Clonal hematopoiesis gene variants in South Asian Indians with premature coronary artery disease

Abstract

BackgroundClonal hematopoiesis of indeterminate potential (CHIP) gene variants greatly elevate the risk of CAD among various populations. Their impact on premature coronary artery disease (pCAD) in the South Asian Indian populations are not known. We investigate whether CHIP gene variants are associated with SAI-pCAD. MethodsThe pCAD patient samples (median age 43 years) were collected (2016-2019) at the Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India. Whole-exome sequencing and analysis of CHIP gene variants were conducted. ResultsA total of 161 pathogenic gene variants were identified in 11 CHIP genes among 842 SAI-pCAD individuals (19.1%). Of these 11 genes, ASXL1 (OR, 79.8; 95% CI, 15.2-429; P = 1.34 x 10-06) and TET2 (OR, 24.8; 95% CI, 3.6-277.2; P = 6.14 x 10-03) were frequently observed in SAI-pCAD after accounting for other factors, such as age, sex, type 2 diabetes, smoking/nicotine use, systemic hypertension, and levels of low-density lipoproteins and triglycerides, using a logistic regression model. However, DNMT3A and JAK2 gene variants, which have often been associated with CAD or pCAD in other global populations, were less prevalent or absent in SAI-pCAD. ConclusionsA total of 19.1% of SAI-pCAD displayed CHIP gene variants across 11 genes, which is unusually high for a median age of 43 years. Two CHIP genes (ASXL1 and TET2) were overrepresented in SAI-pCAD compared to other CHIP genes. The SAI-pCAD exhibits both overlapping and unique CHIP gene variants compared with other global CAD populations.