谷固醇血症合并心脑血管事件患者的基因和血液学表型分析

Genetic and hematological phenotypic studies on sitosteronism patients combined with cardiovascular and cerebrovascular events

目的:分析谷固醇血症(STSL)合并心脑血管事件患者的临床表现、基因及血液学检测结果。方法:收集并分析2020年11月至2023年6月上海交通大学医学院附属瑞金医院门诊的11例STSL患者的临床资料、基因检测以及血液学结果。采用全外显子组测序技术检测脂代谢相关基因突变;酶终点法检测血清总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)浓度;高效液相色谱法检测血清谷固醇浓度;酶联免疫吸附法检测C反应蛋白(CRP)、白细胞介素(IL)-6以及肿瘤坏死因子(TNF)-α水平;凝固法检测纤维蛋白原含量、蛋白C以及凝血因子Ⅷ(FⅧ)活性;免疫比浊法检测血管性血友病因子(vWF)抗原及活性,发色底物法检测抗凝血酶Ⅲ(ATⅢ)活性。结果:11例患者均发生心脑血管事件,其中3例冠心病,6例脑梗死,2例冠心病合并脑梗死,4例伴有眼睑黄褐瘤,2例伴有关节炎。基因测序发现3种ABCG5基因突变(exon9:c.G1166A:p.R389H、exon9:c.T1195C:p.F399L、exon12:c.1762+1G>A)和3种ABCG8基因突变(exon4:c.445_453del:p.A149_V151del、exon11:c.1720G>A:p.Gly574Arg、exon13:c.1949T>G:p.Leu650Arg)。STSL患者的外周血口红细胞比例为(11.3±8.6)%,血清TC、LDL-C和谷固醇浓度分别为(6.8±2.4)mmol/L、(4.4±2.0)mmol/L和40.0(22.0,203.7)μmol/L;血清CRP、IL-6、TNF-α浓度分别为15.5(7.2,29.6)mg/L、(4.2±2.0)pg/ml和(6.7±1.5)pg/ml;PC、FⅧ以及ATⅢ的活性分别为(114±51)%、(110±41)%和(83±33)%,纤维蛋白原含量为(3.2±1.4)g/L,vWF抗原及活性分别为(305±168)%和(275±112)%。结论:谷固醇血症合并心脑血管事件的患者存在复杂的脂代谢相关基因缺陷,其炎症介质CRP、凝血参数vWF等血液学指标明显升高。

Objective To analyze the clinical manifestations,genetic and hematological test results of patients with sitosteronism(STSL)complicated with cardiovascular and cerebrovascular events.Methods Clinical data were collected from 11 STSL patients at the outpatient department of Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine between November 2020 to June 2023.The whole exome sequencing technology was used to detect gene mutations associated with lipid metabolism,the serum total cholesterol(TC)and low-density lipoprotein cholesterol(LDL-C)were tested by the enzyme endpoint method;serum phytosterol levels by high-performance liquid chromatography;serum concentration of C-reactive protein(CRP),interleukin-6(IL-6)and tumor necrosis factor(TNF-α)by enzyme-linked immunosorbent assay,concentration of fibrinogen,the activity of protein C and coagulation factorⅧ(FⅧ)by the coagulation method;the antigen and activity of von Willebrand factor(vWF)by immunoturbidimetric assay;and the activity of antithrombinⅢ(ATⅢ)by chromogenic substrate assay.Results There were 3 cases of coronary heart disease,6 cases of cerebral infarction,2 cases of coronary heart disease combined with cerebral infarction,4 cases of eyelid melasma,and 2 cases of arthritis.Gene mutation was as follows:ABCG5 gene mutation including exon9:c G1166A:p R389H,exon9:c T1195C:p F399L,exon12:c.1762+1G>A,and ABCG8 gene mutation including exon 11 c.1720G>A:p.Gly574Arg,exon4:c.445_453del:p.A149_V151del,exon13 c.1949T>G:p.Leu650Arg.The percent of stomatocytes in the peripheral blood swears was(11.3±8.6)%.The concentrations of TC,LDL-C and sitosterol was(6.8±2.4),(4.4±2.0)mmol/L and 40.0(22.0,203.7)μmol/L.The level of CRP,interleukin IL-6,and TNF-αwas 15.5(7.2,29.6)mg/L,(4.2±2.0)pg/ml and(6.7±1.5)pg/ml,respectively.The activity of PC,FⅧand ATⅢwas(114±51)%,(110±41)%and(83±33)%.The values of FIB was(3.2±1.4)g/L.vWF antigen and vWF activity was(305±168)%and(275±112)%.Conclusions STSL patients combined with cardiovascular and cerebrovascular events not only had complex dysfunctional lipid metabolism related gene defects,but also had significantly increased hematological indicators such as inflammatory mediator CRP,coagulation parameter vWF.