脂蛋白(a)基因单核苷酸多态性与钙化性主动脉瓣疾病及冠心病的关系

Correlations of lipoprotein(a)gene polymorphisms with calcific aortic valve disease and coronary heart disease

目的探讨脂蛋白(a)[Lp(a)]基因单核苷酸多态性(SNP)与钙化性主动脉瓣膜疾病(CAVD)、冠心病(CHD)的相关性。方法前瞻性研究。纳入2018年1—12月天津市胸科医院心内科CAVD或CHD住院患者248例,根据心脏超声多普勒、冠状动脉造影或冠状动脉CT检查结果分为两组:CAVD组101例、CHD组147例;同时选取2018年3—12月天津市胸科医院体检中心排除CAVD或CHD的171位健康体检者为对照组。检测各组Lp(a)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、载脂蛋白A(ApoA)、载脂蛋白B(ApoB)等生化指标,采用SNaPshot SNP分型技术对Lp(a)基因rs7770628、rs6415084、rs10455872三个位点进行基因分型;采用二元logistic回归分析不同基因型及Lp(a)水平对钙化性主动脉瓣疾病及冠心病发病的影响,采用线性回归分析不同基因型及ApoB水平对Lp(a)水平的影响。结果三组间比较,患者BMI和饮酒史差异均无统计学意义(P值均>0.05),性别、年龄、吸烟史、糖尿病史、高血压病史差异均有统计学意义(P值均<0.05)。Lp(a)检测值在对照组、CAVD组、CHD组分别为23.6(9.4,48.6)、37.2(16.5,79.6)、46.7(21.5,104.6)nmol/L,三组间比较差异有统计学意义(H=13.337,P<0.01);LDL值各组分别为(2.74±0.80)、(3.07±0.81)、(3.14±1.18)mmol/L,三组间差异有统计学意义(F=3.662,P<0.05);HDL值各组分别为(1.24±0.93)、(1.18±0.30)、(1.09±0.33)mmol/L,三组间比较差异有统计学意义(F=4.281,P<0.05);ApoA值各组分别为(1.42±0.25)、(1.30±0.26)、(1.26±0.26)g/L,三组间比较差异有统计学意义(F=7.339,P<0.01);ApoB检测值各组分别为0.97(0.82,1.10)、1.04(0.87,1.26)、1.12(0.88,1.31)g/L,三组间比较差异有统计学意义(H=3.948,P<0.05)。Lp(a)基因rs7770628位点对照组、CAVD组、CHD组TT基因型分别为130(76.0%)、75(74.3%)、103(70.1%),CT基因型分别为36(21.1%)、23(22.8%)、40(27.2%),CC基因型分别为5(2.9%)、3(2.9%)、4(2.7%),三组间比较差异无统计学意义(F=1.718,P>0.05);Lp(a)基因rs6415084位点对照组、CAVD组、CHD组TT基因型分别为5(2.9%)、2(2.0%)、4(2.7%),CT基因型分别为33(19.3%)、20(19.8%)、32(21.8%),CC基因型分别为133(77.8%)、79(78.2%)、111(75.5%),三组间比较差异无统计学意义(F=0.551,P>0.05);Lp(a)基因rs10455872位点对照组、CAVD组、CHD组AA基因型分别为171(100%)、99(98.0%)、147(100%),AG基因型分别为0(0.0%)、2(2.0%)、0(0.0%),三组间比较差异无统计学意义(P=0.058)。经logistic回归分析,与对照组相比,CAVD组及CHD组的Lp(a)水平更高,其差异有统计学意义,但未发现Lp(a)基因rs7770628及rs6415084两个位点的基因分布频率的差异有统计学意义(P>0.05)。线性回归结果表明,rs7770628以及rs6415084两个基因位点的基因分布均与Lp(a)水平升高有关。rs10455872位点只有2例SNP基因型为AG,且皆出现于CAVD组。结论Lp(a)基因rs7770628、rs6415084位点的基因分布均与Lp(a)的升高有关,Lp(a)高表达与CAVD以及CHD患病具有相关性。

