Table of Contents
STUDY DESIGN
Year : 2021  |  Volume : 6  |  Issue : 1  |  Page : 65-72

Clinical and genetic characteristics of coronary artery disease in Chinese young adults: Rationale and design of the prospective Genetic characteristics of coRonary Artery disease in ChiNese young aDults (GRAND) study


1 Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai, China
2 Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital; Department of Anthropology and Human Genetics, School of Life Sciences and Human Phenome Institute; State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China

Date of Submission29-Oct-2020
Date of Acceptance18-Feb-2021
Date of Web Publication30-Mar-2021

Correspondence Address:
Jun-Bo Ge
Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai
China
Kang Yao
Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2470-7511.312594

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  Abstract 


Background: Emerging evidence indicates that the worldwide incidence of early-onset coronary artery disease (EOCAD) is increasing. The genetic background has been assumed to harbor pathogenic risk, although the existing findings are mainly restricted to Caucasians. Little is known regarding the clinical profiles of patients with EOCAD and the extent to which genetic factors are related to disease susceptibility and outcomes in Asian people, especially ethnic Chinese. Methods and Results: The Genetic characteristics of coRonary Artery disease (CAD) in ChiNese young aDults (GRAND) study is a multicenter, hospital-based observational clinical study, combined of case-control design and longitudinal prospective cohort. Six thousand nationally representative patients who underwent coronary angiography at 38 centers have been enrolled since May 2017. Clinical data of patients with EOCAD (aged ≤45 years) are collected at the baseline to delineate conventional risk factors, clinical profiles, and therapeutic options of EOCAD and compared with data for patients with late-onset CAD (aged ≥65 years) and age-matched controls without CAD. The patients are followed for 3 years to trace major adverse cardiovascular (CV) events: cardiac death, nonfatal myocardial infarction, and ischemia-driven revascularization. Functional variants contributing to EOCAD risk are identified by high-depth whole-exome sequencing. The genetic profiles are further linked to disease severity and prognosis. A multi-dimensional risk score is established to predict prevalent EOCAD and incident CV events among young Chinese adults. Conclusions: The GRAND study will generate a thorough understanding of the clinical characteristics and genetic basis of EOCAD and may pave the way for genetic screening, early prevention, and future drug discovery for CAD in young Chinese generations.

Keywords: coRonary Artery disease; Genetics; Risk factors; Whole-exome sequencing


How to cite this article:
Shalaimaiti S, Dai YX, Wu HY, Qian JY, Zheng Y, Yao K, Ge JB. Clinical and genetic characteristics of coronary artery disease in Chinese young adults: Rationale and design of the prospective Genetic characteristics of coRonary Artery disease in ChiNese young aDults (GRAND) study. Cardiol Plus 2021;6:65-72

How to cite this URL:
Shalaimaiti S, Dai YX, Wu HY, Qian JY, Zheng Y, Yao K, Ge JB. Clinical and genetic characteristics of coronary artery disease in Chinese young adults: Rationale and design of the prospective Genetic characteristics of coRonary Artery disease in ChiNese young aDults (GRAND) study. Cardiol Plus [serial online] 2021 [cited 2021 Apr 15];6:65-72. Available from: https://www.cardiologyplus.org/text.asp?2021/6/1/65/312594




  Introduction Top


Atherosclerotic coRonary Artery disease (CAD) is a leading cause of death worldwide and is typically predominant in elderly populations. The growing number of early onset CAD (EOCAD) cases had raised major concerns, especially in countries such as China, where the morbidity and mortality of a cardiovascular (CV) disease is continuously rising.[1],[2] The concomitant growing volume of percutaneous coronary intervention in China is not merely indicative of the expanded accessibility of contemporary CV technologies across the country,[3] but it also signals the lack of preventative efforts, particularly in the young population.

To improve the comprehensive prevention and treatment of EOCAD in this context, the clinical and Genetic characteristics of coRonary Artery disease in ChiNese young aDults (GRAND) project was initiated through a collaborative effort involving 38 centers over mainland China, beginning in 2017. This clinical consortium will provide a comprehensive platform where myriad information resources related to clinical profiles and bioinformatics (including genomic, metabolomic, and gut microbiomic data) for thousands of individuals with EOCAD are available. Leveraging these comprehensive datasets will potentiate multidimensional analysis in order to draw complex networks of disease-causing processes and ultimately lay a foundation for future precise medicine in China. As the first study launched by the GRAND collaboration, this ongoing, multicenter, and prospective study is broadly aimed at investigating the clinical and genetic characteristics of EOCAD in individuals aged 45 years or less. This report will outline the rationale, design, and methodology of the study.

