Multi-omics Study of Clinical Endpoints in CHD

Study Overview
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Brief Summary
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This study aimed to explore underlying mechanisms of individual differences in drugs for coronary heart disease treatment and its association with adverse consequences. It will enroll approximately 4000 coronal heart disease patients aged between 18 and 80 years in mainland China and follow-up for at least 1 years. Questionnaires, anthropometric measures, laboratory tests, and biomaterials will be collected . The principal clinical outcomes of the study consist of ischemia attack , cardiac death, renal injury,and myotoxic activity.

Detailed Description
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The study is a multicenter prospective cohort study, aimed to explore underlying mechanisms of individual differences in drugs for coronary heart disease treatment and its association with adverse consequences.The genomic genotype, DNA methylation and metabolome of 1000 patients with coronary heart disease were determined using illumina high-density genotyping chip, high-throughput sequencing and high-resolution mass spectrometry. Blood exposures of statins and metoprolol and its metabolites was determined by UPLC-MS/MS. The biological network using cross-omics analysis was reconstructed to identify potential causative key genes, bacteria, and endogenous metabolite targets that cause differences in individual responses. A machine identification algorithm selecting clinical factors and multi-omics targets was used to establish a predictive mathematical model. A multi-center clinical cohort of 3000 coronal heart disease patients was used to verify the effects of various levels of omic targets on drug blood exposures, efficacy and toxic side effects. A comprehensive model based on multi-target combination of individualized drugs was constructed, and the predictive effect was clinically analyzed.

Official Title
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Multi-omics Study of the Individual Differences of Drug Efficacy and Toxicity in Patients With Coronary Heart Disease

Conditions
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Coronary Heart Disease

Intervention / Treatment
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* Other: risk factors of adverse cardiovascular events
* Other: multi-omics target discovery
* Other: validation
* Other: Predictive mathematical models


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age: 18-80 years Chinese Han patients with coronary artery disease inpatients undergoing coronary angiography or percutaneous coronary intervention Exclusion Criteria: renal insufficiency (defined as serum creatinine concentration > 2 times the upper limit of normal [230 μmol/L], renal transplantation or dialysis) hepatic insufficiency (defined as serum transaminase concentration > 2 times the upper limit of normal [80 U/L], or a diagnosis of cirrhosis) pre-existing bleeding disorders being pregnant or lactating advanced cancer or haemodialysis history of thyroid problems, and use of antithyroid drugs or thyroid hormone medication incomplete information about cardiovascular events during follow-up

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Discovery cohort<br>1000 cases of coronary heart disease follow-up cohort was used for multi-omics target discovery.During the follow-up period, the information about the occurrence and risk factors of adverse cardiovascular events will be collected. | Other: risk factors of adverse cardiovascular events<br>* During the follow-up period,general information(age, sex, BMI, blood pressure, the history of drink and smoke, medical history, etc).Blood biochemistry parameters（Lipid, hsCRP levels, etc）and other laboratory examination parameters will be collected<br>Other: multi-omics target discovery<br>* Genome-wide genotype , DNA methylation and metabolomes were determined using illumina high-density genotyping chips, high-throughput sequencing, and high-resolution mass spectrometry respectly. Blood exposure of statins and metoprolol and its metabolites was determined by UPLC-MS/MS.<br>|
| Validation corhort<br>3000 coronary heart disease follow-up cohorts was used for validating the results from the discovery corhort. During the follow-up period, the occurrence and risk factors of adverse cardiovascular events.Predictive mathematical models based on multi-omics combination will be constructed finally. | Other: risk factors of adverse cardiovascular events<br>* During the follow-up period,general information(age, sex, BMI, blood pressure, the history of drink and smoke, medical history, etc).Blood biochemistry parameters（Lipid, hsCRP levels, etc）and other laboratory examination parameters will be collected<br>Other: validation<br>* The genome-wide genotype of patients with coronary heart disease was detected using the illumina chip. The methylation level of the functional region was detected by the target region enrichment methylation sequencing method. Intestinal flora differences were detected using 16SrDNA high-throughput sequencing.<br>Other: Predictive mathematical models<br>* Machine learning algorithms such as multiple linear regression or Bayesian classification are used to optimize clinical factors and multi-group targets to establish predictive mathematical models.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | All-cause death | from date of baseline examination until the date of first documented death,up to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MACE | MACE was defined as the occurrence of cardiac death, nonfatal myocardial infarctions, coronary revascularisation and cerebral infraction. | from date of baseline examination until the date of first documented cardiovascular events,up to 48 months | 
| Bleeding | Bleeding was the six-month incidence of combined alarming, internal, and nuisance bleeding events defined according to Serebruany et al15. Alarming bleeding included bleeding requiring a transfusion, intracranial bleeding, and life-threatening bleeding. Internal bleeding included haematoma, epistaxis, blood loss from the mouth, vagina, melaena, eye bleed, haematuria, and haematemesis. Nuisance bleeding included easy bruising, bleeding from small cuts, petechiae, and ecchymosis. | from date of baseline examination until the date of first documented bleeding,up to 48 months | 
| Statin-induced myopathy (SIM) | The definition of SIM from statin treatment was based on the patients' subjective sense of muscular pain as well as CK elevations. These muscular side effects included myalgia (muscle pain/ache without serum CK elevations), other muscle-related symptoms such as weakness, cramps, spasms, soreness and twitching, CK elevations without physical symptoms, myositis or other muscle symptoms with CK elevations, and rhabdomyolysis. | from date of baseline examination until the date of first documented SIM,up to 48 months | 
| CI-AKI | CI-AKI was diagnosed if a patient had an absolute increase in serum creatinine (sCr) concentration ≥ 0.3 mg/dl (26.4 μmol/L) from baseline or a relative increase ≥ 50 % in sCr concentration for more than 6 h within 48 h after surgery | more than 6 h within 48 h after Coronary Angiography | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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epigenome, metabolome, microbiome, genome, multi-omics targets, individual drug use