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

ImportanceWhile CHIP gene variants greatly elevate the risk of CAD among various global ancestries, pCAD remains under-researched. In particular, there is a lack of genetic data concerning pCAD in the South Asian Indian population. ObjectivesTo investigate whether CHIP gene variants are associated with SAI-pCAD. If so, are there any differences between SAI-pCAD and other populations. DesignThe pCAD samples for this case-control study were collected between 2016-2019. SettingSamples were obtained within two hours following a myocardial infarction at the Sri Jayadeva Institute of Cardiovascular Sciences and Research, which is among the largest heart care centers in South Asia, located in Bengaluru, India. ParticipantsWhole-exome sequencing and analysis were conducted on 842 SAI-pCAD individuals and 717 control subjects. The definition of pCAD included relatively young patients, specifically those under 55 years. Main Outcomes and MeasuresASXL1 and TET2 were significantly associated with SAI-pCAD. ResultsAll CHIP genes were considered for variant filtering, and among them, only 11 contained pathogenic variants in SAI-pCAD. Of these 11 genes, ASXL1 and TET2 showed significant associations after accounting for other factors like age, sex, type 2 diabetes (T2D), smoking/nicotine use, systemic hypertension, and levels of low-density lipoproteins (LDL) and triglycerides (TG). However, JAK2, a gene often linked with pCAD in other global populations, was not found in SAI-pCAD. Conclusion and RelevanceThe SAI-pCAD exhibits both overlapping and unique CHIP gene variants when compared to other global populations, which contributes to the advancement of precision medicine based on ancestry. Key PointsO_ST_ABSQuestionC_ST_ABSIs there a link between clonal hematopoiesis of indeterminate potential (CHIP) gene variants and premature coronary artery disease (pCAD) among South Asian Indians (SAI)? FindingsIn this research involving 842 pCAD patients and 1746 control subjects, 19% of the individuals were discovered to carry pathogenic variants in CHIP genes. Of the various CHIP genes, only ASXL1 and TET2 showed an association with SAI-pCAD. MeaningSAI-pCAD is associated with ASXL1 and TET2, but not other CHIP genes, such as DNMT3A and JAK2, which are prevalent in other global populations.