EOCAD may represent a disease of distinct phenotype, characterized by its sudden onset, more often manifested as acute myocardial infarction (AMI) with a poor long-term prognosis, although inconsistent findings have been reported in the literatures.[4],[5] Theoretically, EOCAD may also impose the individuals to impaired quality of life and reduced work capacity, which in turn leads to enormous socioeconomic threats. Nevertheless, there are particularly lack of knowledge about the risk factors, clinical characteristics, therapeutic options, and long-term outcomes of EOCAD in mainland China in the setting of modern CV practice.

Of note, the comprehensive prevention of CAD requires manipulating genomic risk. It has been long suggested that EOCAD has a propensity for predominant familial aggregation.[6],[7] Beyond classical risk factors, a vital contributor to CAD in early adulthood, therefore, is genetic susceptibility, which may be responsible for 40%–60% of all CAD cases.[8] As such, routine clinical risk scores, such as the Framingham risk score for predicting CAD susceptibly, are far from sufficient in young adults, whereas incorporating genetic risk scores may be more reliable and even independent of self-reported family histories, but this possibility warrants further studies.[7],[9],[10]

Thus far, genome-wide association studies have identified up to sixty common single-nucleotide polymorphisms associated with the risk for CAD.[11],[12] Yet, this collectively accounts for a limited component (≤28%) of genetic susceptibility, and mostly orchestrates their CAD risks through unknown mechanisms.[8],[11],[12] Recently, functionally significant rare single nuclide variations (SNVs) in protein-coding regions directly related to lipoprotein metabolism, nitric oxide signaling, platelet function, the extracellular matrix, and blood pressure have been identified through exome sequencing.[13],[14],[15],[16],[17],[18] These efforts should persist in unraveling more harmful variants and genes to identify the “missing heritability” and provide disease-causing variants for functional studies, which may reveal new paradigm-changing therapeutic targets such as PCSK9 inhibitors. However, the existing findings are mostly restricted to Western population of different ages, which renders their replicability in with other ethnic groups questionable. Given the potential genetic heterogeneity and differences in environmental risk exposures between Caucasians and Asians, the variants that confer EOCAD risk hitherto have not been well investigated, and not yet been associated with clinical outcomes in Asian patients, especially ethnic Chinese.

Therefore, the prospective GRAND study is being conducted to address those gaps in knowledge. The specific aims are (1) to describe the sociodemographic and clinical characteristics, therapeutic patterns, and long-term outcomes in nationally representative patients throughout mainland China; (2) to characterize conventional risk factors, along with social and mental factors associated to EOCAD; (3) to identify potential causal variants in protein-coding regions and susceptibility genes by high-depth whole-exome sequencing (WES) that contribute to EOCAD risk in Chinese; (4) to assess the influences of the identified variants on the presence and extent of EOCAD and on the risk of major adverse CV events (MACE); and (5) to create a comprehensive risk score by integrating clinical profiles and genetic risk factors to predict the prevalent EOCAD and incident CV events in young Chinese adults.


  Methods Top


Study design

The GRAND study is a multicenter, hospital-based, prospective clinical study that is designed to proceed in a stepwise fashion: a case-control design at baseline and a longitudinal cohort observation during the follow-up period [Figure 1]. No therapeutic interventions are mandated by the protocol. Briefly, the baseline case-control study mainly focuses on clinical characterization and genetic profiling. Then, the follow-up data on patient outcomes are collected for 3 years. The primary outcome is MACE, defined as the composite of cardiac death, nonfatal acute MI, and ischemia-driven revascularization. The secondary outcome is defined as the composite of stent thrombosis, noncardiac death, bleeding, and all-cause death.
Figure 1: Design of the Genetic characteristics of coRonary Artery disease in ChiNese young aDults Study.
CAD: coRonary Artery disease, MACE: Main adverse cardiac events


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Study population

The GRAND study will examine 6000 young and elderly patients who underwent coronary angiography and have been sequentially recruited from 38 centers since May 2017 [Figure 2]. The participants of the GRAND consortium comprise hospitals located in diverse geographic regions including 12 hospitals in north China and 26 in south China [Supplementary Table 1] that well represent a range of CV facilities across the country.
Figure 2: Distribution of centers participating in the Genetic characteristics of coRonary Artery disease in ChiNese young aDults study across China (n = 38).

