Corin基因变异与原发性高血压的相关性
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摘要
目的探讨丝氨酸蛋白酶Corin基因变异与原发性高血压的关系。方法选择2015年7月至2016年6月新疆乌鲁木齐市新疆医科大学第五附属医院原发性高血压患者496例和正常血压的健康体检者500名,采用病例对照的研究方法,使用Haploview软件从人类基因组单体型图(Hapmap)基因库中,选择Corin基因r~2≥0.8且最小等位基因频率>5%的4个标签单核苷酸多肽(tagSNP),即rs17654278、rs2271036、rs6832640、rs7654322,应用SNaPshot技术对4个tagSNP进行分型,分析其与原发性高血压的相关性。结果 Corin基因的4个tagSNP在所有研究对象中均成功分型,除rs7654322位点外,其余3个位点的基因型、等位基因分布均符合Hardy-Weinberg平衡(P>0.05);3个变异位点基因型及等位基因频率在两组分布差异无统计学意义(P>0.05);校正混杂因素性别、年龄和体质量指数后,Logistic回归分析显示,Corin基因上述变异的基因型与原发性高血压患者仍不相关;与正常血压者相比,原发性高血压患者(rs6832640,rs2271036,rs17654278)3个变异的单体型C-T-A频率明显升高(7.5%比4.5%,P<0.05),而单体型C-T-G的频率明显降低(13.2%比17.1%,P<0.05)。结论 Corin基因的rs6832640、rs2271036、rs17654278单个变异与高血压无相关性,3个变异的单体型C-T-A增加高血压患病风险。
Objective To explore the relationship between Corin gene variant and essential hypertension. Methods A case-control study, including 496 hypertensives and 500 normotensives, was conducted in the Fifth Affiliated Hospital of Xinjiang Medical University from July 2015 to June 2016. Four SNPs(rs17654278, rs2271036, rs6832640, rs7654322) in Corin gene were selected using the Haploview software from Hapmap project, with the criteria r~2≥0.8 and minor allele frequence(MAF)>0.05. SNP genotyping was carried out by SNaPshot technique. The relationships between the four tagSNPs of the Corin gene(rs17654278,rs2271036,rs6832640,rs7654322) and essential hypertension were analyzed. Results The four tagSNPs of the Corin gene(rs17654278, rs2271036, rs6832640, rs7654322) were genotyped successfully. Except for the rs7654322 site, allele frequencies of the other three tagSNPs followed the Hardy-Weinberg equilibrium law(P>0.05). There was no significant difference in frequencies of genotype and allele distribution for three variants(rs17654278, rs2271036, rs6832640) in Corin gene between hypertensive cases and controls(P>0.05). After adjusting for age, gender, body mass index(BMI), logistic regression analysis showed the same statistical results. Three variations(rs6832640, rs2271036, rs17654278) in Corin gene build the six common haplotypes, Compared with the controls, the frequency of the haplotype C-T-A in patients with essential hypertension was significantly higher(7.5% vs 4.5%, P<0.05), while the frequency of the haplotype C-T-G in patients with essential hypertension was significantly lower(13.2% vs 17.1%, P<0.05). Conclusion The three SNPs(rs6832640, rs2271036, rs17654278) in Corin gene do not present significant correlations with essential hypertension(P>0.05), while the haplotype C-T-A might increase the susceptibility to hypertension in this population.
Objective To explore the relationship between Corin gene variant and essential hypertension. Methods A case-control study, including 496 hypertensives and 500 normotensives, was conducted in the Fifth Affiliated Hospital of Xinjiang Medical University from July 2015 to June 2016. Four SNPs(rs17654278, rs2271036, rs6832640, rs7654322) in Corin gene were selected using the Haploview software from Hapmap project, with the criteria r~2≥0.8 and minor allele frequence(MAF)>0.05. SNP genotyping was carried out by SNaPshot technique. The relationships between the four tagSNPs of the Corin gene(rs17654278,rs2271036,rs6832640,rs7654322) and essential hypertension were analyzed. Results The four tagSNPs of the Corin gene(rs17654278, rs2271036, rs6832640, rs7654322) were genotyped successfully. Except for the rs7654322 site, allele frequencies of the other three tagSNPs followed the Hardy-Weinberg equilibrium law(P>0.05). There was no significant difference in frequencies of genotype and allele distribution for three variants(rs17654278, rs2271036, rs6832640) in Corin gene between hypertensive cases and controls(P>0.05). After adjusting for age, gender, body mass index(BMI), logistic regression analysis showed the same statistical results. Three variations(rs6832640, rs2271036, rs17654278) in Corin gene build the six common haplotypes, Compared with the controls, the frequency of the haplotype C-T-A in patients with essential hypertension was significantly higher(7.5% vs 4.5%, P<0.05), while the frequency of the haplotype C-T-G in patients with essential hypertension was significantly lower(13.2% vs 17.1%, P<0.05). Conclusion The three SNPs(rs6832640, rs2271036, rs17654278) in Corin gene do not present significant correlations with essential hypertension(P>0.05), while the haplotype C-T-A might increase the susceptibility to hypertension in this population.
