The goal of this multi-center observational clinical trial is to investigate the genetic risk factors of patients with premature CAD and none traditional CAD risk factors through a multi-omics approach.

The main questions it aims to answer are:

• Genetic risk factors & metabolic fingerprints of patients with premature CAD and none traditional CAD risk factors remain unknown.
• How to optimize current primary prevention strategy for this rare CAD subgroup？

Cardiovascular diseases (CVDs) remain the leading cause of global mortality despite continuous efforts in disease prevention and treatment optimization. In 2022 alone, CVD caused an estimated 19.8 million deaths worldwide, and ischemic heart disease had the highest global age-standardized DALYs of all diseases at 2,275.9 per 100,000. Therefore, research on the etiology and pathogenesis of coronary artery disease (CAD) remains first priority.

It is now widely known that risk factors such as diabetes mellitus, hyperlipidemia, hypertension, smoking, and obesity are closely related to CAD, but they only explain 30%-40% of CAD risk factors, and large-sample cohort and twin studies have concluded that CAD heritability is estimated to be 40% to 60%. With the development of the Human Genome Project and high-throughput sequencing technology, in the past decade, increasingly larger genome-wide association studies (GWAS) have been conducted worldwide and biobanks established. Public sequencing data is increasingly being used as external common controls instead of sequencing new controls in every study. Till now, thousands of mutations related to CAD have been identified. Multiple Polygenic risk scores (PRSs) have been developed to improve the prediction of common, complex cardiovascular diseases like CAD on individual level.

Premature CAD has been proved to have strong link with family history of cardiovascular and cerebral vascular disease, which indicates a strong genetic background of premature CAD. However, there is an even more scarce & inconspicuous subgroup of premature CAD, defined as premature CAD without common CAD risk factors in this study. First of all, most of those patients were considered "healthy" or "at very low risk of CVDs" before CAD was diagnosed; secondly, genetic risk factors & metabolic fingerprints of such patients remain unknown; thirdly, we still don't know yet how to optimize current primary prevention strategy for this rare CAD subgroup.

For this regard, we designed this multi-omics study to cover the questions mentioned above.

Inclusion Criteria for cases:

1. In-patients from cardiology department of either following 3 hospitals: a) The First Affiliated Hospital of Nanjing Medical University; b) Qilu Hospital of Shandong University; c) The Second Affiliated Hospital Zhejiang University School of Medicine
2. Confirmed diagnosis of Obstructive CAD (≥50% diameter stenosis in a major epicardial vessel) through coronary angiography
3. Age of the patient when Obstructive CAD was for the first time diagnosed should be no more than 45 years old for the male and 55 years old for the female.

Inclusion Criteria for controls:

1. In-patients from cardiology department of either following 3 hospitals: a) The First Affiliated Hospital of Nanjing Medical University; b) Qilu Hospital of Shandong University; c) The Second Affiliated Hospital Zhejiang University School of Medicine
2. Coronary artery stenosis was ruled out through either coronary angiography or coronary CTA.

Exclusion Criteria for both cases and controls:

1. Patients with hypertension (grade 1-3)
2. Patients with type 1 or type 2 diabetes mellitus
3. BMI >28.0 Kg/m^2
4. Patients with non-ideal blood lipids level on admission(defined as either LDL-C≥2.6mmol/L OR non-HDL cholesterol≥3.4mmol/L OR Lipoprotein(a) ≥300mg/L)
5. Smoker (Smoking for more than 6 consecutive or cumulative months in a lifetime, whether quit smoking or not)
6. Patients with hyperuricemia or gout
7. eGFR<60 ml/min·1.73m^2
8. Patients with structural heart diseases, inherited cardiomyopathies & arrhythmias
9. Other reasons a participant considered unsuitable for inclusion by researchers.

In-patients from cardiology department of either following 3 hospitals: a) The First Affiliated Hospital of Nanjing Medical University; b) Qilu Hospital of Shandong University; c) The Second Affiliated Hospital Zhejiang University School of Medicine. Those patients who meet the criteria for cases or controls and willing to give an informed consent will be enrolled.

Individual level data will not be published until further permission granted from domestic Human Genetic Resource Administration.