缓激肽释放酶基因-1多态性位点rs5516与血脂异常及血脂水平的相关性研究
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摘要
目的:探讨缓激肽释放酶基因-1单核苷酸多态性(SNP)位点rs5516与血脂异常及血脂水平的相关性。方法:选取于北京安贞医院体检中心及周边社区接受健康体检的无血缘关系参与者645例,详细记录研究对象的临床信息,采集静脉血后检测各项生化指标,应用TaqMan荧光定量法对缓激肽释放酶基因-1 rs5516位点进行基因分型,评估该多态性位点与血脂异常发病风险的关系。结果:在rs5516与血脂异常的相关性研究中,rs5516在未患血脂异常的对照组人群中符合Hardy-Weinberg平衡。在血脂异常组中rs5516位点CC、CG、GG基因型频率分别为3.1%、38.8%、58.1%,对照组相应基因型频率分别为4.9%、29.8%、65.2%,两组基因型分布差异有统计学意义(P=0.042)。病例组中C、G等位基因频率分别为22.5%、 77.5%;对照组中C、G等位基因频率分别为19.8%、80.2%,等位基因在两组中差异无统计学意义;将CC+CG合并为C等位基因携带者后进行分析,病例组中CC+CG频率为41.9%,对照组中为34.8%,两者差异无统计学意义。在校正了可能对血脂水平产生影响的因素后,rs5516在等位基因模型、加性模型、显性模型、隐形模型、纯合子模型中均与是否患血脂异常无显著相关性。亚组分析中,基因型及等位基因频率在两组间差异均无统计学意义,多因素相关性分析,亦未见明显相关。将血脂异常细分为高TC、高TG、混合型高脂血症、低HDL-C血症后,亦未发现rs5516与各类型血脂异常有相关性。在rs5516与血脂水平的相关性研究中,各血脂指标水平在CC、CG、GG研究对象之间或C等位基因携带者(CC+CG)与GG基因型研究对象之间,差异无统计学意义,在多元线性回归分析中,经校正可能对血脂水平产生影响的因素后,各血脂指标水平也与rs5516无明显线性相关,在亚组分析中也得出同样的结果。结论:缓激肽释放酶基因-1多态性位点rs5516与血脂异常及血脂水平可能并无相关性。
Objective: Our study was designed to explore the possible relationship between single nucleotide polymorphism rs5516 on the gene kallikrein-1 and the risk of dyslipidemia or levels of serum lipids. Methods: 645 unrelated individuals, including 320 cases with dyslipidemia and 325 controls, who received general physical examinations in medical center of Beijing Anzhen Hospital and other surrounding community health center were selected as candidates of our research, their clinical information was documented in detail and their blood samples were collected to get their biochemical indexes. Genotyping was performed by TaqMan to identify rs5516 polymorphisms of kallikrein-1. Statistical method were then utilized to determine the possible relationship between rs5516 single nucleotide polymorphism and the risk of dyslipidemia or levels of serum lipids. Results: In the analysis of relationship between rs5516 and dyslipidemia, the genotype distribution was in accordance with Hardy-Weinberg equilibrium in the control group. In the case group, genotype frequencies for CC\\CG\\GG were 3.1%\\38.8%\\58.1% respectively, while the genotype frequencies for CC\\CG\\GG were 4.9%\\29.8%\\65.2% among control individuals, and the difference was statistically significant(P=0.042). The frequencies for allele C\\allele G were 22.5%\\77.5% in cases, and the frequencies were 19.8%\\80.2% in controls, suggesting there was no significant difference between the two groups in terms of allele distribution. After adjusting confounding factors which might influence the level of serum lipids, we could not find any statistically significant association between rs5516 polymorphism and dyslipidemia in allele comparison, additive genetic model, dominant genetic model, recessive genetic model or homozygote comparison. In subgroup analysis, there was no statistical significance found, either. We further classified participants with dyslipidemia into hypercholesterolemia group, hypertriglyceridemia group, mixed hyperlipidemia group or low HDL-C group, and no significant results were deduced. In the analysis of relation between rs5516 and levels of serum lipids, any of these lipid indexes showed no statistically significant difference in different genotypes, and there was no significant finding in the process of multiple linear regression analysis. Furthermore, resembling results were reached in subgroup analysis. Conclusions: The conclusion can be drawn that single nucleotide polymorphism rs5516 on the gene kallikrein-1 might be in no association with the risk of dyslipidemia and have too little impact on levels of serum lipid indexes.
