背景:肌肉减少症是老年人常见的一种有害疾病,目前尚无治疗方法。已知肿瘤坏死因子(TNF)样弱凋亡诱导剂(TWEAK)及其受体成纤维细胞生长因子诱导型14(FN14)在肌肉减少症的发病机理中起重要作用。这项研究调查了TWEAK和Fn14中甲基化的改变,以确定管理肌肉减少症的潜在靶标。
方法:通过流行病学调查,我们通过亚硫酸氢盐测序检测了新疆社区居住的老年人TWEAK和Fn14中CpG岛(CpG)的甲基化。通过焦磷酸测序在152名老年个体中选择与肌肉减少症相关的显著CpG进行检测。CpG甲基化之间的关联,血浆炎症标志物水平,和肌少症进行了分析。
结果:在60个人中检测到TWEAK中的38个CpG和Fn14中的30个CpG,与对照个体相比,6个CpG在少肌症患者中显示出较低的甲基化。在152名老年人中,带有年龄调整的协方差分析,性别,甘油三酯水平,肥胖,糖尿病,和高血压显示6个CpGs的甲基化水平(TWEAK的CpG8,CpG12,CpG13,CpG20和CpG21,肌肉减少症患者的Fn14)和CpG24显着低于对照组。随着对其他混杂因素的调整,协变量方差分析显示,血浆TWEAK,肌肉减少组TNF-α和IL-10水平明显高于对照组(P=0.007,P<0.001,P=0.003)。多因素logistic回归分析显示,CpG8、CpG13、CpG21和TWEAK的总甲基化(OR=0.767,95%CI=0.622-0.947;OR=0.740,95%CI=0.583-0.941;OR=0.734,95%CI=0.561-0.958;OR=0.883,95%CI=0.795-0.980;CpG22和总甲基化分别与0.0.0.0.从偏相关分析来看,血浆TWEAK与血浆TNF-α相关(r=0.172,P=0.042)。
结论:新疆社区老年人群肌肉减少症与TWEAK低甲基化和TWEAK及其下游炎症因子TNF-α血浆水平升高有关。
BACKGROUND: Sarcopenia is a harmful condition common among older adults for which no treatment is available. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor inducible 14 (FN14) are known to play important roles in the pathogenesis of sarcopenia. This
study investigated alterations in methylation in TWEAK and Fn14 to identify potential targets for the managing sarcopenia.
METHODS: Through an epidemiological investigation, we detected methylation of CpG islands (CpGs) in TWEAK and Fn14 in community-dwelling older adult of Xinjiang by bisulfite sequencing. Significant CpGs associated with sarcopenia were selected for detection in 152 older individuals by pyrosequencing. Associations between CpG methylation, plasma inflammatory marker levels, and sarcopenia were analyzed.
RESULTS: Of 38 CpGs in TWEAK and 30 CpGs in Fn14 detected in 60 individuals, 6 CpGs showed lower methylation in sarcopenia patients compared with control individuals. In 152 older adults, covariance analysis with adjustment for age, gender, triglyceride level, obesity, diabetes, and hypertension showed that the methylation levels of 6 CpGs (CpG8, CpG12, CpG13, CpG20 and CpG21of TWEAK, and CpG24 of Fn14) were significantly lower in sarcopenia patients than in control individuals. With adjustment for additional confounding factors, covariate variance analysis showed that plasma TWEAK, TNF-α and IL-10 levels in the sarcopenia group were significant higher than those in the control group (P = 0.007, P < 0.001, P = 0.003). Multivariate logistic regression analysis showed that CpG8, CpG13, CpG21, and total methylation of TWEAK (OR = 0.767, 95 % CI = 0.622-0.947; OR = 0.740, 95 % CI = 0.583-0.941; OR = 0.734, 95 % CI = 0.561-0.958; OR = 0.883, 95 % CI = 0.795-0.980) as well as CpG22 and total methylation of Fn14 were significantly associated with sarcopenia (OR = 826, 95 % CI = 0.704-0.968; OR = 0.918, 95 % CI = 0.852-0.989). From partial correlation analysis, plasma TWEAK was correlated with plasma TNF-α (r = 0.172, P = 0.042).
CONCLUSIONS: Sarcopenia is associated with hypomethylation of TWEAK and increased plasma levels of TWEAK and its downstream inflammatory factor TNF-α in a community-dwelling population of older adults in Xinjiang.