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CAD is defined by coronary angiography as ≥50% luminal narrowing of one or more main coronary arteries, involving the left main coronary artery, left anterior descending branch, left circumflex branch, or right coronary artery, which manifested as occult CAD, stable angina pectoris, unstable angina pectoris, non-ST-segment elevation MI (NSTEMI), or ST-segment elevation MI (STEMI).

Patients fulfilling any of the following conditions are considered eligible for the study [Figure 1]: (1) patients aged 18–45 years old who meet the CAD diagnostic criteria described above; (2) patients who manifest CAD for the first time at ≥65 years of age and meet the CAD diagnostic criteria described above; (3) age-matched individuals with no obvious coronary artery obstructions (coronary stenosis <50%) and who are free from any documented ischemia. Accordingly, there are three comparison groups: the EOCAD, late-onset CAD, and age-matched control groups. Patients who are (1) severely sick with a limited life-expectancy of <1 year; or (2) have malignancies; or (3) are pregnant or planning to become pregnant are excluded from the study.

Data collection and management

Data collection begins at the time of coronary angiography. Baseline and in-hospital clinical information are abstracted from electronic medical records (EMRs) and catheterization reports. Specifically, at the time of enrollment and hospital discharge, investigators obtain standardized information regarding the clinical data elements shown in [Table 1]. EMRs are reviewed to document objective medical data (including laboratory results and ancillary tests), treatment strategies, and complications. Catheterization reports are reviewed by cardiologists to assess angiographic findings and to ascertain the study group assignments. In addition, all participants are asked to complete the baseline questionnaire regarding their lifestyles, dietary habits, and physical activates. They also complete questionnaires comprising the Perceived Stress Scale (version PPS-14)[19] and the Depression Anxiety and Stress Scale (version DASS-21)[20] and questions pertaining to a list of stress-related symptoms at enrollment. In addition, male subjects with EOCAD answer the internationally validated five-item short form of the questionnaire, namely, the International Index of Erectile Function.[21] Serial assessments are performed for 3 years, beginning 1 month after discharge and then annually, through planned outpatient visits, telephone interviews, and rehospitalizations (if applicable) to record adverse events [Figure 1]. Electronic data-capture entry is used to accurately document case report forms by abstractors with formal medical training. Physicians assist in identifying data elements that require more advanced medical knowledge for recognition. Rigorous monitoring is mandated to ensure the data quality by an independent data-monitoring board at regular intervals. Once accuracy is ensured, the data are locked and encrypted by the data administrator.
Table 1. Standardized information for the clinical data elements

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Biospecimen management

Concurrent participants provide blood samples at the time of enrollment. All biospecimens are stored locally and frozen at −80°C based on best-practice guidelines established for biobanking.[22] Each center that completes target enrollment sends the samples to the Beijing Genomics Institute (Shenzhen, China) for further genetic tests.

Genetic profiling

A two-stage analysis is conducted to detect variants in protein-coding area that influence the genetic predisposition for EOCAD. SNVs, both common and rare, relevant to EOCAD are first screened using high-throughput WES and then validated by Sanger sequencing. Candidate SNVs are examined by SNV-association analysis to verify the causal variants, after which gene-wise analysis is performed to further detect rare variants enrichment genes, both at the discovery and replication stages. External databases are integrated with original samples to improve the association power. Once confirmed by replication, functional studies will be tailed with both in vitro and in vivo experiments to investigate the potential roles of candidate mutations. The polygenic risk score (PRS) is calculated using the sequencing data with PRSice software, based on multiple cross-validation methods. Genotype–phenotype-correlation analysis is performed by comparing known cardiometabolic profiles and angiographic results at the times of enrollment and adverse CV events during follow-up, among groups with different genetic profiles. Eventually, an integrated risk score is generated based on clinical and genetic data to predict disease susceptibilities and long-term outcomes.

