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Volume 17 Issue 10
Nov.  2020
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Jie LIU, Ru-Tai HUI, Lei SONG. Precision cardiovascular medicine in China. J Geriatr Cardiol 2020; 17(10): 638-641. doi: 10.11909/j.issn.1671-5411.2020.10.005
Citation: Jie LIU, Ru-Tai HUI, Lei SONG. Precision cardiovascular medicine in China. J Geriatr Cardiol 2020; 17(10): 638-641. doi: 10.11909/j.issn.1671-5411.2020.10.005

Precision cardiovascular medicine in China

doi: 10.11909/j.issn.1671-5411.2020.10.005
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  • Corresponding author: Lei SONG, E-mail: songlqd@126.com
  • Publish Date: 2020-10-28
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  • [1] Chen WW, Gao RL, Liu LS, et al.[Summary report of China cardiovascular disease 2015]. Chinese Circulation Journal 2016; 31: 521-528.[In Chinese].
    [2] World Economic Forum. 3 ways China is leading the way in precision medicine. World Economic Forum of precision medicine Web site. https://www.weforum.org/agenda/2017/11/3-ways-china-is-leading-the-way-in-precision-medicine/ (accessed October 2, 2020).
    [3] Chen Z, Chen J, Collins R, et al. China Kadoorie Biobank of 0.5 million people: survey methods, baseline characteristics and long-term follow-up. Int J Epidemiol 2011; 40: 1652-1666. doi:  10.1093/ije/dyr120
    [4] Liu K, Qin F, Sun X, et al. Analysis of the genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients. J Hypertens 2018; 36: 502-509. doi:  10.1097/HJH.0000000000001556
    [5] Zou Y, Song L, Wang Z, et al. Prevalence of idiopathic hypertrophic cardiomyopathy in China: a population-based echocardiographic analysis of 8080 adults. Am J Med 2004; 116: 14-18. doi:  10.1016/j.amjmed.2003.05.009
    [6] Groth KA, Hove H, Kyhl K, et al. Prevalence, incidence, and age at diagnosis in Marfan syndrome. Orphanet J Rare Dis 2015; 10: 153. doi:  10.1186/s13023-015-0369-8
    [7] Zhu T, Ding Q, Bai X, et al. Normal ranges and genetic variants of antithrombin, protein C and protein S in the general Chinese population. Results of the Chinese Hemostasis Investigation on Natural Anticoagulants Study I Group. Haematologica 2011; 96: 1033-1040. doi:  10.3324/haematol.2010.037515
    [8] Song L, Zou YB, Wang DW, et al.[Guidelines for the diagnosis and treatment for Chinese adult patients with hypertrophic cardiomyopathy]. Zhonghua Xin Xue Guan Bing Za Zhi 2017; 45: 1015-1032.[In Chinese]. http://en.cnki.com.cn/Article_en/CJFDTotal-ZGFB201802002.htm
    [9] Section of Precision Cardiovascular Medicine of Chinese Society of Cardiology, Precision Cardiovascular Medicine Branch of China International Exchange, Promotive Association for Medical, et al.[Guideline for the genetic diagnosis of monogenic cardiovascular diseases]. Zhonghua Xin Xue Guan Bing Za Zhi 2019; 47: 175-196.[In Chinese].
    [10] Wang F, Liu J, Hong L, et al. The phenotype characteristics of type 13 long QT syndrome with mutation in KCNJ5 (Kir3.4-G387R). Heart Rhythm 2013; 10: 1500-1506. doi:  10.1016/j.hrthm.2013.07.022
    [11] Chen L, Song J, Chen X, et al. A novel genotype-based clinicopathology classification of arrhythmogenic cardiomyopathy provides novel insights into disease progression. Eur Heart J 2019; 40: 1690-1703. doi:  10.1093/eurheartj/ehz172
    [12] Duru F, Hauer RNW. Multiple facets of arrhythmogenic cardiomyopathy: the Fuwai classification of a unique disease based on clinical features, histopathology, and genotype. Eur Heart J 2019; 40: 1704-1706. doi:  10.1093/eurheartj/ehz253
    [13] Yan L, Huang L, Xu L, et al. Live births after simultaneous avoidance of monogenic diseases and chromosome abnormality by next-generation sequencing with linkage analyses. Proc Natl Acad Sci USA 2015; 112: 15964-15969. doi:  10.1073/pnas.1523297113
    [14] Sun L, Liang B, Zhu L, et al. The rise of the genetic counseling profession in China. Am J Med Genet C Semin Med Genet 2019; 181: 170-176. doi:  10.1002/ajmg.c.31693