引文
[1] 陈伟伟,高润霖,刘力,等.《中国心血管病报告2017》概要[J].中国循环杂志,2018,33(1):1-8.
[2] Armando I,Villar VA,Jose PA.Genomics and pharmacogenomics of salt-sensitive hypertension[J].Curr Hypertens Rev,2015,11(1):49-56.
[3] Armaly Z,Assady S,Abassi Z.Corin:a new player in the regulation of salt-water balance and blood pressure[J].Curr Opin Nephrol Hypertens,2013,22(6):713-722.
[4] Dries DL,Victor RG,Rame JE,et al.Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension[J].Circulation,2005,112(16):2403-2410.
[5] Rame JE,Drazner MH,Post W,et al.Corin I555(P568) allele is associated with enhanced cardiac hypertrophic response to increased systemic after-load[J].Hypertension,2007,49(4):857-864.
[6] Hu BC,Li Y,Liu M,et al.Blood pressure and urinary sodium excretion in relation to 16 genetic polymorphisms in the natriuretic peptide system in Chinese[J].Endocr J,2014,61(9):861-874.
[7] Dong N,Fang C,Jiang Y,et al.Corin mutation R539C from hypertensive patients impairs zymogen activation and generates an inactive alternative ectodomain fragment[J].J Biol Chem,2013,288(11):7867-7874.
[8] Zhang Y,Li H,Zhou J,et al.A corin variant identified in hypertensive patients that alters cytoplasmic tail and reduces cell surface expression and activity[J].Sci Rep,2014,4:7378.
[9] Chen YL,Li TJ,Hao Y,et al.Association of rs2271037 and rs3749585 polymorphisms in CORIN with susceptibility to hypertension in a Chinese Han population:A case-control study[J].Gene,2018,651:79-85.
[10] 中国高血压防治指南修订委员会.中国高血压防治指南2010[J].中华高血压杂志,2011,19(8):701-743.
[11] Chan JC,Knudson O,Wu F,et al.Hypertension in mice lacking the proatrial natriuretic peptide convertase corin[J].Proc Natl Acad Sci,2005,102(3):785-790.
[12] Wang W,Shen J,Cui Y,et al.Impaired sodium excretion and salt-sensitive hypertension in corin-deficient mice[J].Kidney Int,2012,82(1):26-33.
[13] Wang W,Liao X,Fukuda K,et al.Corin variant associated with hypertension and cardiac hypertrophy exhibits impaired zymogen activation and natriuretic peptide processing activity[J].Circ Res,2008,103(5):502-508.
[14] Wang W,Cui Y,Shen J,et al.Salt-sensitive hypertension and cardiac hypertrophy in transgenic mice expressing a corin variant identified in blacks[J].Hypertension,2012,60(5):1352-1358.
[15] Ngo DT,Horowitz JD,Sverdlov AL.Heart failure:a corin-deficient state?[J].Hypertension,2013,61(2):284-285.
[16] Ichiki T,Boerrigter G,Huntley BK,et al.Differential expression of the pronatriuretic peptide convertases corin and furin in experimental heart failure and atrial fibrosis[J].Am J Physiol Regul Integr Comp Physiol,2013,304(2):R102-R109.
[17] Gladysheva IP,Wang D,McNamee RA,et al.Corin overexpression improves cardiac function,heart failure,and survival in mice with dilated cardiomyopathy[J].Hypertension,2013,61(2):327-332.
[18] Bouley R.Corin:a key protein of an adaptive renal mechanism to respond to salt variation?[J].Kidney Int,2012,82(1):7-8.
[19] Fang C,Shen L,Dong L,et al.Reduced urinary corin levels in patients with chronic kidney disease[J].Clin Sci(Lond),2013,124(12):709-717.
[20] Zhou Y,Wu Q.Role of corin and atrial natriuretic peptide in preeclampsia[J].Placenta,2013,34(2):89-94.