Statistical considerations

Data from 38 study centers are being pooled for analysis. The population disease prevalence is assumed to be 5%, and the significance level is set to 1.0 × 10−7. Power analyses is performed using the Genetic Power Calculator.[23] The planned sample size of 6000 is based on 80% statistical power to detect genetic variations with a minor allele frequency (MAF) of <5% associated with CAD, yielding an odds ratio of ≥2.0. Standard statistical methods will be used for summarizing baseline patient characteristics, the treatments received, and in-hospital outcomes. In particular, continuous variables will be presented as the mean and standard deviation in the case of a normal distribution or as median and interquartile range in the case of an asymmetric distribution, and analysis of variance or Kruskal-Wallis testing will be used for comparison purposes where appropriate. Discrete variables will be expressed in terms of absolute frequencies and percentages, whereas comparisons between groups will be performed by the Chi-square test or Fisher's exact test where appropriate.

For SNV-association analysis, a genetic model using logistic regression with adjustment of the top principal components will be applied for common SNVs (MAF >5%) and Fisher's exact test for rare SNVs (MAF ≤5%). The data are analyzed separately at the discovery and replication stages. Gene-based association analysis is performed on the predefined SNV sets (the most possible rare damaging SNVs) using the collapse test.

Logistic regression analyses and the Cox proportional-hazard model are adopted to examine the influences of risk factors on disease severity and prognosis, respectively. An integrated risk score system consisting of both clinical and genetic variables will be constructed by developing and validating a nomogram for predicting EOCAD susceptibility and outcome, using R software. A receiver-operating characteristics curve will be generated to define the predictive accuracy of the PRS and integrated risk score. Tests of hypotheses will be two tailed. All test for statistical significance and confidential intervals will use an α level of 5%.

Ethics

The study protocol has been approved by the central ethics committee at Zhongshan Hospital (Fudan University, Shanghai, China) and by the internal ethics committees at all other centers (B2017-051). Each participant provides written informed consent. The study is listed at www. clinicaltrials. gov (identifier NCT02496858).


  Discussion Top


EOCAD, which is known to have a particularly strong genetic component, imposes substantial public health and economic burdens.[8],[11],[12] The GRAND study is an important and relevant project, as it will challenge our understanding of the natural history of EOCAD in the new era of bioinformatics technologies. The present study, the first conceived research for the GRAND project, is aimed to delineate the clinical characteristics and outcomes of patients with EOCAD, and is mainly designed to uncover genetic and nongenetic risk factors related to the prevalent EOCAD and future CV events in Han Chinese.

Atherosclerosis is principal for CAD development, which is a multifaceted process that results from a complex interplay between atherogenic environmental factors and genetic susceptibility.[8],[11] This study includes the largest number of subjects with angiographically confirmed EOCAD to date, which reduces the probability of confounding heterogeneous etiologies of coronary disease other than atherosclerotic coronary obstruction, such as ischemia or MI with nonobstructive coronary arteries.[24],[25] Unlike previous genetic studies on CAD, the current study particularly includes patients with a wide clinical spectrum, from asymptomatic CAD to AMI, rather than analyzing a limited disease subtype.[13],[14],[15],[16],[17],[18] This design will not only allow enrolling a sizable population of patients with EOCAD but will also potentiate determining relationships between genetic and environmental risk factors versus disease susceptibly in subjects presenting with various clinical severities and outcomes.

In recent decades, air pollution has worsened and western lifestyles have become more popular, which may partially account for the rise in EOCAD cases across China.[26],[27] A few cross-sectional and longitudinal observational reports showed that family history, smoking, male sex, and common cardiometabolic abnormalities play pivotal roles in EOCAD, albeit with distinct ethnic heterogeneities.[28],[29] In addition, data from previous studies supported the conclusion that premature graying of hair, lower levels of testosterone, and inflammation were also related to EOCAD risk.[30],[31],[32] Moreover, the current GRAND study additionally includes certain socioenvironmental factors such as psychological stress, mental well-being, and the quality of sexual life to jointly investigate environmental risk factors associated with EOCAD in young Chinese adults.

