家族性高胆固醇血症遗传类型与PCSK9抑制剂疗效的关系  

The relationship between genotype of familial hypercholesterolemia and the efficacy of PCSK9 inhibitors

作　　者：张航[1] 叶朴聪 王绪敏[3] 吴雪[1] 彭洁[1] 王世龙 蔺洁[1] Zhang Hang;Ye Pucong;Wang Xumin;Wu Xue;Peng Jie;Wang Shilong;Lin Jie(Department of Arteriosclerosis,Beijing Anzhen Hospital,Capital Medical University,Beijing Institute of Heart,Lung and Blood Vessel Diseases,Beijing 100029,China;Department of Emergency Intensive Care Unit,Beijing Shijitan Hospital,Capital Medical University,Beijing 100038,China;Beijing Institute of Genomics,Chinese Academy of Sciences,Beijing 100101,China)

机构地区：[1]首都医科大学附属北京安贞医院动脉硬化科,北京市心肺血管疾病研究所,100029 [2]首都医科大学附属北京世纪坛医院危重症医学科,100038 [3]中国科学院北京基因组研究所,100101

出　　处：《中华心血管病杂志》2021年第6期572-579,共8页Chinese Journal of Cardiology

基　　金：国家自然科学基金(81370443)。

摘　　要：目的通过分析不同等位基因分级的家族性高胆固醇血症(FH)患者前蛋白转化酶枯草溶菌素/kexin9型(PCSK9)抑制剂治疗前后低密度脂蛋白胆固醇(LDL-C)的变化,探讨FH表型分子病因分类对PCSK9抑制剂降脂疗效的提示作用。方法选取2019年1月至2020年10月就诊于北京安贞医院的FH表型患者,收集其年龄、性别等临床信息,经二代测序技术进行致病基因检测。依据受累等位基因数量及基因受损程度将患者分为单等位基因-缺失突变组、单等位基因-缺陷突变组、多等位基因-缺失突变组、多等位基因-缺陷突变组以及无主要致病基因突变组。检测不同等位基因分级的患者干预前、4~6周的强化他汀治疗后、联合PCSK9抑制剂治疗1个月后的LDL-C水平和降幅,分析基线LDL-C水平与降幅的相关性以及各基因型分组治疗后LDL-C水平达到靶目标值的比例。结果共纳入66例FH表型患者,其中男性47例(71.2%),女性19例(28.8%),年龄(43.1±13.4)岁。单等位基因-缺失突变组7例(10.6%),单等位基因-缺陷突变组25例(37.9%),多等位基因-缺失突变组8例(12.1%),多等位基因-缺陷突变组18例(27.3%),无主要致病突变组8例(12.1%)。PCSK9抑制剂联合治疗的LDL-C降幅由大到小依次是单等位基因组>无主要致病突变组>多等位基因组,整体分布于0~90%范围内,单等位基因2个分组和无主要致病基因组>50%>多等位基因2个分组。PCSK9抑制剂联合治疗下LDL-C进一步降幅由大到小依次为单等位基因组>无主要致病突变组>多等位基因组。总体FH表型患者中高强度他汀联合PCSK9抑制剂治疗后LDL-C降幅随基线LDL-C的水平升高而减小(r=0.46,P<0.001),高强度他汀治疗基础上PCSK9抑制剂的进一步LDL-C降幅随基线LDL-C水平升高而减小(r=0.40,P=0.001)。与其他组相比,单等位基因组高强度他汀联合PCSK9抑制剂治疗后LDL-C降幅较高且稳定,其中单等位基因-缺陷突变组LDL-C降幅�Objective This study intends to explore the difference in the efficacy of PCSK9 inhibitors in patients with different FH phenotypes by analyzing the level of blood lipids before and after treatment with PCSK9 inhibitors in patients with familial hypercholesterolemia(FH)with different allele grades.Methods Patients with FH phenotype,who admitted to Beijing Anzhen Hospital from January 2019 to October 2020,were enrolled.Age,sex and other clinical information were collected from enrolled,and the pathogenic genes were detected by the second generation sequencing technique.The patients were divided into five groups according to the number of alleles involved and the degree of gene damage:single allele-null mutation group,single allele-defect mutation group,multi-allele-null mutation group,multi-allele-defect mutation group and no major pathogenic gene mutation group.The results of blood lipids were collected before medication,4-6 weeks of intensive statin treatment and one month after combined treatment with PCSK9 inhibitor(PCSK9i).The LDL-C level were compared among groups.ASCVD risk stratification was performed in all patients,and the proportion of LDL-C level reaching the corresponding risk stratification target value of each genotype group after treatment was analyzed.Results A total of 66 patients with FH phenotype were included,including 47 males(71.2%)and 19 females(28.8%),the mean age was(43.1±13.4 years).There were 7 cases in single allele-null mutation group(10.6%),25 cases in single allele-defect mutation group(37.9%),8 cases in multi-allele-null mutation group(12.1%),18 cases in multi-allele-defect mutation group(27.3%)and 8 cases in no major pathogenic mutation group(12.1%).The degree of LDL-C reduction post combined PCSK9 inhibitor therapy was as follows:single allele mutation group>no major pathogenic mutation group>multi-allele mutation group,general distribution was in the range of 0-90.0%.Two groups of single allele mutation and no major pathogenic mutation group>50.0%>multi-allele mutation group.Un

关 键 词：家族性高胆固醇血症 前蛋白转化酶枯草溶菌素/kexin9型 遗传异质性 等位基因分型 LDL-C降幅 

分 类 号：R589.2[医药卫生—内分泌]