[21] Li H,Zhang Y,Wu Q.Role of corin in the regulation of blood pressure[J].Curr Opin Nephrol Hypertens,2017,26(2):67-73.
[22] Shimodaira M,Nakayama T,Sato N,et al.Association of HSD3B1 and HSD3B2 gene polymorphisms with essential hypertension,aldosterone level,and left ventricular structure[J].Eur J Endocrinol,2010,163(4):671-680.
[2] Armando I,Villar VA,Jose PA.Genomics and pharmacogenomics of salt-sensitive hypertension[J].Curr Hypertens Rev,2015,11(1):49-56.
[3] Armaly Z,Assady S,Abassi Z.Corin:a new player in the regulation of salt-water balance and blood pressure[J].Curr Opin Nephrol Hypertens,2013,22(6):713-722.
[4] Dries DL,Victor RG,Rame JE,et al.Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension[J].Circulation,2005,112(16):2403-2410.
[5] Rame JE,Drazner MH,Post W,et al.Corin I555(P568) allele is associated with enhanced cardiac hypertrophic response to increased systemic after-load[J].Hypertension,2007,49(4):857-864.
[6] Hu BC,Li Y,Liu M,et al.Blood pressure and urinary sodium excretion in relation to 16 genetic polymorphisms in the natriuretic peptide system in Chinese[J].Endocr J,2014,61(9):861-874.
[7] Dong N,Fang C,Jiang Y,et al.Corin mutation R539C from hypertensive patients impairs zymogen activation and generates an inactive alternative ectodomain fragment[J].J Biol Chem,2013,288(11):7867-7874.
[8] Zhang Y,Li H,Zhou J,et al.A corin variant identified in hypertensive patients that alters cytoplasmic tail and reduces cell surface expression and activity[J].Sci Rep,2014,4:7378.
[9] Chen YL,Li TJ,Hao Y,et al.Association of rs2271037 and rs3749585 polymorphisms in CORIN with susceptibility to hypertension in a Chinese Han population:A case-control study[J].Gene,2018,651:79-85.
[10] 中国高血压防治指南修订委员会.中国高血压防治指南2010[J].中华高血压杂志,2011,19(8):701-743.
[11] Chan JC,Knudson O,Wu F,et al.Hypertension in mice lacking the proatrial natriuretic peptide convertase corin[J].Proc Natl Acad Sci,2005,102(3):785-790.
[12] Wang W,Shen J,Cui Y,et al.Impaired sodium excretion and salt-sensitive hypertension in corin-deficient mice[J].Kidney Int,2012,82(1):26-33.
[13] Wang W,Liao X,Fukuda K,et al.Corin variant associated with hypertension and cardiac hypertrophy exhibits impaired zymogen activation and natriuretic peptide processing activity[J].Circ Res,2008,103(5):502-508.
[14] Wang W,Cui Y,Shen J,et al.Salt-sensitive hypertension and cardiac hypertrophy in transgenic mice expressing a corin variant identified in blacks[J].Hypertension,2012,60(5):1352-1358.
[15] Ngo DT,Horowitz JD,Sverdlov AL.Heart failure:a corin-deficient state?[J].Hypertension,2013,61(2):284-285.
[16] Ichiki T,Boerrigter G,Huntley BK,et al.Differential expression of the pronatriuretic peptide convertases corin and furin in experimental heart failure and atrial fibrosis[J].Am J Physiol Regul Integr Comp Physiol,2013,304(2):R102-R109.
[17] Gladysheva IP,Wang D,McNamee RA,et al.Corin overexpression improves cardiac function,heart failure,and survival in mice with dilated cardiomyopathy[J].Hypertension,2013,61(2):327-332.
[18] Bouley R.Corin:a key protein of an adaptive renal mechanism to respond to salt variation?[J].Kidney Int,2012,82(1):7-8.
[19] Fang C,Shen L,Dong L,et al.Reduced urinary corin levels in patients with chronic kidney disease[J].Clin Sci(Lond),2013,124(12):709-717.
[20] Zhou Y,Wu Q.Role of corin and atrial natriuretic peptide in preeclampsia[J].Placenta,2013,34(2):89-94.
[21] Li H,Zhang Y,Wu Q.Role of corin in the regulation of blood pressure[J].Curr Opin Nephrol Hypertens,2017,26(2):67-73.
[22] Shimodaira M,Nakayama T,Sato N,et al.Association of HSD3B1 and HSD3B2 gene polymorphisms with essential hypertension,aldosterone level,and left ventricular structure[J].Eur J Endocrinol,2010,163(4):671-680.
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