, and its two receptors (proto-oncogene tyrosine-protein kinase receptor Ret [RET], GDNF family receptor alpha-like [GFRAL]) among 3936 Chinese adults (mean BMI 24.0 kg/m), using Olink and SomaScan platforms. We assessed associations of individual proteins and GDF15/receptor ratios with smoking and adiposity using linear regression. In two-sample Mendelian randomization (MR) analyses, we used genetic variants for smoking intensity from publicly available GWAS as instruments to assess their causal associations with adiposity and plasma levels of proteins in East Asian and European populations. We further assessed the effects of GDF15 and GDF15/receptor ratios in mediating smoking-related weight change.
Overall, smokers had significantly lower BMI (23.1 [0.2] kg/m) than never-smokers (24.0 [0.1] kg/m), while former smokers had the highest levels of BMI (24.6 [0.2] kg/m) and other measures of adiposity (e.g., waist circumference, waist/hip ratio, and body fat percentage). In observational analyses, smoking was positively associated with GDF15 and with GDF15/receptor ratios from both platforms, with GDF15 levels increasing steeply with number of cigarettes smoked on the assessment day. In MR analyses, smoking intensity was significantly associated with a reduced BMI in East Asians and with higher GDF15 levels in both East Asian and European populations. SomaScan_GDF15 partially mediated the associations of smoking with all adiposity measures, while Olink_GDF15 mediated the association with body fat percentage. The GDF15/RET ratio more robustly mediated the smoking-adiposity relationships than GDF15 alone in both platforms.
In Chinese adults GDF15 plays a role in mediating smoking-related weight change, and could serve as a therapeutic target to facilitate smoking cessation and minimise cessation-induced weight gain.
British Heart Foundation, Cancer Research UK, Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, UK Medical Research Council, National Natural Science Foundation of China, Wellcome Trust.
吸烟者的体重低于非吸烟者，而戒烟会导致体重增加。了解其中的机制有助于确定潜在的治疗靶点，以提高戒烟成功率。
我们使用Olink和SomaScan平台，测量了3936名中国成年人（平均BMI为24.0kg/m²）血浆中生长/分化因子15（GDF15，一种应激反应蛋白）及其两种受体（原癌基因酪氨酸蛋白激酶受体Ret [RET]、胶质细胞源性神经营养因子家族受体α样蛋白 [GFRAL]）的水平。我们使用线性回归分析了个体蛋白及GDF15/受体比值与吸烟和肥胖的关联。在两样本孟德尔随机化（MR）分析中，我们使用公开可用的全基因组关联研究（GWAS）中吸烟强度的基因变异作为工具，评估其与东亚和欧洲人群肥胖及血浆蛋白水平的因果关联。我们进一步评估了GDF15及GDF15/受体比值在介导吸烟相关体重变化中的作用。
总体而言，吸烟者的BMI（23.1[0.2]kg/m²）显著低于从不吸烟者（24.0[0.1]kg/m²），而曾经吸烟者的BMI水平最高（24.6[0.2]kg/m²），且其他肥胖指标（如腰围、腰臀比和体脂百分比）也最高。在观察性分析中，吸烟与GDF15以及两个平台的GDF15/受体比值呈正相关，GDF15水平随着评估日吸烟量的增加而急剧上升。在MR分析中，吸烟强度与东亚人的BMI降低显著相关，与东亚和欧洲人群的GDF15水平升高显著相关。SomaScan_GDF15部分介导了吸烟与所有肥胖指标的关联，而Olink_GDF15介导了与体脂百分比的关联。在两个平台上，GDF15/RET比值比单独的GDF15更有力地介导了吸烟与肥胖的关系。
在中国成年人中，GDF15在介导吸烟相关体重变化中起作用，可作为促进戒烟并最小化戒烟引起的体重增加的治疗靶点。
英国心脏基金会、英国癌症研究中心、中国科学技术部、嘉道理慈善基金会、英国医学研究理事会、中国国家自然科学基金、惠康信托基金会。
