目的 分析中国天津地区汉族冠状动脉性心脏病(coronary heart disease,CHD)患者胆固醇酯转运蛋白(cholesteryl ester transfer protein,CETP)基因-629C/A多态性,从药物基因组学角度探讨遗传因素对于阿托伐他汀钙调脂疗效以及患者长期预后的影响,为个体化治疗提供理论依据.方法 研究对象为经冠状动脉造影检查证实的CHD患者232例.应用聚合酶链反应-限制性片段长度多态性方法检测其CETP 629C/A基因型,用酶联免疫吸附测定法(enzyme-linked immunosorbent assay,ELISA)测定血清CETP含量.所有患者接受阿托伐他汀钙20 mg/d调脂治疗1年后复查血脂,随访12～23个月,记录MACE事件(包括死亡、非致死性心肌梗死、再次血运重建和卒中).采用Kaplan-Meier生存曲线Log-rank 检验分析不同基因型对于生存率的影响.结果 A突变等位基因频率为0.475,C等位基因频率为0.525；CC、CA、AA基因型相比,血清高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)水平呈升高趋势,血清CETP水平呈降低趋势,但差异均无统计学意义(F=0.893,P=0.411;F=1.279,P=0.282).血清HDL-C水平与CETP浓度呈负向变化趋势,但其相关性无统计学意义(r=-0.151,P=0.081).阿托伐他汀钙20 mg/d调脂治疗1年后,CC基因型携带者低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)水平下降最多,达35.41％,CA基因型次之,为18.84％,AA基因型下降最少,为8.15％,差异有统计学意义(P=0.001).血清脂蛋白(a)水平变化在不同基因型3组间差异有统计学意义(P=0.021),CC基因型下降最明显,为30.41％；3种基因型患者HDL-C水平的变化尽管呈梯度变化的趋势,但差异无统计学意义(P=0.470)；CC基因型HDL-C水平升高最明显,为14.37％,CA基因型为10.48％,AA基因型为6.64％；对总胆固醇、甘油三酯、极低密度脂蛋白胆固醇、以及载脂蛋白ApoAI和ApoB的调节效果未受到CETP多态性的影响.随访(18.66±5.99)月,发生MACE事件18例(7.76％),其中死亡2例(0.86％),非致死性心肌梗死5例(2.16％),再次血运重建9例(3.88％),卒中2例(0.86％).3种基因型无MACE生存率分别为CC型92.4％,CA型85.3％,AA型65.0％,差异无统计学意义(Log-rank P=0.444).结论-629AA基因型患者具有较高基线HDL-C水平和较低的CETP浓度,而-629CC基因型携带者有更好的他汀类调脂效果,LDL-C和脂蛋白水平下降更明显.3种基因型患者长期临床预后无显著差异.
目的 分析中國天津地區漢族冠狀動脈性心髒病(coronary heart disease,CHD)患者膽固醇酯轉運蛋白(cholesteryl ester transfer protein,CETP)基因-629C/A多態性,從藥物基因組學角度探討遺傳因素對于阿託伐他汀鈣調脂療效以及患者長期預後的影響,為箇體化治療提供理論依據.方法 研究對象為經冠狀動脈造影檢查證實的CHD患者232例.應用聚閤酶鏈反應-限製性片段長度多態性方法檢測其CETP 629C/A基因型,用酶聯免疫吸附測定法(enzyme-linked immunosorbent assay,ELISA)測定血清CETP含量.所有患者接受阿託伐他汀鈣20 mg/d調脂治療1年後複查血脂,隨訪12～23箇月,記錄MACE事件(包括死亡、非緻死性心肌梗死、再次血運重建和卒中).採用Kaplan-Meier生存麯線Log-rank 檢驗分析不同基因型對于生存率的影響.結果 A突變等位基因頻率為0.475,C等位基因頻率為0.525；CC、CA、AA基因型相比,血清高密度脂蛋白膽固醇(high-density lipoprotein cholesterol,HDL-C)水平呈升高趨勢,血清CETP水平呈降低趨勢,但差異均無統計學意義(F=0.893,P=0.411;F=1.279,P=0.282).血清HDL-C水平與CETP濃度呈負嚮變化趨勢,但其相關性無統計學意義(r=-0.151,P=0.081).阿託伐他汀鈣20 mg/d調脂治療1年後,CC基因型攜帶者低密度脂蛋白膽固醇(low-density lipoprotein cholesterol,LDL-C)水平下降最多,達35.41％,CA基因型次之,為18.84％,AA基因型下降最少,為8.15％,差異有統計學意義(P=0.001).血清脂蛋白(a)水平變化在不同基因型3組間差異有統計學意義(P=0.021),CC基因型下降最明顯,為30.41％；3種基因型患者HDL-C水平的變化儘管呈梯度變化的趨勢,但差異無統計學意義(P=0.470)；CC基因型HDL-C水平升高最明顯,為14.37％,CA基因型為10.48％,AA基因型為6.64％；對總膽固醇、甘油三酯、極低密度脂蛋白膽固醇、以及載脂蛋白ApoAI和ApoB的調節效果未受到CETP多態性的影響.隨訪(18.66±5.99)月,髮生MACE事件18例(7.76％),其中死亡2例(0.86％),非緻死性心肌梗死5例(2.16％),再次血運重建9例(3.88％),卒中2例(0.86％).3種基因型無MACE生存率分彆為CC型92.4％,CA型85.3％,AA型65.0％,差異無統計學意義(Log-rank P=0.444).結論-629AA基因型患者具有較高基線HDL-C水平和較低的CETP濃度,而-629CC基因型攜帶者有更好的他汀類調脂效果,LDL-C和脂蛋白水平下降更明顯.3種基因型患者長期臨床預後無顯著差異.