    [15] Lander ES. Cutting the Gordian helix--regulating genomic testing in the era of precision medicine. N Engl J Med 2015; 372: 1185-1186. doi:  10.1056/NEJMp1501964
    [16] Denny JC, Van Driest SL, Wei WQ, et al. The influence of big (clinical) data and genomics on precision medicine and drug development. Clin Pharmacol Ther 2018; 103: 409-418. doi:  10.1002/cpt.951
    [17] Li D, Simon G, Chute CG, et al. Using association rule mining for phenotype extraction from electronic health records. AMIA Jt Summits Transl Sci Proc 2013; 2013: 142-146. http://www.ncbi.nlm.nih.gov/pubmed/24303254
    [18] Li J, Yang W, Xie Z, et al. Impact of VKORC1, CYP4F2 and NQO1 gene variants on warfarin dose requirement in Han Chinese patients with catheter ablation for atrial fibrillation. BMC Cardiovasc Disord 2018; 18: 96. doi:  10.1186/s12872-018-0837-x
    [19] Jia L, Wang Z, Men J, et al. Polymorphisms of VKORC1 and CYP2C9 are associated with warfarin sensitivity in Chinese population. Ther Clin Risk Manag 2017; 13: 421-425. doi:  10.2147/TCRM.S130198
    [20] Wang F, Guo J, Zhang A. Efficacy and safety of genotype-guided warfarin dosing in the Chinese population: a meta-analysis of randomized controlled trials. J Cardiovasc Pharmacol 2019; 73: 127-135. doi:  10.1097/FJC.0000000000000656
    [21] Li H, Zhang YJ, Li MP, et al. Association of N6AMT1 rs2254638 polymorphism with clopidogrel response in Chinese patients with coronary artery disease. Front Pharmacol 2018; 9: 1039. doi:  10.3389/fphar.2018.01039
    [22] Zhuo ZL, Xian HP, Long Y, et al. Association between CYP2C19 and ABCB1 polymorphisms and clopidogrel resistance in clopidogrel-treated Chinese patients. Anatol J Cardiol 2018; 19: 123-129. http://europepmc.org/abstract/MED/29350207
    [23] Li M, Wang H, Xuan L, et al. Associations between P2RY12 gene polymorphisms and risks of clopidogrel resistance and adverse cardiovascular events after PCI in patients with acute coronary syndrome. Medicine (Baltimore) 2017; 96: e6553. doi:  10.1097/MD.0000000000006553
    [24] Shen DL, Wang B, Bai J, et al. Clinical value of CYP2C19 genetic testing for guiding the antiplatelet therapy in a Chinese population. J Cardiovasc Pharmacol 2016; 67: 232-236. doi:  10.1097/FJC.0000000000000337
    [25] Xiang Q, Chen SQ, Ma LY, et al. Association between SLCO1B1 T521C polymorphism and risk of statin-induced myopathy: a meta-analysis. Pharmacogenomics J 2018; 18: 721-729. doi:  10.1038/s41397-018-0054-0
    [26] Zhao M, Wang X, He M, et al. Homocysteine and stroke risk: modifying effect of methylenetetrahydrofolate reductase C677T polymorphism and folic acid intervention. Stroke 2017; 48: 1183-1190. doi:  10.1161/STROKEAHA.116.015324
    [27] Wu D, Li G, Deng M, et al. Associations between ADRB1 and CYP2D6 gene polymorphisms and the response to β-blocker therapy in hypertension. J Int Med Res 2015; 43: 424-434. doi:  10.1177/0300060514563151
    [28] Ji X, Qi H, Li DB, et al. Associations between human aldosterone synthase CYP11B2 (-344T/C) gene polymorphism and antihypertensive response to valsartan in Chinese patients with essential hypertension. Int J Clin Exp Med 2015; 8: 1173-1177. http://pubmedcentralcanada.ca/pmcc/articles/PMC4358565/
    [29] He F, Luo J, Luo Z, et al. The KCNH2 genetic polymorphism (1956, C > T) is a novel biomarker that is associated with CCB and α, β-ADR blocker response in EH patients in China. PLoS One 2013; 8: e61317. doi:  10.1371/journal.pone.0061317
    [30] Zhang YP, Zuo XC, Huang ZJ, et al. CYP3A5 polymorphism, amlodipine and hypertension. J Hum Hypertens 2014; 28: 145-149. doi:  10.1038/jhh.2013.67
    [31] Wang J, Wang Y, Zou Y, et al. Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. Eur J Heart Fail 2014; 16: 950-957. doi:  10.1002/ejhf.144
    [32] Balaresque PL, Ballereau SJ, Jobling MA. Challenges in human genetic diversity: demographic history and adaptation. Hum Mol Genet 2007; 16: R134-R139. doi:  10.1093/hmg/ddm242
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Precision cardiovascular medicine in China

