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Ageing and inflammation with focus on end-stage renal diseases : genetic and epigenetic factors

机译：关注终末期肾脏疾病的衰老和炎症：遗传和表观遗传因素

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The presence of ageing-associated disorders at a relatively young age in patients suffering from chronic kidney disease (CKD) has led to the hypothesis that CKD is characterized by accelerated ageing, resulting in a marked discrepancy between chronological and biological age. Factors that accelerate biological ageing, such as inflammation, oxidative stress, and toxins, impact the processes of cellular senescence and/or apoptosis, thereby shortening the life span of cells, and consequently, of the organism as a whole. Numerous studies have linked increased cellular senescence and apoptosis to disorders commonly associated with ageing, such as cardiovascular disease (CVD), osteoporosis, and cognitive dysfunction – all of which are common in the uremic phenotype. In Study I, we demonstrate that increased arterial gene expression of cyclin-dependent kinase inhibitor 2A (CDKN2A), a known inducer of cellular senescence, is associated with the presence of CVD and vascular calcification (VC) in CKD patients. Furthermore, there is a positive correlation between CDKN2A expression and the expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2), both of which are involved in osteogenesis. We also show a tentative relationship between a higher degree of VC and increasing p16INK4a expression, a cognate protein of CDKN2A. In Study II, we use telomere length as a biomarker of biological age, showing that CKD patients have shorter telomeres than non-CKD controls. In addition, our results indicate a possible association between longitudinal telomere length, folate, and immunosuppressive treatment in patients undergoing renal transplantation (RTx). This suggests that anti- metabolite therapy may have an impact on biological ageing in RTx patients. In Study III, we show that the global methylation status in dialysis and RTx patients at baseline and after 12 months of renal replacement therapy (RRT) differs at several sites in the genome from that of age- and gender-matched healthy controls. Furthermore, differences in methylation between patients and controls can be found at CpG sites located in genes with known functional relevance to CKD, cellular ageing, CVD and/or metabolic disease. Continuing our investigations of factors affecting epigenetic status, Study IV investigates the association between the degree of self-reported physical activity and global DNA methylation in Swedish seniors. In this study, we demonstrate that individuals who reported higher physical activity had less global DNA methylation than those who were less physically active. Study V describes the application of a multifactorial mathematical model for predicting the presence of inflammation in a dataset generated from 225 incident dialysis patients. Eight ofthe ten features with the highest predictive factor were single nucleotide polymorphisms (SNPs), suggesting a large genetic influence on inflammation in CKD patients.In Study VI, the interplay between inflammatory status, genotype, and mortality is demonstrated in two cohorts of incident dialysis patients. The mortality was reduced in inflamed individuals carrying a 32 base-pair deletion in the C-C motif chemokine receptor 5 (CCR5) gene compared to individuals who were inflamed but lacked the deletion.
机译：患有慢性肾脏病（CKD）的患者在相对年轻的年龄中就存在与衰老相关的疾病，这导致了这样一个假设，即CKD的特征是衰老加速，导致时间和生物学年龄之间存在显着差异。加速生物衰老的因素，例如炎症，氧化应激和毒素，会影响细胞衰老和/或凋亡的过程，从而缩短细胞的寿命，从而缩短整个生物体的寿命。许多研究已经将细胞衰老和细胞凋亡的增加与通常与衰老相关的疾病联系在一起，例如心血管疾病（CVD），骨质疏松症和认知功能障碍-所有这些在尿毒症表型中都很常见。在研究I中，我们证明了细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）（一种已知的细胞衰老诱导剂）的动脉基因表达增加与CKD患者中CVD和血管钙化（VC）的存在有关。此外，CDKN2A表达与基质Gla蛋白（MGP）和矮子相关转录因子2（RUNX2）的表达之间存在正相关，两者均与成骨有关。我们还显示了较高程度的VC和增加的p16INK4a表达（CDKN2A的同源蛋白）之间的暂时关系。在研究II中，我们使用端粒长度作为生物学年龄的生物标记，表明CKD患者的端粒比非CKD对照短。此外，我们的结果表明，在接受肾移植（RTx）的患者中，纵向端粒长度，叶酸和免疫抑制治疗之间可能存在关联。这表明抗代谢药物治疗可能会对RTx患者的生物衰老产生影响。在研究III中，我们显示了在基线和肾脏替代治疗（RRT）12个月后，透析和RTx患者的总体甲基化状态在基因组的几个位点与年龄和性别匹配的健康对照者不同。此外，可以在位于与CKD，细胞衰老，CVD和/或代谢疾病具有已知功能相关的基因中的CpG位点发现患者和对照之间的甲基化差异。继续我们对影响表观遗传状态的因素的研究，研究IV研究了瑞典老年人中自我报告的体育活动程度与全球DNA甲基化之间的关系。在这项研究中，我们证明了报告较高身体活动水平的人比那些身体活动较少的人具有较少的总体DNA甲基化。研究V描述了一种用于预测225名透析患者的数据集中炎症的存在的多因素数学模型的应用。十个预测因子最高的特征中有八个是单核苷酸多态性（SNPs），表明对CKD患者的炎症有很大的遗传影响。在研究VI中，两个事件透析显示了炎症状态，基因型和死亡率之间的相互作用。耐心。与发炎但缺乏缺失的个体相比，在C-C基序趋化因子受体5（CCR5）基因中携带32个碱基对缺失的发炎个体，死亡率降低。

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    Luttropp Karin;

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  • 年度 2016
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