Contribution of genetic variants in the development of familial premature coronary artery disease in a cohort of cardiac patients

• Published in: Clinical genetics Vol. 105; no. 6; pp. 611 - 619
• Main Authors: Mehvari, Sepideh, Karimian Fathi, Nahid, Saki, Sara, Asadnezhad, Maryam, Arzhangi, Sanaz, Ghodratpour, Fatemeh, Mohseni, Marzieh, Zare Ashrafi, Farzane, Sadeghian, Saeed, Boroumand, Mohammadali, Shokohizadeh, Fatemeh, Rostami, Elham, Boroumand, Rahnama, Najafipour, Reza, Malekzadeh, Reza, Riazalhosseini, Yasser, Akbari, Mohammadreza, Lathrop, Mark, Najmabadi, Hossein, Hosseini, Kaveh, Kahrizi, Kimia
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2024
• Subjects: Adult; Angiography; atherosclerosis; Cardiovascular disease; Cardiovascular diseases; CD36 antigen; Cohort Studies; Computed tomography; Coronary artery disease; Coronary Artery Disease - epidemiology; Coronary Artery Disease - genetics; Coronary vessels; Exome Sequencing; Female; Genetic diversity; Genetic Predisposition to Disease; Genetic Variation; Humans; Iran - epidemiology; Male; Middle Aged; myocardial infarction; Pedigree; premature coronary artery disease; rare variant; Risk Factors; Ryanodine receptors; Vein & artery diseases; Iran; atherosclerosis; coronary artery disease; premature coronary artery disease; rare variant; myocardial infarction
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.14491

Coronary artery disease (CAD), the most prevalent cardiovascular disease, is the leading cause of death worldwide. Heritable factors play a significant role in the pathogenesis of CAD. It has been proposed that approximately one‐third of patients with CAD have a positive family history, and individuals with such history are at ~1.5‐fold increased risk of CAD in their lifespans. Accordingly, the long‐recognized familial clustering of CAD is a strong risk factor for this disease. Our study aimed to identify candidate genetic variants contributing to CAD by studying a cohort of 60 large Iranian families with at least two members in different generations afflicted with premature CAD (PCAD), defined as established disease at ≤45 years in men and ≤55 years in women. Exome sequencing was performed for a subset of the affected individuals, followed by prioritization and Sanger sequencing of candidate variants in all available family members. Subsequently, apparently healthy carriers of potential risk variants underwent coronary computed tomography angiography (CCTA), followed by co‐segregation analysis of the combined data. Putative causal variants were identified in seven genes, ABCG8, CD36, CYP27A1, PIK3C2G, RASSF9, RYR2, and ZFYVE21, co‐segregating with familial PCAD in seven unrelated families. Among these, PIK3C2G, RASSF9, and ZFYVE21 are novel candidate CAD susceptibility genes. Our findings indicate that rare variants in genes identified in this study are involved in CAD development. Exome sequencing was performed for individuals afflicted with premature CAD, followed by Sanger sequencing of candidate variants in all available family members. Subsequently, asymptomatic carriers of potential risk variants underwent CT angiography, followed by co‐segregation analysis of the combined data. Ultimately, putative causal variants were identified in seven genes.