2. 精准医学与支气管哮喘治疗

1、精准医学与支气管哮喘治疗基因测序蛋白质组学生物大数据分析鉴定验证应用病因治疗靶点疾病亚分类精确诊断精确治疗精准医学概念精准医学在疾病诊断治疗中的应用疾病类别疾病名称生物标志物干预肿瘤慢性粒细胞白血病BCR-ABL伊马替尼肺癌EGFR吉非替尼/厄洛替尼黑色素瘤/甲状腺癌BRAF V600E曲美替尼乳腺癌HER2曲妥珠单抗结肠癌/胰腺癌HER-1西妥昔单抗结直肠癌VEGFR-A贝伐单抗弥漫性大B细胞淋巴瘤CD20+利妥昔单抗精准医学在疾病诊断治疗中的应用类别疾病名称生物标志物干预心血管疾病冠状动脉疾病CYP2C19氯吡格雷精神疾病酒精利用障碍GRIK1托吡酯传染病HIV/AIDSHIV病毒载量、C

2、D4+T细胞鸡尾酒疗法眼科疾病先天性黑朦RPE65基因治疗肝脏疾病乙型肝炎HBV病毒载量核苷类似物、干扰素肺病囊性纤维化G551D依伐卡托药物基因组学戒烟CYP2A6伐尼克兰支气管哮喘目前的治疗模式及现状/pharmacology-treatment-of-asthma.常用的支气管哮喘药物Gina. 2016.升阶梯治疗支气管哮喘目前的治疗模式目前治疗模式下存在的问题以ICS为主的单独及联合LABA或LATRA的前三级治疗模式对大多数相应的患者达到了良好的控制目标；但随后的升级疗法（4-5级）并未能取得良好的控制效果，这其中包括激素抵抗型患者。这类患者消耗半数以上与哮喘相关的医疗保健支出，并

3、且具有更高的哮喘相关死亡风险。Godard P, Chanez P, Siraudin L, et al. European Respiratory Journal, 2001, 19(1): 61-67. 哮喘的严重程度与哮喘的医疗资源花费导致目前这些问题的原因何在？根据疾病控制的水平，给予以ICS为基石的抗炎治疗，而未考虑疾病的表型及内因型哮喘发病机制中复杂的炎症网络哮喘是一种异质性疾病哮喘的表型分类没有与其发病机制紧密相结合目前的治疗没有将药物选择与发病机制中优势型炎症机制相关联哮喘表型的探索使哮喘有了粗略的外在分类表型（Phenotype）、内因型（Endotype ）、基因型（Gen

4、otype )哮喘的哮喘表型（Phenotype）表型，是指生物体的外在可见特征，是基因型和环境因素相互作用的临床表现结果；哮喘表型分类方法繁多： Clinical features which define phenotypes include: age of onset, triggers (allergens, viruses, exercise, cigarette smoke), atopic vs. nonatopic disease, natural history (epidemiologic phenotypes), symptom-based phenotypes (epi

5、sodic vs. multitrigger), severity, exacerbation-prone, and response to therapy过敏性哮喘、阿司匹林哮喘、职业性哮喘、运动性哮喘触发因素分类常见的哮喘表型分类早发型晚发型发病年龄可根据如下指标分类：pattern of inflammation (eosinophilic, neutrophilic, paucigranulocytic), biomarkers (exhaled nitric oxide, eosinophilia, urinary leukotriene E4), bronchial hyper-r

6、esponsiveness (BHR), and lung function. 哮喘内因型（Endotype）哮喘的内因型分类是根据哮喘发病病理生理机制进行分类。嗜酸粒细胞型哮喘中性粒细胞型哮喘混合粒细胞型哮喘寡粒细胞型哮喘诱导痰细胞学分类常见的内因型分类表型与内因型的关系一种表型可包含多种内因型；一种内因型可表现为多种表型。表型与内因型的关系哮喘的基因型（Genotype ）根据基因的突变、异常、多态性对哮喘进行的疾病分类；这种分类理论上最精确，最能反映疾病的本质；但哮喘是一种多基因遗传疾病，临床实践中无法实施。哮喘与基因多态性走出哮喘治疗困境- 精准分类指导的治疗从表型到内因型基于发病机制

7、，划分更细致、更准确、更精密！Figure 1. Biomarker discovery and phenotyping in severe asthma: actuality and perspectives. FeNO:Fractional exhaled nitric oxide; FRC:Functional residual capacity; Gal-3:Galectin-3; IgE:Immunoglobulin E; RV:Residual volume; uLTE4:Urinary leukotriene E4.Published in: Laura De Ferrari;

8、Alessandra Chiappori; Diego Bagnasco; Anna Maria Riccio; Giovanni Passalacqua; Giorgio Walter Canonica; Expert Review of Respiratory Medicine 2016, 10, 29-38.DOI: 10.1586/17476348.2016.1111763Copyright 2015 Taylor & FrancisEmerging pediatric phenotypes/endotypes associated with response to asthma th

9、erapiesMoving towards precision care for childhood asthma. Mokhallati, Nadine; Guilbert, Theresa Current Opinion in Pediatrics. 28(3):331-338, June 2016.DOI: 10.1097/MOP.0000000000000361Figure 2. The primary defined Th2-high and Th2-low severe asthma phenotypes. ICS: Inhaled corticosteroid.Published

10、 in: Laura De Ferrari; Alessandra Chiappori; Diego Bagnasco; Anna Maria Riccio; Giovanni Passalacqua; Giorgio Walter Canonica; Expert Review of Respiratory Medicine 2016, 10, 29-38.DOI: 10.1586/17476348.2016.1111763Copyright 2015 Taylor & Francis如何精准分类精准治疗？Figure 3. Currently known aspects of asthma

11、 phenotypes. CXCR2:CXC chemokine receptor 2; FeNO:Fractional exhaled nitric oxide; Ig:Immunoglobulin; IL4R:Interleukin 4 receptor alpha; LT:Leukotriene.Published in: Laura De Ferrari; Alessandra Chiappori; Diego Bagnasco; Anna Maria Riccio; Giovanni Passalacqua; Giorgio Walter Canonica; Expert Review of Respiratory Medicine 2016, 10, 29-38.DOI: 10.1586/17476348.2016.1111763Copyright 2015 Taylor & Francis哮喘内因型精准医学面临的问题1. 哮喘发病机制复杂，至今仍