Related gene analysis of atherosclerotic cardiovascular disease high risk population based on gene chip detection
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摘要: 目的 通过比较分析动脉粥样硬化性心血管疾病(ASCVD)高风险人群与健康人群相关的基因多态性差异，探讨ASCVD相关的发病机制。方法 选择2019年6月—2020年5月于四川省人民医院心内科门诊和住院治疗的患者，进行总体心血管危险评估，纳入危险分层为极高危和高危患者203例(病例组)；另选择同期排除了慢性心脑血管疾病的健康体检者74例(对照组)。提取全血基因组DNA，采用针对东亚人群的Illumina ASA芯片进行基因组扫描，根据基因组数据库定位相关基因。比较两组人群在相关基因位点上不同基因型的分布情况，采用logistic回归分析相关基因位点与ASCVD的关系。结果 通过Illumina ASA芯片检测到的与ASCVD可能有关的CYP21A2、ACVRL1、COL3A1、SCN5A、KCNA5、LDLR、PCSK9基因的突变位点中≥3例的位点包括：rs6467、rs202242769、rs121909285、rs587779580、rs1805124、rs121908591、rs13306515、rs11583680。其中CYP21A2基因的rs6467、PCSK9基因的rs11583680、SCN5A基因的rs1805124(均P< 0.001)，病例组与对照组人群的基因型分布差异有统计学意义。高血压亚组患者和对照组人群在rs6467和rs11583680位点上的基因型分布差异有统计学意义(P< 0.001)。在校正混杂因素(年龄、性别、BMI、吸烟和体育锻炼)后，多因素logistic回归分析结果显示，与PCSK9基因位点rs11583680位点的CC基因型相比，C等位基因突变(CT+TT基因型)是ASCVD(OR=0.07，95%CI：0.008~0.68，P=0.02)及高血压(OR=0.045，95%CI：0.01~0.95，P=0.045)的保护性因素。结论 PCSK9基因的rs11583680位点与ASCVD有关。
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关键词:
- 动脉粥样硬化性心血管疾病 /
- 高血压 /
- 基因芯片 /
- 单核苷酸多态性
Abstract: Objective To explore the possible pathogenic mechanism of atherosclerotic cardiovascular disease(ASCVD) by comparing and analyzing the genetic polymorphisms between ASCVD high risk groups and healthy people.Methods Patients who were treated in the Sichuan Provincial People's Hospital from June 2019 to May 2020 were selected for the ASCVD overall risk assessment, and 203 patients with extremely high risk and high risk were included in the case group. Other 74 healthy subjects excluded from chronic cardiovascular and cerebrovascular diseases in the same period were selected into the control group. Genomic DNA was extracted from whole blood, and genome scanning was performed using Illumina ASA chip for East Asian populations, and relevant genes were located according to the genome database. The distribution of different genotypes at relevant gene loci was compared between the two groups, and the relationship between relevant gene loci and ASCVD was analyzed by logistic regression.Results Among the mutation sites of CYP21A2, ACVRL1, COL3A1, SCN5A, KCNA5, LDLR, and PCSK9 genes that may be related to ASCVD detected by the Illumina ASA chip, the sites with ≥ 3 cases included rs6467, rs202242769, rs121909285, rs587779580, rs1805124, rs121908591, rs13306515, and rs11583680. The genotype distribution differences in rs6467 at CYP21A2, rs11583680 at PCSK9, and rs1805124 at SCN5A(allP< 0.001) between the case group and the control group was statistically significant. The genotype distributions of rs6467 and rs11583680 between the hypertensive subgroup and the control group were statistically significant(P< 0.001). After adjusting for confounding factors(age, sex, BMI, smoking, and physical exercise), multivariate logistic regression analysis showed that the C allele mutation(CT + TT genotype) was a protective factor for ASCVD(OR=0.07, 95%CI: 0.008-0.68,P=0.02) and hypertension(OR=0.045, 95%CI: 0.01-0.95,P=0.045) compared with CC genotype at rs11583680 of PCSK9 locus.Conclusion rs11583680 at the PCSK9 gene may be associated with ASCVD -
