Correlation between <i>CYP2C19</i> gene polymorphism and heart failure pathogenesis and prognosis_West China Medical Journal

Authors：

YONG Jiahui ^1,2 , TAO Jing ^1,2 , LI Xia ³ , WANG Kaiyang ^1,2 ,  YANG Yining ^1,2

1. Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830000, P. R. China;
2. Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi 830000, P. R. China;
3. Department of Radiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830011, P. R. China;

Corresponding author：

YANG Yining, Email: yangyn5126@163.com

Keywords：

Heart failure; CYP2C19; gene polymorphism; genomic analysis

DOI：

10.7507/1002-0179.202404197

Video：

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Objective To investigate the correlation between CYP2C19 gene polymorphisms and the incidence and prognosis of heart failure. Methods 1 368 patients who underwent parallel genomic testing and visited the Department of Cardiology at the People’s Hospital of Xinjiang Uygur Autonomous Region between June 2021 and December 2022 were selected. After quality control of genotype data, the patients were divided into a heart failure group and a control group based on diagnostic criteria. Genotyping of 31 genes and 62 single nucleotide polymorphism (SNPs) was performed using TaqMan-SNP genotyping technology. Differences in allele distribution and clinical indicators between the two groups were compared, and the incidence of cardiovascular adverse events in the heart failure group was followed up and calculated. Results A total of 1 352 patients were included. Among them, there were 169 cases in the heart failure group and 1 183 cases in the control group. At the rs12769205 locus of the CYP2C19 gene, the risk of disease for patients carrying the G allele was lower than those carrying the A allele (odds ratio=0.733, P=0.023). In addition to age, coronary heart disease, BMI, and the type of allele was also an independent influencing factor for heart failure (P＜0.05). Moreover, the level of cardiac troponin T in carriers of two mutant alleles was significantly higher than in carriers of one mutant allele (P =0.044) and in carriers of the wild-type allele (P=0.028). During the follow-up period, no significant differences were observed in the cumulative incidence of major cardiovascular adverse events among the three genotypes at the rs12769205 locus. Conclusion The polymorphic locus rs12769205 of the CYP2C19 gene is associated with the occurrence of heart failure, which may provide a theoretical basis for the diagnosis and treatment of heart failure.

Citation： YONG Jiahui, TAO Jing, LI Xia, WANG Kaiyang, YANG Yining. Correlation between CYP2C19 gene polymorphism and heart failure pathogenesis and prognosis. West China Medical Journal, 2024, 39(9): 1398-1405. doi: 10.7507/1002-0179.202404197 Copy