Objective: Our study was designed to explore the possible relationship between single nucleotide polymorphism rs5516 on the gene kallikrein-1 and the risk of dyslipidemia or levels of serum lipids. Methods: 645 unrelated individuals, including 320 cases with dyslipidemia and 325 controls, who received general physical examinations in medical center of Beijing Anzhen Hospital and other surrounding community health center were selected as candidates of our research, their clinical information was documented in detail and their blood samples were collected to get their biochemical indexes. Genotyping was performed by TaqMan to identify rs5516 polymorphisms of kallikrein-1. Statistical method were then utilized to determine the possible relationship between rs5516 single nucleotide polymorphism and the risk of dyslipidemia or levels of serum lipids. Results: In the analysis of relationship between rs5516 and dyslipidemia, the genotype distribution was in accordance with Hardy-Weinberg equilibrium in the control group. In the case group, genotype frequencies for CC\\CG\\GG were 3.1%\\38.8%\\58.1% respectively, while the genotype frequencies for CC\\CG\\GG were 4.9%\\29.8%\\65.2% among control individuals, and the difference was statistically significant(P=0.042). The frequencies for allele C\\allele G were 22.5%\\77.5% in cases, and the frequencies were 19.8%\\80.2% in controls, suggesting there was no significant difference between the two groups in terms of allele distribution. After adjusting confounding factors which might influence the level of serum lipids, we could not find any statistically significant association between rs5516 polymorphism and dyslipidemia in allele comparison, additive genetic model, dominant genetic model, recessive genetic model or homozygote comparison. In subgroup analysis, there was no statistical significance found, either. We further classified participants with dyslipidemia into hypercholesterolemia group, hypertriglyceridemia group, mixed hyperlipidemia group or low HDL-C group, and no significant results were deduced. In the analysis of relation between rs5516 and levels of serum lipids, any of these lipid indexes showed no statistically significant difference in different genotypes, and there was no significant finding in the process of multiple linear regression analysis. Furthermore, resembling results were reached in subgroup analysis. Conclusions: The conclusion can be drawn that single nucleotide polymorphism rs5516 on the gene kallikrein-1 might be in no association with the risk of dyslipidemia and have too little impact on levels of serum lipid indexes.
引文
[1] 诸骏仁,高润霖,赵水平,等. 中国成人血脂异常防治指南(2016年修订版)[J]. 中国循环杂志,2016(10):937-953.
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[7] Damas J, Garbacki N, Lefebvre PJ. The kallikrein-kinin system, angiotensin converting enzyme inhibitors and insulin sensitivity[J]. Diabetes Metab Res Rev,2004,20(4):288-297.
[8] Jiang S, Hsu YH, Venners SA, et al. Effects of protein coding polymorphisms in the kallikrein 1 gene on baseline blood pressure and antihypertensive response to irbesartan in Chinese hypertensive patients[J]. J Hum Hypertens,2011,25(5):327-333.
[9] Liu J, Wang L, Liu Y, et al. The association between endothelial nitric oxide synthase gene G894T polymorphism and hypertension in Han Chinese: a case-control study and an updated meta-analysis[J]. Ann Hum Biol,2015,42(2):184-194.
[10] 金永鑫,李闯,刘洁琳,等. Mfn2基因SNP位点rs17037564与肥胖型高血压的相关性研究[J]. 心肺血管病杂志,2018,37(03):244-247.
[11] 刘洁琳,张蓓,李梅,等. β3肾上腺素能受体基因Trp64Arg多态性与肥胖和血脂水平的相关性[J]. 中华医学杂志; National Medical Journal of China,2015(20):1558-1562.