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表 1 与ASCVD和(或)高血压可能相关的单核苷酸多态性位点
Table 1. SNPs that may associated with ASCVD and/or hypertension
SNP 染色体 位点 基因 野生型 等位基因 功能 rs6467 6 632039081 CYP21A2 CC C/G 编码21羟化酶[6-7] rs202242769 6 32040723 CYP21A2 GG G/A rs121909285 12 51913187 ACVRL1 GG G/T 影响TGF-β通路，导致内皮细胞和平滑肌细胞功能障碍[8] rs587779580 2 189004338 COL3A1 GG G/A 编码3型胶原蛋白α1链[9] rs1805124 3 38603929 SCN5A TT T/C 编码钠通道Nav1.5 α亚基，受血清和糖皮质激素诱导激酶(SGK1)调控，SGK1与血压等有关[10-11] rs121908591 12 5045727 KCNA5 CC C/T 调节钾离子稳态，可能参与调控PCSK9的表达[12-13] rs13306515 19 11110767 LDLR CC C/A 影响血脂代谢 rs11583680 1 55039995 PCSK9 CC C/T 失功能性突变，可能降低血浆胆固醇浓度 
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表 2 病例组与对照组突变位点的比较
Table 2. Detected SNPs in ASCVD group and control group
位点 对照组(74例)突变型/野生型 病例组(203例)突变型/野生型 χ2 P值 rs6467 0/74 29/174 11.81 ＜0.001 rs202242769 0/74 3/200 0.16 0.690 rs121909285 0/74 5/198 0.73 0.390 rs587779580 0/74 5/198 0.73 0.390 rs1805124 6/68 0/203 13.22 ＜0.001 rs121908591 1/73 3/200 0.24 0.620 rs13306515 3/71 0/203 4.97 0.026 rs11583680 8/66 1/202 15.23 ＜0.001
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表 3 高血压亚组与对照组突变位点比较
Table 3. Detected SNPs in hypertension subgroup and control group
位点 对照组(74例)突变型/野生型 高血压亚组(167例)突变型/野生型 χ2 P值 rs6467 0/74 25/142 12.36 ＜0.001 rs11583680 8/66 1/166 12.17 ＜0.001 rs1805124 6/68 0/167 10.75 0.001
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表 4 高脂血症亚组与对照组突变位点比较
Table 4. Detected SNPs in hyperlipidemia subgroup and control group
位点 对照组(74例)突变型/野生型 高脂血症亚组(68例)突变型/野生型 χ2 P值 rs6467 0/74 10/58 9.568 0.002 rs11583680 8/66 0/68 5.89 0.015 rs1805124 6/68 0/68 3.93 0.048
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表 5 ASCVD相关基因位点的logistic回归分析
Table 5. Risk factors of ASCVD analyzed by logistic regression analysis
位点 类型 例数 B SE Wals P值 OR值 95% CI rs6467 CC 243 1.00 CG+GG 29 20.03 6564.82 0.00 0.998 < 0.001 rs11583680 CC 263 1.00 CT+TT 9 -2.61 1.14 5.28 0.02 0.07 0.008~0.68 rs1805124 CC 268 1.00 CT 4 -21.68 18565.87 0.00 0.999 0.00
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表 6 高血压相关基因位点的logistic回归分析
Table 6. Risk factors of hypertension analyzed by logistic regression analysis
位点 类型 例数 B SE Wals P值 OR值 95% CI rs6467 CC 211 1.00 CG+GG 24 20.50 6957.64 0.00 0.998 < 0.001 rs11583680 CC 226 1.00 CT+TT 9 -2.287 1.14 4.00 0.045 0.10 0.01~0.95
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[1] 中国心血管健康与疾病报告2019[J]. 心肺血管病杂志, 2020, 39(10): 1157-1162.