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2.	Zhang Y, Zhang J, Butler J, et al. Contemporary epidemiology, management, and outcomes of patients hospitalized for heart failure in China: results from the China heart failure (China-HF) registry. J Card Fail, 2017, 23(12): 868-875.
3.	Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther, 2013, 138(1): 103-141.
4.	Zordoky BN, El-Kadi AO. Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases. Pharmacol Ther, 2010, 125(3): 446-463.
5.	Michaelis UR, Fleming I. From endothelium-derived hyperpolarizing factor (EDHF) to angiogenesis: epoxyeicosatrienoic acids (EETs) and cell signaling. Pharmacol Ther, 2006, 111(3): 584-595.
6.	Yang TH, Kon M, DeLisi C. Genome-wide association studies. Methods Mol Biol, 2013, 939: 233-251.
7.	Thibord F, Klarin D, Brody JA, et al. Cross-ancestry investigation of venous thromboembolism genomic predictors. Circulation, 2022, 146(16): 1225-1242.
8.	Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet, 2018, 50(9): 1234-1239.
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10.	Roger VL, Go AS, Lloyd-Jones DM, et al. Executive summary: heart disease and stroke statistics-2012 update: a report from the American heart association. Circulation, 2012, 125(1): 188-197.
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13.	Reynolds HR, Shaw LJ, Min JK, et al. Outcomes in the ISCHEMIA trial based on coronary artery disease and ischemia severity. Circulation, 2021, 144(13): 1024-1038.
14.	Elbekai RH, El-Kadi AO. Cytochrome P450 enzymes: central players in cardiovascular health and disease. Pharmacol Ther, 2006, 112(2): 564-587.
15.	Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev, 2002, 82(1): 131-185.
16.	Gebremedhin D, Ma YH, Falck JR, et al. Mechanism of action of cerebral epoxyeicosatrienoic acids on cerebral arterial smooth muscle. Am J Physiol, 1992, 263(2 Pt 2): H519-H525.
17.	Node K, Huo Y, Ruan X, et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science, 1999, 285(5431): 1276-1279.
18.	Guengerich FP. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol, 2001, 14(6): 611-650.
19.	Kala P, Hnat T, Padrova K, et al. Eicosanoids in human heart failure: pilot study of plasma epoxyeicosatrienoic and dihydroxyeicosatrienoic acid levels. Arch Med Sci. 2023, 19(2): 513-517.
20.	Qiu H, Li N, Liu JY, et al. Soluble epoxide hydrolase inhibitors and heart failure. Cardiovasc Ther, 2011, 29(2): 99-111.
21.	Yu Z, Xu F, Huse LM, et al. Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ Res, 2000, 87(11): 992-998.
22.	Metra M, Tomasoni D, Adamo M, et al. Worsening of chronic heart failure: definition, epidemiology, management and prevention. A clinical consensus statement by the heart failure association of the European society of cardiology. Eur J Heart Fail, 2023, 25(6): 776-791.
23.	Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart, 2007, 93(9): 1137-1146.
24.	Bustamante M, Garate-Carrillo A, R Ito B, et al. Unmasking of oestrogen-dependent changes in left ventricular structure and function in aged female rats: a potential model for pre-heart failure with preserved ejection fraction. J Physiol, 2019, 597(7): 1805-1817.
25.	Lentine KL, Rocca-Rey LA, Bacchi G, et al. Obesity and cardiac risk after kidney transplantation: experience at one center and comprehensive literature review. Transplantation, 2008, 86(2): 303-312.
26.	Lauer MS, Anderson KM, Kannel WB, et al. The impact of obesity on left ventricular mass and geometry. The framingham heart study. JAMA, 1991, 266(2): 231-236.
27.	Pocock SJ, Ferreira JP, Packer M, et al. Biomarker-driven prognostic models in chronic heart failure with preserved ejection fraction: the EMPEROR-preserved trial. Eur J Heart Fail, 2022, 24(10): 1869-1878.
28.	Fang KM, Lee AS, Su MJ, et al. Free fatty acids act as endogenous ionophores, resulting in Na⁺ and Ca²⁺ influx and myocyte apoptosis. Cardiovasc Res, 2008, 78(3): 533-545.
29.	Chen M, Zheng YY, Song YT, et al. Pretreatment with low-dose gadolinium chloride attenuates myocardial ischemia/reperfusion injury in rats. Acta Pharmacol Sin, 2016, 37(4): 453-462.
30.	Fritsche LG, Patil S, Beesley LJ, et al. Cancer PRSweb: an online repository with polygenic risk scores for major cancer traits and their evaluation in two independent biobanks. Am J Hum Genet, 2020, 107(5): 815-836.
31.	Muse ED, Chen SF, Torkamani A. Monogenic and polygenic models of coronary artery disease. Curr Cardiol Rep, 2021, 23(8): 107.

