METHODS: Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the overall and independent effects of ten dental traits (dentures, bleeding gums, painful gums, loose teeth, toothache, ulcers, periodontitis, number of teeth, and two measures of caries) on four EAA subtypes (GrimAge acceleration [GrimAA], PhenoAge acceleration [PhenoAA], HannumAge acceleration [HannumAA] and intrinsic EAA [IEAA]), and used two-step Mendelian randomization to evaluate twelve potential mediators of the associations. Comprehensive sensitivity analyses were used to verity the robustness, heterogeneity, and pleiotropy.
RESULTS: Univariable inverse variance weighted MR analyses revealed a causal effect of dentures on greater GrimAA (β: 2.47, 95% CI: 0.93-4.01, p = 0.002), PhenoAA (β: 3.00, 95% CI: 1.15-4.85, p = 0.001), and HannumAA (β: 1.96, 95% CI: 0.58-3.33, p = 0.005). In multivariable MR, the associations remained significant after adjusting for periodontitis, caries, number of teeth and bleeding gums. Three out of 12 aging risk factors were identified as mediators of the association between dentures and EAA, including body mass index, body fat percentage, and waist circumference. No evidence for reverse causality and pleiotropy were detected (p > 0.05).
CONCLUSIONS: Our findings supported the causal effects of genetic liability for denture wearing on epigenetic aging, with partial mediation by obesity. More attention should be paid to the obesity-monitoring and management for slowing EAA among denture wearers.
方法:使用主要是欧洲血统的全基因组关联研究的汇总统计,我们进行了单变量和多变量孟德尔随机化(MR)来估计十个牙齿特征的总体和独立影响(假牙,牙龈出血,牙龈疼痛,牙齿松动,牙痛,溃疡,牙周炎,齿数,和两种龋齿测量)对四种EAA亚型(GrimAge加速度[GrimAA],PhenoAge加速度[PhenoAA],HannumAge加速度[HannumAA]和固有EAA[IEAA]),并使用两步孟德尔随机化来评估12个潜在的关联介质。使用综合敏感性分析来验证稳健性,异质性,和多功能性。
结果:单变量逆方差加权MR分析揭示了假牙对较大GrimAA的因果影响(β:2.47,95%CI:0.93-4.01,p=0.002),PhenoAA(β:3.00,95%CI:1.15-4.85,p=0.001),和HannuAA(β:1.96,95%CI:0.58-3.33,p=0.005)。在多变量MR中,在调整牙周炎后,这种关联仍然很重要,龋齿,牙齿数量和牙龈出血。12个衰老危险因素中的3个被确定为假牙和EAA之间关联的介体,包括体重指数,身体脂肪百分比,和腰围。未检测到反向因果关系和多效性的证据(p>0.05)。
结论:我们的研究结果支持假牙佩戴的遗传责任对表观遗传老化的因果影响,通过肥胖的部分调解。应更加重视肥胖的监测和管理,以减缓义齿佩戴者的EAA。