[2] 中华医学会心血管病学分会, 中国康复医学会心脏预防与康复专业委员会, 中国老年学和老年医学会心脏专业委员会, 等. 中国心血管病一级预防指南[J]. 中华心血管病杂志, 2020, 48 (12): 1000-1038. doi: 10.3760/cma.j.cn112148-20201009-00796
[3] Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel[J]. Eur Heart J, 2020, 41(24): 2313-2330. doi: 10.1093/eurheartj/ehz962
[4] 中国心血管病风险评估和管理指南编写联合委员会. 中国心血管病风险评估和管理指南[J]. 中华预防医学杂志, 2019, 53(1): 13-35. doi: 10.3760/cma.j.issn.0253-9624.2019.01.004
[5] 中国成人血脂异常防治指南修订联合委员会. 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, 31(10): 937-953. doi: 10.3969/j.issn.1000-3614.2016.10.001
[6] Lu XF, Wang LY, Lin X, et al. Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension[J]. Hum Mol Genet, 2015, 24(3): 865-874. doi: 10.1093/hmg/ddu478
[7] Falhammar H, Nordenstrom A. Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome[J]. Endocrine, 2015, 50(1): 32-50. doi: 10.1007/s12020-015-0656-0
[8] González-Núñez M, Muñoz-Félix JM, López-Novoa JM. The ALK-1/Smad1 pathway in cardiovascular physiopathology. A new target for therapy?[J]. Biochim Biophys Acta, 2013, 1832(10): 1492-510. doi: 10.1016/j.bbadis.2013.05.016
[9] Yim J, Cho H, Rabkin SW. Gene expression and gene associations during the development of heart failure with preserved ejection fraction in the Dahl salt sensitive model of hypertension[J]. Clin Exp Hypertens, 2018, 40(2): 155-166. doi: 10.1080/10641963.2017.1346113
[10] Lang F, Shumilina E. Regulation of ion channels by the serum- and glucocorticoid-inducible kinase SGK1[J]. FASEB J, 2013, 27(1): 3-12. doi: 10.1096/fj.12-218230
[11] Lang F, Voelkl J. Therapeutic potential of serum and glucocorticoid inducible kinase inhibition[J]. Expert Opin Investig Drugs, 2013, 22(6): 701-714 doi: 10.1517/13543784.2013.778971
[12] Mirchi LF, Chylíková B, Jankü M, et al. Transcriptomic analysis of left ventricle myocardium in an SHR congenic line with ameliorated cardiac fibrosis[J]. Physiol Res, 2019, 68(5): 747-755.
[13] Bensenor I, Padilha K, Lima IR, et al. Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study[J]. Front Genet, 2021, 12: 728526. doi: 10.3389/fgene.2021.728526
[14] 方明华, 杨丽丽, 吕文山, 家族性高胆固醇血症分子遗传学机制及干预进展[J]. 国际遗传学杂志, 2019, 42 (3): 234-239. doi: 10.3760/cma.j.issn.1673-4386.2019.03.009
[15] 陆言巧, 沈兰, 何奔. PCSK9抑制剂的机制及其临床进展[J]. 临床心血管病杂志, 2020, 36(1): 14-19. https://www.cnki.com.cn/Article/CJFDTOTAL-LCXB202001003.htm
[16] 彭道泉, 杨阳. 血脂管理与ASCVD的回顾与展望[J]. 临床心血管病杂志, 2020, 36(9): 783-786. https://www.cnki.com.cn/Article/CJFDTOTAL-LCXB202009001.htm
[17] Dron JS, Hegele RA. Complexity of mechanisms among human proprotein convertase subtilisin-kexin type 9 variants[J]. Curr Opin Lipidol, 2017, 28(2): 161-169. doi: 10.1097/MOL.0000000000000386
[18] Small AM, Huffman JA, Klarin D, et al. PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort[J]. PLoS One, 2020, 15(11): e0239752. doi: 10.1371/journal.pone.0239752
[19] Mefford MT, Marcovina SM, Bittner V, et al. PCSK9 loss-of-function variants and Lp(a) phenotypes among black US adults[J]. J Lipid Res, 2019, 60(11): 1946-1952. doi: 10.1194/jlr.P119000173
[20] Kent ST, Rosenson RS, Avery CL, et al. PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites[J]. Circ Cardiovasc Genet, 2017, 10(4): e001632.
[21] Schmidt AF, Swerdlow DI, Holmes MV, et al. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study[J]. Lancet Diabetes Endocrinol, 2017, 5(2): 97-105. doi: 10.1016/S2213-8587(16)30396-5
[22] Wu NQ, Li JJ. PCSK9 gene mutations and low-density lipoprotein cholesterol[J]. Clin Chim Acta, 2014, 431: 148-153. doi: 10.1016/j.cca.2014.01.043
[23] Lacaze P, Riaz M, Sebra R, et al. Protective lipid-lowering variants in healthy older individuals without coronary heart disease[J]. Open Heart, 2021, 8(2).
[24] Tran NT, Aslibekyan S, Tiwari HK, et al. PCSK9 variation and association with blood pressure in African Americans: preliminary findings from the HyperGEN and REGARDS studies[J]. Front Genet, 2015, 6: 136.
[25] Berger JM, Vaillant N, Le May C, et al. PCSK9-deficiency does not alter blood pressure and sodium balance in mouse models of hypertension[J]. Atherosclerosis, 2015, 239(1): 252-259.
[26] Hypertensive Group of Chinese Society of Cardiology of Chinese Medical, Editorial Board of Chinese Journal of Cardiology. Expert consensus on the comprehensive management of blood pressure and dyslipidemia in Chinese hypertensive patients[J]. Zhonghua Xin Xue Guan Bing Za Zhi, 2021, 49(6): 554-563.
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