1. Hao G, Wang X, Chen Z, et al. Prevalence of heart failure and left ventricular dysfunction in China: the China hypertension survey, 2012‐2015. Eur J Heart Fail, 2019, 21(11): 1329‐1337.
2. Zhang Y, Zhang J, Butler J, et al. Contemporary epidemiology, management, and outcomes of patients hospitalized for heart failure in China: results from the China heart failure (China-HF) registry. J Card Fail, 2017, 23(12): 868-875.
3. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther, 2013, 138(1): 103-141.
4. Zordoky BN, El-Kadi AO. Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases. Pharmacol Ther, 2010, 125(3): 446-463.
5. Michaelis UR, Fleming I. From endothelium-derived hyperpolarizing factor (EDHF) to angiogenesis: epoxyeicosatrienoic acids (EETs) and cell signaling. Pharmacol Ther, 2006, 111(3): 584-595.
6. Yang TH, Kon M, DeLisi C. Genome-wide association studies. Methods Mol Biol, 2013, 939: 233-251.
7. Thibord F, Klarin D, Brody JA, et al. Cross-ancestry investigation of venous thromboembolism genomic predictors. Circulation, 2022, 146(16): 1225-1242.
8. Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet, 2018, 50(9): 1234-1239.
9. Mancia G, Kreutz R, Brunström M, et al. 2023 ESH Guidelines for the management of arterial hypertension the task force for the management of arterial hypertension of the European society of hypertension: endorsed by the international society ofhypertension (ISH) and the European renal association (ERA). J Hypertens, 2023, 41(12): 1874-2071.
10. Roger VL, Go AS, Lloyd-Jones DM, et al. Executive summary: heart disease and stroke statistics-2012 update: a report from the American heart association. Circulation, 2012, 125(1): 188-197.
11. US Preventive Services Task Force; Davidson KW, Barry MJ, et al. Screening for prediabetes and type 2 diabetes: US preventive services task force recommendation statement. JAMA, 2021, 326(8): 736-743.
12. Tao J, Abudoukelimu M, Shen X, et al. Investigation of the association between obesity and insulin-induced gene 1 polymorphism at 7q36. 3 region in Uygur population in Xinjiang, China. Biosci Rep, 2019, 39(12): BSR20190498.
13. Reynolds HR, Shaw LJ, Min JK, et al. Outcomes in the ISCHEMIA trial based on coronary artery disease and ischemia severity. Circulation, 2021, 144(13): 1024-1038.
14. Elbekai RH, El-Kadi AO. Cytochrome P450 enzymes: central players in cardiovascular health and disease. Pharmacol Ther, 2006, 112(2): 564-587.
15. Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev, 2002, 82(1): 131-185.
16. Gebremedhin D, Ma YH, Falck JR, et al. Mechanism of action of cerebral epoxyeicosatrienoic acids on cerebral arterial smooth muscle. Am J Physiol, 1992, 263(2 Pt 2): H519-H525.
17. Node K, Huo Y, Ruan X, et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science, 1999, 285(5431): 1276-1279.
18. Guengerich FP. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol, 2001, 14(6): 611-650.
19. Kala P, Hnat T, Padrova K, et al. Eicosanoids in human heart failure: pilot study of plasma epoxyeicosatrienoic and dihydroxyeicosatrienoic acid levels. Arch Med Sci. 2023, 19(2): 513-517.
20. Qiu H, Li N, Liu JY, et al. Soluble epoxide hydrolase inhibitors and heart failure. Cardiovasc Ther, 2011, 29(2): 99-111.
21. Yu Z, Xu F, Huse LM, et al. Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ Res, 2000, 87(11): 992-998.
22. Metra M, Tomasoni D, Adamo M, et al. Worsening of chronic heart failure: definition, epidemiology, management and prevention. A clinical consensus statement by the heart failure association of the European society of cardiology. Eur J Heart Fail, 2023, 25(6): 776-791.
23. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart, 2007, 93(9): 1137-1146.
24. Bustamante M, Garate-Carrillo A, R Ito B, et al. Unmasking of oestrogen-dependent changes in left ventricular structure and function in aged female rats: a potential model for pre-heart failure with preserved ejection fraction. J Physiol, 2019, 597(7): 1805-1817.
25. Lentine KL, Rocca-Rey LA, Bacchi G, et al. Obesity and cardiac risk after kidney transplantation: experience at one center and comprehensive literature review. Transplantation, 2008, 86(2): 303-312.
26. Lauer MS, Anderson KM, Kannel WB, et al. The impact of obesity on left ventricular mass and geometry. The framingham heart study. JAMA, 1991, 266(2): 231-236.
27. Pocock SJ, Ferreira JP, Packer M, et al. Biomarker-driven prognostic models in chronic heart failure with preserved ejection fraction: the EMPEROR-preserved trial. Eur J Heart Fail, 2022, 24(10): 1869-1878.
28. Fang KM, Lee AS, Su MJ, et al. Free fatty acids act as endogenous ionophores, resulting in Na⁺ and Ca²⁺ influx and myocyte apoptosis. Cardiovasc Res, 2008, 78(3): 533-545.
29. Chen M, Zheng YY, Song YT, et al. Pretreatment with low-dose gadolinium chloride attenuates myocardial ischemia/reperfusion injury in rats. Acta Pharmacol Sin, 2016, 37(4): 453-462.
30. Fritsche LG, Patil S, Beesley LJ, et al. Cancer PRSweb: an online repository with polygenic risk scores for major cancer traits and their evaluation in two independent biobanks. Am J Hum Genet, 2020, 107(5): 815-836.
31. Muse ED, Chen SF, Torkamani A. Monogenic and polygenic models of coronary artery disease. Curr Cardiol Rep, 2021, 23(8): 107.

West China Medical Journal

Correlation between CYP2C19 gene polymorphism and heart failure pathogenesis and prognosis

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