doi: 10.11909/j.issn.1671-5411.2020.10.005
Jie LIU, Ru-Tai HUI, Lei SONG. Precision cardiovascular medicine in China. J Geriatr Cardiol 2020; 17(10): 638-641. doi: 10.11909/j.issn.1671-5411.2020.10.005
Citation: Jie LIU, Ru-Tai HUI, Lei SONG. Precision cardiovascular medicine in China. J Geriatr Cardiol 2020; 17(10): 638-641. doi: 10.11909/j.issn.1671-5411.2020.10.005
  • In mainland China, hospitalization expenses for patients with cardiovascular and cerebrovascular diseases have rapidly increased since 2004 and currently exceed the growth rate of the national gross domestic product.[1] One reason for these high expenses is that the traditional "one-size-for-all" medical model results in low treatment efficacy. Precision and individualized medical models may help reduce the medical burden and provide a sustainable medical model.

  • The essence of precision medicine has long been embodied in the philosophy of traditional Chinese medicine, such as the ideas of bianzhengshizhi, tongbingyizhi, and yibingtongzhi. In recent years, Chinese society has made great efforts to develop precision medicine. The government, academia, enterprises, health care providers, patients and the public are working together to establish precision medicine as the driver of the medical and healthcare system in China. In 2014, the National Health Commission of the People's Republic of China assigned the first high-throughput sequencing technology pilot units for clinical applications in three areas: genetic disease diagnosis, prenatal screening and diagnosis, and preimplantation genetic diagnosis (PGD). The Chinese Central Government launched a precision medicine initiative on July 29, 2015. Immediately, after former U.S. president Obama announced the Precision Medicine Initiative, the "China Precision Medicine" programme, an independent national project, was integrated into the 13th Five-Year National Science and Technology Innovation Plan and the Healthy China 2030 Plan. A total of $9 billion was allocated, compared with $215 million announced for the Precision Medicine Initiative in the United States.[2]

    In the area of genomic data collection and analysis, the Beijing Genome Institute is one of the world's largest sequencers and repositories of genetic material. In early 2017, the China National GeneBank in Shenzhen had over 500 million genetic sequences from over 8, 000 species, stored in more than 40 databases.[2] The Chinese Academy of Medical Sciences collaborated with Oxford University in the UK to launch a study, called the China Kadoorie Biobank, to investigate the main genetic and environmental causes of common chronic diseases among the Chinese population between 2004 and 2008. More than 510, 000 adults were recruited from ten geographically defined regions in China.[3]

    Under the auspices of the China International Exchange and Promotive Association for Medical and Health Care, scientists from various fields of precision medicine, including cardiovascular disease, cerebrovascular disease, genetics, molecular imaging, reproductive medicine, medical statistics, bioinformatics and big data analysis, established a national professional academic organization known as the Precision Cardiovascular Medicine League (PCML). The PCML's goals are to (1) establish a precision-based system for diagnosing cardiovascular diseases (CVDs) for clinical decision making; (2) search for genetic markers, risk factors and targets to improve clinical outcomes, minimize or avoid adverse effects, and guide drug treatment; (3) train personnel and formulate industry standards, norms and guidelines of Chinese precision cardiovascular medicine (PCM); and (4) construct a nationwide network to promote the clinical translation and application of the results of scientific research in precision medicine. During the past four years, the PCML established countrywide PCM collaboration centres and conducted basic and clinical studies on monogenic and polygenic (or complex) CVDs, covering half of the Chinese population.

  • In China, approximately 20 million patients have monogenic CVDs, and at least half of these patients have detectable specific pathogenic mutations.[4-7] The "Guideline for Diagnosis and Treatment of Chinese Adult Hypertrophic Cardiomyopathy" and the "Guideline for Genetic Diagnosis of Monogenic Cardiovascular Disease" were published in 2017 and 2019, respectively.[8, 9] Twenty-three relatively common monogenic CVDs, including a variety of cardiomyopathies, ion channel diseases, monogenic pathogenic hypertension, hereditary diseases of the aorta, familial pulmonary hypertension, hereditary thrombophilia and inherited lipid metabolic abnormalities, were systematically discussed. New precision medicine concepts, such as "gene diagnosis", "genetic interruption" and "genetic counselling", were formally put forward in clinical CVD guidelines for the first time. These guidelines will help promote the use of rational and standardized gene detection methods by hospitals, institutions, and commercial companies throughout China.

    In 2013, researchers from China and other countries identified the type 13 long QT syndrome genotype in a cooperative study.[10] Arrhythmogenic cardiomyopathy has recently been classified based on its clinical features, histopathology and genotype and was named "the Fuwai Classification".[11, 12]

    Diagnosing single-gene diseases and chromosomal aneuploidy usually requires 3-5 cells biopsied from a preimplantation embryo. A team from Peking University developed a new PGD method, known as mutated allele revealed by sequencing with aneuploidy and linkage analyses (MARSALA), which is based on single-cell genome sequencing, to simultaneously detect chromosomal abnormalities and point mutations and perform linkage analyses of single genes.[13] Hundreds of healthy babies, free of known genetic diseases, were born after a PGD using MARSALA.

