Genetic and Epigenomic Modifiers of Diabetic Neuropathy

Diabetic neuropathy (DN), the most common chronic and progressive complication of diabetes mellitus (DM), strongly affects patients’ quality of life. DN could be present as peripheral, autonomous or, clinically also relevant, uremic neuropathy. The etiopathogenesis of DN is multifactorial, and genetic components play a role both in its occurrence and clinical course. A number of gene polymorphisms in candidate genes have been assessed as susceptibility factors for DN, and most of them are linked to mechanisms such as reactive oxygen species production, neurovascular impairments and modified protein glycosylation, as well as immunomodulation and inflammation. Different epigenomic mechanisms such as DNA methylation, histone modifications and non-coding RNA action have been studied in DN, which also underline the importance of “metabolic memory” in DN appearance and progression. In this review, we summarize most of the relevant data in the field of genetics and epigenomics of DN, hoping they will become significant for diagnosis, therapy and prevention of DN.     

不同品系北京鸭血清前白蛋白多态性的研究

应用聚丙烯酰胺凝胶电泳法研究了北京鸭的血清前白蛋多态性,在2个位点观察到多态,Pam位点为单态,在Pas位点发现有5种表现型,它们的频率是：Pas2-2O 26．67％,Pas1-2为12％,Pas2-1为45.33%,Pas1-1为2．67％,Pas2-0为13．33％,在Paf位点发现有4种表现型,它们的频率是：PafF为29．33％,PafS为41．33％,PafFS为10．67％,Paf0为18．67％,并计算了它们的基因频率,群体平均杂合度和遗传距离,遗传分析表明,樱桃谷鸭和奥白星鸭遗传结构相似,而与B系北京鸭遗传结构有明显差异。     

面向等离子体W材料改善韧性的方法与机制

目的: 探讨胰岛素样生长因子1（IGF-1）基因多态性与抗高血压药物治疗后血压水平的关联性。方法: 运用流行病学现况调查方法,收集服用复方利血平、降压片和珍菊降压片的780例高血压患者的一般临床特征并测量其血压和临床生化指标。选择IGF-1基因的5个标签位点,采用TaqMan技术进行基因分型。采用协方差分析及分层分析对其基因多态性与药物治疗后血压水平的关系进行评价。结果: 在服用降压片的高血压病人中,rs6219位点不同基因型之间舒张压水平差异有统计学意义（P=0.01）。在服用复方利血平的高血压病人中,rs5742612和rs6218位点不同基因型之间收缩压水平差异有统计学意义（P值分别为0.04、0.017）。在服用珍菊降压片的高血压患者中,rs6218位点不同基因型之间舒张压水平及rs6219位点不同基因型之间收缩压水平差异均有关联（P值分别为0.017、0.033）。进一步分层分析发现,服用降压片的患者中,随着rs35767位点遗传变异女性收缩压的水平呈线性下降,而男性舒张压水平呈线性上升,校正混杂因素后P值分别为0.028、0.038。结论: IGF-1基因多态性与复方利血平、降压片和珍菊降压片三种抗高血压药物治疗后血压水平均有显著相关,提示IGF-1基因可能是高血压重要的药物疗效生物标记。     

Glucagon-like Peptide-1 Receptor Agonists in the Management of Type 2 Diabetes Mellitus and Obesity: The Impact of Pharmacological Properties and Genetic Factors

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antihyperglycemic drugs that enhance appropriate pancreatic β-cell secretion, pancreatic α-cell (glucagon) suppression, decrease liver glucose production, increase satiety through their action on the central nervous system, slow gastric emptying time, and increase insulin action on peripheral tissue. They are effective in the management of type 2 diabetes mellitus and have a favorable effect on weight loss. Their cardiovascular and renal safety has been extensively investigated and confirmed in many clinical trials. Recently, evidence has shown that in addition to the existing approaches for the treatment of obesity, semaglutide in higher doses promotes weight loss and can be used as a drug to treat obesity. However, some T2DM and obese patients do not achieve a desired therapeutic effect of GLP-1 receptor agonists. This could be due to the multifactorial etiologies of T2DM and obesity, but genetic variability in the GLP-1 receptor or signaling pathways also needs to be considered in non-responders to GLP-1 receptor agonists. This review focuses on the pharmacological, clinical, and genetic factors that may influence the response to GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus and obesity.     

Genomic mining for complex disease traits with “random chemistry”

Our rapidly growing knowledge regarding genetic variation in the human genome offers great potential for understanding the genetic etiology of disease. This, in turn, could revolutionize detection, treatment, and in some cases prevention of disease. While genes for most of the rare monogenic diseases have already been discovered, most common diseases are complex traits, resulting from multiple gene–gene and gene-environment interactions. Detecting epistatic genetic interactions that predispose for disease is an important, but computationally daunting, task currently facing bioinformaticists. Here, we propose a new evolutionary approach that attempts to hill-climb from large sets of candidate epistatic genetic features to smaller sets, inspired by Kauffman’s “random chemistry” approach to detecting small auto-catalytic sets of molecules from within large sets. Although the algorithm is conceptually straightforward, its success hinges upon the creation of a fitness function able to discriminate large sets that contain subsets of interacting genetic features from those that don’t. Here, we employ an approximate and noisy fitness function based on the ReliefF data mining algorithm. We establish proof-of-concept using synthetic data sets, where individual features have no marginal effects. We show that the resulting algorithm can successfully detect epistatic pairs from up to 1,000 candidate single nucleotide polymorphisms in time that is linear in the size of the initial set, although success rate degrades as heritability declines. Research continues into seeking a more accurate fitness approximator for large sets and other algorithmic improvements that will enable us to extend the approach to larger data sets and to lower heritabilities.     