Objective To investigate the relationships of lipoprotein(a)[Lp(a)]gene polymorphism with calcified aortic valve disease(CAVD)and coronary heart disease(CHD).Methods Prospective study.A total of 248 patients with CHD or CAVD diagnosed in the Department of Cardiology of Tianjin Chest Hospital from January to December 2018 were divided into two groups,namely,the CAVD group(101 cases)and the CHD group(147 cases),in accordance with the results of color Doppler echocardiography,coronary angiography,and computed tomography angiography.The control group,which was composed of 171 cases who neither had CHD nor CAVD,was selected from the physical examination center from March to December 2018.Biomarkers,including Lp(a),low-density lipoprotein(LDL),high-density lipoprotein(HDL),apolipoprotein A(ApoA),and apolipoprotein B(ApoB)were tested.The SNaPshot single nucleotide polymorphism method was used to detect Lp(a)gene loci rs10455872,rs6415084,and rs7770628.Binary logistic regression was performed to analyze the effects of different genotypes and Lp(a)levels on CAVD or CHD,and linear regression was conducted to analyze the effects of different genotypes and ApoB levels on Lp(a)levels.Results There were no statistically significant differences in BMI and drinking history among the three groups(all P values>0.05),and there were statistically significant differences in gender,age,smoking history,history of diabetes and hypertension(all P values<0.05).The Lp(a)quartile values of the control,CAVD,and CHD groups were 23.6(9.4,48.6),37.2(16.5,79.6),and 46.7(21.5,104.6)nmol/L,respectively,and exhibited a statistically significant difference(H=13.337,P<0.01).The LDL values of the control,CAVD,and CHD groups were(2.74±0.80),(3.07±0.81),and(3.14±1.18)mmol/L,respectively,and demonstrated a statistically significant difference(F=3.662,P<0.05).The HDL values of the control,CAVD,and CHD groups were(1.24±0.93),(1.18±0.30),and(1.09±0.33)mmol/L,respectively,and presented a statistically significant difference(F=4.281,P<0.05).The ApoA values of the control,CAVD,and CHD groups were 1.42±0.25,1.30±0.26,and 1.26±0.26 g/L,respectively,and had a statistically significant difference(F=7.339,P<0.01).The ApoB quartile values of the control,CAVD,and CHD groups were 0.97(0.82,1.10),1.04(0.87,1.26),and 1.12(0.88,1.31)g/L,respectively,and exhibited a statistically significant difference(H=3.948,P<0.05).The TT genotypes of the rs7770628 gene loci in the control,CAVD,and CHD groups were 130(76.0%),75(74.3%),and 103(70.1%),respectively;the CT genotypes were 36(21.1%),23(22.8%),and 40(27.2%),respectively;the CC genotypes were 5(2.9%),3(2.9%),and 4(2.7%),respectively;and no statistically significant difference was observed among the three groups(F=1.718,P>0.05).The TT genotypes of the rs6415084 gene loci in the control,CAVD,and CHD groups were 5(2.9%),2(2.0%),and 4(2.7%),respectively;the CT genotypes were 33(19.3%),20(19.8%),and 32(21.8%),respectively;the CC genotypes were 133(77.8%),79(78.2%),and 111(75.5%),respectively;and no statistically significant difference was noted among the three groups(F=0.551,P>0.05).The AA genotypes of the rs10455872 gene loci in the control,CAVD,and CHD groups were 171(100%),99(98.0%),and 147(100%),respectively;the AG genotypes were 0(0.0%),2(2.0%),and 0(0.0%),respectively;and no statistically significant difference was recorded among the three groups(P=0.058).The results of the logistic regression analysis showed that the Lp(a)level and the risks of CAVD and CHD increased compared with the control group.However,no statistically significant difference was found in the gene distribution frequency of the rs7770628 and rs6415084 gene loci between the CAVD and control groups.In addition,the difference in the gene distribution frequency between the CHD and control groups was not statistically significant(P>0.05).Linear regression indicated that the gene distribution of the rs7770628 and rs6415084 gene loci were related to the increase in Lp(a)concentration.The data of the rs10455872 gene loci disclosed that only two cases carried AG minor alleles among the 419 subjects,and both cases belong to the CAVD group.The remaining 417 cases carried AA minor alleles.Conclusions Lp(a)rs6415084 and rs7770628 genetic variations are associated with increased plasma Lp(a)level.High plasma Lp(a)levels are correlated with increased risk of CAVD and CHD.