    Genetic counselling in China remains in its infancy. The genetic counselling profession remains to be established; experienced genetic counsellors are scarce, and the public's awareness of genetic counselling is limited. In recent years, the Chinese Genetic Society has organized training courses and trained more than 4, 000 medical staff members on genetic counselling, but the number of genetic counsellors still does not meet China's clinical needs.[14]

    Some issues in this field remain perplexing, including the dilemma of genotype-phenotype associations due to heterogeneity. Furthermore, the relatively low incidence of monogenic diseases makes it difficult to obtain comprehensive and representative data. With the development of the high-throughput sequencing technology, many "pathogenic mutations" discovered in the past were found to be non-pathogenic single-nucleotide polymorphisms, and multiple gene variants were revealed to be associated with one disease. Thus, stricter requirements are needed to interpret sequencing results. Finally, most genetic testing is conducted in individual centres or by third parties in China, and the results are often difficult to repeat and interpret.[15] Therefore, multicentre, large-scale studies, with long-term follow-ups, big data analysis techniques and shared genomic databases, are crucial.[16, 17]

  • In precision medicine for polygenic (or complex) CVDs, which include coronary heart diseases and hypertension, pharmacogenomics is thus far the most practical and reliable approach. Data from pharmacogenomic studies help guide tailored therapeutics using an individual's genetic makeup, rational drug development and repurposed medications.

    Many studies have demonstrated that the sensitivity to warfarin differs between Chinese and Caucasian populations and that variations in metabolism-related genes can alter the efficacy of warfarin.[18, 19] A meta-analysis of randomized controlled trials found that genotype-guided warfarin dosing algorithms could improve the efficacy and safety of anticoagulation with warfarin.[20] The heritability of a platelet response to clopidogrel has also been found to be highly divergent among individuals and associated with clopidogrel resistance.[21-23] Individual antiplatelet therapy guided by CYP2C19 gene detection was reported to significantly reduce the incidence of major adverse cardiovascular events without increasing bleeding rates in the Chinese population.[24] Implementation of genetic testing has been suggested to prevent statin-induced myopathy, an adverse side effect of statin drugs.[25] Elevated blood homocysteine concentrations increase the risk of stroke, and the methylenetetrahydrofolate reductase (MTHFR) C677T genotype can significantly modify this effect in Chinese hypertensive patients.[26] Many attempts have been made to investigate the association between gene polymorphisms and blood pressure response to antihypertensive drugs, such as β-blockers, angiotensin II receptor blockers and calcium channel blockers.[27-30] However, most clinicians in China do not routinely use pharmacogenomics because of the lack of Chinese data regarding evidence-based medicine.

  • There are several challenges ahead for PCM as follows:

    (1) Ethnic differences. Native Chinese populations exhibit genetic mutation profiles different from those in Western populations.[31] Much of these variations may be due to individual environmental adaptations to pathogens, climate, altitude, diet and possibly cognitive challenges.[32] China has fifty-six ethnic groups with different geographic environments, lifestyles and cultures. Therefore, genomic data of transethnic origins must be evaluated before genomic information can be applied in the clinic.

    (2) Talent training. For clinicians, the amount of data needed for genetic testing is too large, the genomic analysis process is daunting, and the results may be inaccurately interpreted. These issues may discourage clinicians from trying to apply precision medicine-based diagnoses and treatments. Moreover, no national institution exists to conduct formal training, certification and assessment in genomics for clinicians.

    (3) Economic burden. Advances in genomics over the past quarter century have substantially reduced the costs of genome sequencing, but the expense of genetic testing remains too high for many patients (whole-exon sequencing services are commercially available or provided by a university laboratory at a cost of approximately $1, 000). It may be years before China's health insurance and commercial insurances begin covering these tests.

    (4) Propaganda and education. Propaganda and education should be organized to help patients, doctors, researchers, the government and relevant enterprises understand the benefits and disadvantages of precision medicine to broaden the knowledge of PCM and prevent doctors and patients from having unrealistic expectations to prevent "overselling" precision medicine.

  • In China, although there is a long way to go, we firmly believe that making efforts to implement PCM will be fruitful in reducing CVD incidence, mortality and medical costs, bringing new opportunities for early warning and intervention, improving patient's quality of life, and extending their life expectancy.

  • This study was supported by the National Natural Science Foundation of China (No.81870286) and the CAMS Innovation Fund for Medical Sciences (CAMS-I2M, 2016-I2M-1-002). All authors had no conflicts of interest to disclose.

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