A Pharmacogenetics Study in Mozambican Patients Treated with Nevirapine: Full Resequencing of TRAF3IP2 Gene Shows a Novel Association with SJS/TEN Susceptibility

Steven–Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe adverse drug reactions, characterized by extensive epidermal detachment and erosions of mucous membrane. SJS/TEN is one of the most serious adverse reactions to Nevirapine (NVP) treatment, commonly used in developing countries as first-line treatment of human immunodeficiency virus infection. In the last years TRAF3IP2 gene variants had been described as associated with susceptibility to several diseases such as psoriasis and psoriatic arthritis. We hypothesized that this gene, involved in immune response and in NF-κB activation, could also be implicated in the SJS/TEN susceptibility. We performed a full resequencing of TRAF3IP2 gene in a population of patients treated with NVP. Twenty-seven patients with NVP-induced SJS/TEN and 78 controls, all from Mozambique, were enrolled. We identified eight exonic and three intronic already described variants. The case/control association analysis highlighted an association between the rs76228616 SNP in exon 2 and the SJS/TEN susceptibility. In particular, the variant allele (C) resulted significantly associated with a higher risk to develop SJS/TEN (p = 0.012 and OR = 3.65 (95% CI 1.33–10.01)). A multivariate analysis by logistic regression confirmed its significant contribution (p = 0.027, OR = 4.39 (95% CI 1.19–16.23)). In conclusion, our study suggests that a variant in TRAF3IP2 gene could be involved in susceptibility to SJS/TEN.     

OCT2、MDR1基因多态性与婴幼儿万古霉素血药浓度及临床疗效的相关性研究

目的: 考察有机阳离子转运体2（OCT2）和多药耐药基因1（MDR1）的基因多态性与婴幼儿万古霉素稳态谷浓度及临床疗效的相关性。方法: 收集91例万古霉素治疗的婴幼儿患者血样,酶免疫放大分析法测定万古霉素血药浓度,聚合酶链式反应（PCR）和DNA测序技术检测基因分型。比较OCT2 G808T（rs316019）和MDR1 C3435T（rs1045642）不同基因型对万古霉素谷浓度及临床疗效的影响。结果: 91例患者中,谷浓度达到10～20 μg/mL的比例为16.5%;5～<10 μg/mL和10～20 μg/mL浓度范围万古霉素的临床有效率（88%,93.3%）显著高于5 μg/mL以下浓度（44%）（P<0.05）,同时5～<10 μg/mL和10～20 μg/mL浓度范围万古霉素的临床有效率相近。OCT2 G808T纯合突变型（TT）患者万古霉素谷浓度（10.15±2.35） μg/mL和谷浓度/剂量比（0.98±0.27） μg·mL-1·mg-1·kg均显著高于野生型（GG）患者（6.92±2.83） μg/mL和（0.59±0.22） μg·mL-1·mg-1·kg（P<0.05）;同时,TT型患者临床有效率（100%）明显高于GG型（73.2%）（P<0.05）;而MDR1 C3435T突变型和野生型患者的万古霉素谷浓度、谷浓度/剂量比及临床疗效相近（P>0.05）。结论: OCT2 G808T基因突变可能与婴幼儿患者万古霉素的稳态谷浓度及临床疗效相关。     

miR-499、miR-196a2、miR-149单核苷酸多态性与系统性红斑狼疮的关联性

目的：探讨系统性红斑狼疮（systemic lupus erythematosus,SLE）患者与 miR-499、miR-196a2及 miR-149单核苷酸多态性（single nucleotide polymorphism,SNP）的关联性。方法选取111例 SLE 患者（SLE 组）与120例健康者（对照组）为研究对象,收集临床资料并抽取2 mL 外周静脉血,提取基因组 DNA。利用 PCR-RFLP 技术对研究对象 miR-499 rs22928323、miR-196a2 rs11614913、miR-149 rs3746444的单核苷酸多态性进行检测,分析 SLE与 SNP 的关联性。结果miR-196a2 rs11614913表现为 TT、TC、CC 3种基因型,与 miR-196a2基因型 TT＋TC相比,基因型为 CC 的患者发病风险增加,OR＝1．28,95％CI 为1．03～1．84,P ＝0．017;miR-149 rs22928323表现为 TT、TC、CC 3种基因型,与 miR-149基因型 TT＋TC 相比,基因型为 CC 的患者发病风险不增加,OR ＝0．61,95％CI 为0．38～1．38,P ＝0．283;miR-499 rs3746444表现为 AA、AG、GG 3种基因型,与 miR-449基因型 AA＋AG 相比,基因型为 GG 的患者发病风险不增加,OR ＝0．78,95％ CI 为0．58～1．11,P ＝0．188。结论miR-196a2内的SNP rs11614913与中国华东地区人群 SLE 的遗传易感性有关;miR-499、miR-149内的 SNPs rs3746444、rs22928323与中国华东地区人群 SLE 的遗传易感性无关。