新疆地区原发性醛固酮增多症不同亚型与KCNJ5基因及其相关类固醇关系的研究

Primary aldosteronism (PA) is currently considered as the most common specifically treatable and potentially curable form of secondary hypertension, which mainly include unilateral aldosterone adenoma（APA） and bilateral adrenal hyperplasia（IHA）. The former type can be mostly cured by adrenalectomy, while the latter need to be treated by oral mineralocorticoid receptor antagonist. The proper therapeutic regimen depend on exact classification diagnosis, so the early diagnosis of PA and lateralization is very important. The gold standard for classification of PA is the adrenal venous sampling (AVS) , while this operation is sophisticated and require high technical term. Several studies found that steroid levels from peripheral blood and lateralatized adrenal venous in APA patients were significantly higher than IHA. Furthermore, this elevating is closely connected with the KCNJ5 gene mutation, which suggested that elevated concentrations of steroids may predict subtype of PA and KCNJ5 mutation. This study propose to measuring steroid concentrations in adrenal venous and peripheral venous and detecting KCNJ5 gene mutation of adrenal tissue. We aim to analyze the connection between steroid levels, PA subtypes and KCNJ5 genotype, then to find a special KCNJ5 related biomarker for differentiating subtypes of PA and KCNJ5 genotype in Xinjiang region. Finally we could use these KCNJ5 Genotype-Specific Steroids to predict APA patients with KCNJ5 gene mutation.

原发性醛固酮增多症（PA）具有治疗特异性及可治愈性的特点，主要包括单侧醛固酮瘤（APA）和双侧肾上腺增生(IHA)两种亚型，前者多数可通过手术治愈，后者则需特殊药物保守治疗，故PA的早期诊断及分型定侧至关重要。肾上腺静脉取血术（AVS）是PA分型定侧的金标准，然而技术要求高、操作复杂且有创。研究发现APA患者的类固醇水平在外周血及肾上腺静脉优势侧较IHA明显升高，且与KCNJ5基因突变关系密切，推测类固醇浓度对PA分型及KCNJ5基因突变的预测有重要意义。因此本研究拟通过测定PA患者肾上腺及外周静脉血类固醇浓度、检测肾上腺病变组织的KCNJ5基因突变，将类固醇指标与PA分型及KCNJ5基因型结合，找出类固醇与不同亚型PA及KCNJ5基因突变的关系，寻找新疆地区PA患者分型诊断及KCNJ5基因突变的特异性外周标记物，为早期识别APA及KCNJ5基因突变提供理论依据。

原发性醛固酮增多症（PA）属于内分泌性高血压，患病率高、心血管损害重，主要包括单侧醛固酮瘤（APA）和双侧肾上腺增生(IHA)两种亚型，前者首选手术治疗，后者则需长期服用盐皮质激素受体拮抗剂，早期靶向治疗显著改善预后，故PA的早期诊断及分型定侧至关重要。肾上腺静脉取血术（AVS）是PA分型定侧的金标准，然而技术要求高、操作复杂且有创。国外有研究发现APA患者的血浆类固醇水平较IHA明显升高，且可能与KCNJ5基因突变有关，推测类固醇浓度对PA分型及KCNJ5基因突变的预测有重要意义。本课题首次在国内采用液相色谱-质谱法（LC-MS/MS）分析了待分型PA患者的外周血及肾上腺类固醇浓度，研究结果显示与金标准AVS结果比较，外周血类固醇18-羟皮质醇（18-OHF）对单侧型PA具有较好的预测价值；并与KCNJ5体细胞突变呈正相关；肾上腺静脉优势侧与对侧类固醇（18-OHF）比值对预测单侧型PA也有一定诊断价值。本研究首次在国内PA患者中采用LC-MS/MS法测定了血浆类固醇（18-OHF）浓度，结果表明外周血18-OHF浓度可作为预测单侧型PA的生物标志物，并与KCNJ5基因体细胞突变有关。由于KCNJ5突变型APA患者的病理类型更为复杂，临床表型及病情较其他类型PA患者更重，而该型患者早期识别及手术治疗的预后较其他类型更佳，因此该指标对单侧型PA及预后的预测价值具有较大的临床应用潜力，本研究结果还需要在今后的PA队列研究中进一步证实。