목적 분석중국천진지구한족관상동맥성심장병(coronary heart disease,CHD)환자담고순지전운단백(cholesteryl ester transfer protein,CETP)기인-629C/A다태성,종약물기인조학각도탐토유전인소대우아탁벌타정개조지료효이급환자장기예후적영향,위개체화치료제공이론의거.방법 연구대상위경관상동맥조영검사증실적CHD환자232례.응용취합매련반응-한제성편단장도다태성방법검측기CETP 629C/A기인형,용매련면역흡부측정법(enzyme-linked immunosorbent assay,ELISA)측정혈청CETP함량.소유환자접수아탁벌타정개20 mg/d조지치료1년후복사혈지,수방12～23개월,기록MACE사건(포괄사망、비치사성심기경사、재차혈운중건화졸중).채용Kaplan-Meier생존곡선Log-rank 검험분석불동기인형대우생존솔적영향.결과 A돌변등위기인빈솔위0.475,C등위기인빈솔위0.525；CC、CA、AA기인형상비,혈청고밀도지단백담고순(high-density lipoprotein cholesterol,HDL-C)수평정승고추세,혈청CETP수평정강저추세,단차이균무통계학의의(F=0.893,P=0.411;F=1.279,P=0.282).혈청HDL-C수평여CETP농도정부향변화추세,단기상관성무통계학의의(r=-0.151,P=0.081).아탁벌타정개20 mg/d조지치료1년후,CC기인형휴대자저밀도지단백담고순(low-density lipoprotein cholesterol,LDL-C)수평하강최다,체35.41％,CA기인형차지,위18.84％,AA기인형하강최소,위8.15％,차이유통계학의의(P=0.001).혈청지단백(a)수평변화재불동기인형3조간차이유통계학의의(P=0.021),CC기인형하강최명현,위30.41％；3충기인형환자HDL-C수평적변화진관정제도변화적추세,단차이무통계학의의(P=0.470)；CC기인형HDL-C수평승고최명현,위14.37％,CA기인형위10.48％,AA기인형위6.64％；대총담고순、감유삼지、겁저밀도지단백담고순、이급재지단백ApoAI화ApoB적조절효과미수도CETP다태성적영향.수방(18.66±5.99)월,발생MACE사건18례(7.76％),기중사망2례(0.86％),비치사성심기경사5례(2.16％),재차혈운중건9례(3.88％),졸중2례(0.86％).3충기인형무MACE생존솔분별위CC형92.4％,CA형85.3％,AA형65.0％,차이무통계학의의(Log-rank P=0.444).결론-629AA기인형환자구유교고기선HDL-C수평화교저적CETP농도,이-629CC기인형휴대자유경호적타정류조지효과,LDL-C화지단백수평하강경명현.3충기인형환자장기림상예후무현저차이.
Objective To investigate cholesteryl ester transfer protein (CETP) gene polymorphism -629C/A among Han Chinese patients with coronary heart disease (CHD) in Tianjin region,and to assess the influence of genetic factors on therapeutic effect of atorvastatin and clinical outcome in order to provide a pharmacogenomic basis for individual treatment.Methods From October 2010 to July 2011,232 patients with angiographically confirmed CHD were recruited.Polymorphism of position-629 of the CETP gene promoter was determined with polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) method.Serum level of CETP was determined with enzyme-linked immunosorbent assay (ELISA).Lipid level in all patients was determined at baseline and after 12 months of treatment with 20 mg/d atorvastatin.Clinical follow-up was carried out for more than a year (12-23 months).Major adverse cardiac events including death,non-fatal infarction,revascularization and stroke (MACE) were recorded.A Kaplan-Meier log-rank test was used to compare MACE-free survival for individuals with various genotypes.Results The frequency of-629A allele was 0.408.Compared with CC or CA genotypes,individuals with AA genotype had lower CETP levels and higher high-density lipoprotein cholesterol (HDL-C) levels,albeit without statistical significance (F-=0.893,P=0.411 and F=1.279,P=0.282,respectively).There also appeared to be a negative correlation between serum HDL-C and CETP levels,though no statistic significance was detected (r=-0.151,P=0.081).After 12 months atorvastatin therapy,individuals with CC genotype had greater reduction of low-density lipoprotein cholesterol (LDL-C),reduced LP (a) and elevated HDL-C compared with CA or AA genotypes.LDL-C level has decreased by 35.41％ in CC homozygotes,18.84 ％ in CA heterozygotes and 8.15 ％ in AA homozygotes (P=0.001).HDL-C level has increased by 14.37％ in CC homozygotes,10.48％ in CA heterozygotes and 6.64％ in AA homozygotes,respectively.However,above changes did not reach statistic significance (P=0.470).The incidence of MACE after a mean follow-up of (18.66±5.99) months was 7.76％,which included 2 (0.86％) deaths,5 (2.16％) non-fatal infarctions,9 (3.88％) revascularizations and 2 (0.86％) strokes.The cumulative MACE-free survival rates were 92.4％,85.3％ and 65.0％ for CC,CA and AA genotypes,respectively (Log-rank P=0.444).Conclusion Our results suggested that AA variant for the-629A allele of CETP gene had higher HDL-C levels and reduced CETP levels,though patients with CC genotype appeared to have better benefited from statin therapy with reduction in LDLC and LP(a) levels.Long-term clinical prognosis was however not affected by the 3 genotypes.