Of note, the family history remained a strong independent risk factor in previous studies, indicating that genetic factors may be crucial for the development of CAD among the young, since limited time has elapsed for exposure to nongenetic factors that raise the odds of disease in the elderly.[6],[7] Exome sequencing, a comprehensive approach for detect rare genetic variants with large effects on disease phenotypes, was used to identify coding variants in genes related to lipoprotein metabolism, namely, LDLR, PCSK9, APOA5, APOC3, and NPC1 L1.[13],[14],[15] The presence of mutations in both GUCY1A3 and CCT7, associated with significant defects in nitric oxide signaling and platelet function, was also uncovered in a family-based analysis.[16] Interestingly, a smaller study revealed that rare variants in SPTBN5, NID2, and ADAMTSL4, which all encode important extracellular matrix proteins, may protect patients with a high burden of risk factors from CAD.[17] To date, both common and rare mutations in LDLR have been reported in young Chinese patients with severe hypercholesterolemia but not in those with CAD.[33],[34] The GRAND study is unique in that it tests the hypothesis that genetic risk factors are responsible for EOCAD development, which has not yet been done in a large multicenter cohort of Chinese young adults. Further functional studies will be initiated once the clinical significances of such genetic variations are confirmed, in order to discover the potential mechanisms and new therapeutic targets.

Importantly, disease progression is presumed to be more aggressive during early life due to distinct pathogenic mechanisms, leading to CAD development, and longer time to live with the disease for young subjects as for the elders, but this remains largely elusive. The majority of relevant genetic studies were underpowered due to a lack of follow-up data for subjects with genetic mutations,[13],[14],[15],[16],[17],[18] which restricts our understanding of the extents to which these genetic variants are related to the future CV events. This GRAND study will provide a 3-year-outcome comparison by age and further verify the prognostic significance of the genetic makeup among young Chinese.

In addition, the polygenic nature of CAD underscores the importance of gene-environment interactions that may mediate nearly 80% of the estimated CAD heritability, according to current evidence.[8],[11],[12],[35] In particular, certain genetic variants did not manifest until a specific modifier was present, such as smoking. Thus, synergetic effects of multiple loci and environmental factors make understanding the underlying genetic architectures of such a complex disease more challenging. A special interest exists in the current study on interconnecting genetic and environmental risk factors that jointly promote CAD development at a younger age. Finally and importantly, a comprehensive risk score system, not yet established hitherto in a large Chinese cohort, will be further investigated by incorporating genetic and nongenetic variables to improve the prognostic value beyond preexisting risk score systems[9],[10] to predict EOCAD susceptibility and the atherosclerotic burden and establish a prognosis.

Strengths and limitations

The prospective GRAND study has several strengths including its large projected sample size, strict angiographic diagnostic criteria for EOCAD, lengthy follow-up time, prospective and standardized data collection, and availability of biologic samples for approximately 95% of all participants. However, the GRAND study has some limitations that should be addressed. Pertinent to all observational studies, the reliability of data abstraction and documentation are the fundamental determinants that may influence the study findings. We have made efforts to apply rigorous quality controls to minimize inaccuracies and reduce the risk of measurement bias. Moreover, the sample size in this high-depth WES study is relatively small in comparison with those of previous studies,[13],[14],[15]s owing to the stringent angiographic criteria for enrollment. Control subjects from other cohorts will be included wherever possible to increase the rare-mutation association power, although additional variants with rarer frequencies, smaller effect sizes, or less penetrance might be missed with this strategy. Limitations also include potential accuracies in terms of exposure measurements regarding dietary intake, smoking, physical activities, psychological stress, and sexual behaviors obtained from questionnaires, which largely depend on a patient's willingness to provide accurate personal information. Furthermore, telephone interviews are used to track outcomes for nonlocal patients following hospitalization, which brings the objectivities of the reported outcomes into question. Only hospitals from major cities and provincial capitals are included, which restricts the findings to urban areas. Finally, the participants of this study are restricted to Han Chinese; hence, the findings cannot be simply extended to other ethnic groups.


  Conclusion Top


In summary, the results of the GRAND study may potentially uncover the genetic basis of EOCAD, generate comprehensive risk scores for early screening and prevention, and provide pathophysiological insights and targets for novel therapies. More specifically, if genetic screening in young adults can identify those with an increased likelihood of disease progression with a worse outcome, current clinical strategies will be challenged and alternative treatments for delaying progression may need to be considered, such as the use of early and aggressive statin therapy. This will pave the way for developing a Chinese-specific comprehensive prevention program for EOCAD in young generations.

Acknowledgments

We acknowledge the contributions from all the members of the GRADN consortium.

Financial support and sponsorship

Financial support and sponsorship National Key R and D Program of China (No.2016YFC1301200), and Clinical Research Plan of Shanghai Hospital Development Center (No. SHDC2020CR1007A).

Conflicts of interest

Jun-Bo Ge is the Editorial Board member of the journal.



 
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