[12] 刘力生. 中国高血压防治指南2010[J]. 中华高血压杂志,2011(08):701-743.
[13] Zhao W, Wang L, Lu X, et al. A coding polymorphism of the kallikrein 1 gene is associated with essential hypertension: a tagging SNP-based association study in a Chinese Han population[J]. J Hypertens,2007,25(9):1821-1827.
[14] Kellermeyer RW, Graham RJ. Kinins--possible physiologic and pathologic roles in man[J]. N Engl J Med,1968,279(14):754-759.
[15] Kaplan AP, Joseph K, Silverberg M. Pathways for bradykinin formation and inflammatory disease[J]. J Allergy Clin Immunol,2002,109(2):195-209.
[16] Kellermeyer RW, Graham RJ. Kinins--possible physiologic and pathologic roles in man[J]. N Engl J Med,1968,279(16):859-866.
[17] Rett K, Wicklmayr M, Dietze GJ, et al. Insulin-induced glucose transporter (GLUT1 and GLUT4) translocation in cardiac muscle tissue is mimicked by bradykinin[J]. Diabetes,1996,45 Suppl 1:S66-S69.
[18] Zhao C, Wang P, Xiao X, et al. Gene therapy with human tissue kallikrein reduces hypertension and hyperinsulinemia in fructose-induced hypertensive rats[J]. Hypertension,2003,42(5):1026-1033.
[19] Potier L, Waeckel L, Fumeron F, et al. Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man[J]. J Endocrinol,2014,221(2):297-308.
[20] Slim R, Torremocha F, Moreau T, et al. Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity[J]. J Am Soc Nephrol,2002,13(4):968-976.
[21] Biros E, Norman PE, Walker PJ, et al. A single nucleotide polymorphism in exon 3 of the kallikrein 1 gene is associated with large but not small abdominal aortic aneurysm[J]. Atherosclerosis,2011,217(2):452-457.
[22] Ordovas JM, Robertson R, Cleirigh EN. Gene-gene and gene-environment interactions defining lipid-related traits[J]. Curr Opin Lipidol,2011,22(2):129-136.
[23] Rideout TC, Harding SV, Jones PJ. Consumption of plant sterols reduces plasma and hepatic triglycerides and modulates the expression of lipid regulatory genes and de novo lipogenesis in C57BL/6J mice[J]. Mol Nutr Food Res,2010,54 Suppl 1:S7-S13.
[24] Rothschild AM, Melo VL, Reis ML, et al. Kininogen and prekallikrein increases in the blood of streptozotocin-diabetic rats are normalized by insulin in vivo and in vitro[J]. Naunyn Schmiedebergs Arch Pharmacol,1999,360(2):217-220.
[25] Mori MA, Araujo RC, Reis FC, et al. Kinin B1 receptor deficiency leads to leptin hypersensitivity and resistance to obesity[J]. Diabetes,2008,57(6):1491-1500.
[2] 刘静,赵冬,秦兰萍,等. 低密度脂蛋白胆固醇与心血管病发病关系的前瞻性研究[J]. 中华心血管病杂志,2001(09):52-56.
[3] 王薇,赵冬,刘静,等. 中国35～64岁人群胆固醇水平与10年心血管病发病危险的前瞻性研究[J]. 中华心血管病杂志,2006(02):169-173.
[4] Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study[J]. JAMA,1986,256(20):2835-2838.
[5] 王伟,周玉杰,王绿娅. 2016版欧洲血脂异常管理新指南解读[J]. 心肺血管病杂志,2017(3):230-233.
[6] Aguilar SC, Zamora M, Gomez-Diaz RA, et al. Familial combined hyperlipidemia: controversial aspects of its diagnosis and pathogenesis[J]. Semin Vasc Med,2004,4(2):203-209.
[7] Damas J, Garbacki N, Lefebvre PJ. The kallikrein-kinin system, angiotensin converting enzyme inhibitors and insulin sensitivity[J]. Diabetes Metab Res Rev,2004,20(4):288-297.
[8] Jiang S, Hsu YH, Venners SA, et al. Effects of protein coding polymorphisms in the kallikrein 1 gene on baseline blood pressure and antihypertensive response to irbesartan in Chinese hypertensive patients[J]. J Hum Hypertens,2011,25(5):327-333.
[9] Liu J, Wang L, Liu Y, et al. The association between endothelial nitric oxide synthase gene G894T polymorphism and hypertension in Han Chinese: a case-control study and an updated meta-analysis[J]. Ann Hum Biol,2015,42(2):184-194.
[10] 金永鑫,李闯,刘洁琳,等. Mfn2基因SNP位点rs17037564与肥胖型高血压的相关性研究[J]. 心肺血管病杂志,2018,37(03):244-247.
[11] 刘洁琳,张蓓,李梅,等. β3肾上腺素能受体基因Trp64Arg多态性与肥胖和血脂水平的相关性[J]. 中华医学杂志; National Medical Journal of China,2015(20):1558-1562.
[12] 刘力生. 中国高血压防治指南2010[J]. 中华高血压杂志,2011(08):701-743.
[13] Zhao W, Wang L, Lu X, et al. A coding polymorphism of the kallikrein 1 gene is associated with essential hypertension: a tagging SNP-based association study in a Chinese Han population[J]. J Hypertens,2007,25(9):1821-1827.
[14] Kellermeyer RW, Graham RJ. Kinins--possible physiologic and pathologic roles in man[J]. N Engl J Med,1968,279(14):754-759.
[15] Kaplan AP, Joseph K, Silverberg M. Pathways for bradykinin formation and inflammatory disease[J]. J Allergy Clin Immunol,2002,109(2):195-209.
[16] Kellermeyer RW, Graham RJ. Kinins--possible physiologic and pathologic roles in man[J]. N Engl J Med,1968,279(16):859-866.
[17] Rett K, Wicklmayr M, Dietze GJ, et al. Insulin-induced glucose transporter (GLUT1 and GLUT4) translocation in cardiac muscle tissue is mimicked by bradykinin[J]. Diabetes,1996,45 Suppl 1:S66-S69.
[18] Zhao C, Wang P, Xiao X, et al. Gene therapy with human tissue kallikrein reduces hypertension and hyperinsulinemia in fructose-induced hypertensive rats[J]. Hypertension,2003,42(5):1026-1033.
[19] Potier L, Waeckel L, Fumeron F, et al. Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man[J]. J Endocrinol,2014,221(2):297-308.
[20] Slim R, Torremocha F, Moreau T, et al. Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity[J]. J Am Soc Nephrol,2002,13(4):968-976.
[21] Biros E, Norman PE, Walker PJ, et al. A single nucleotide polymorphism in exon 3 of the kallikrein 1 gene is associated with large but not small abdominal aortic aneurysm[J]. Atherosclerosis,2011,217(2):452-457.
[22] Ordovas JM, Robertson R, Cleirigh EN. Gene-gene and gene-environment interactions defining lipid-related traits[J]. Curr Opin Lipidol,2011,22(2):129-136.
[23] Rideout TC, Harding SV, Jones PJ. Consumption of plant sterols reduces plasma and hepatic triglycerides and modulates the expression of lipid regulatory genes and de novo lipogenesis in C57BL/6J mice[J]. Mol Nutr Food Res,2010,54 Suppl 1:S7-S13.
[24] Rothschild AM, Melo VL, Reis ML, et al. Kininogen and prekallikrein increases in the blood of streptozotocin-diabetic rats are normalized by insulin in vivo and in vitro[J]. Naunyn Schmiedebergs Arch Pharmacol,1999,360(2):217-220.
[25] Mori MA, Araujo RC, Reis FC, et al. Kinin B1 receptor deficiency leads to leptin hypersensitivity and resistance to obesity[J]. Diabetes,2008,57(6):1491-1500.