Distinct genetic architecture of coronary heart disease in dyslipidemia patients

BACKGROUND: Mutations of LDLR, APOB and PCSK9 have been well-established to cause hypercholesterolemia while the pathogenic effects of LPL has been confirmed by cohorts and functional studies in hypertriglyceridemia. However, these mutations do not fully account for all dyslipidemia, and it remains unexplained why some patients with dyslipidemia develop coronary heart disease (CHD) while others do not. METHODS: We enrolled 108 patients with lipid disturbances (67 with hypercholesterolemia and 41 with hypertriglyceridemia) and 414 controls from Tongji Hospital, Wuhan, China. Whole exome sequencing (WES) was performed, and candidate genes were assessed using the optimal sequence kernel association test (SKAT-O). Subgroup analysis compared genetic profiles between CHD and non-CHD patients. RESULTS: We identified 13 pathogenic or likely pathogenic (PP/LPP) variants in LDLR in hypercholesterolemia patients and four in LPL as well as two in APOA5 in hypertriglyceridemia patients. With exclusion of patients with PP/LPP variants, SKAT-O identified 192 and 184 additional genes associated with hypercholesterolemia and hypertriglyceridemia, respectively. In subgroup analysis, 119 genes showed relevance to CHD by comparison of patients with and without CHD in hypercholesterolemia cohort. Further enrichment analysis identified COL5A1, COL24A1, COL6A6, COL6A2, SLC3A1, ATP1A4 and SLC7A9 as candidate causal genes of CHD. CONCLUSIONS: This study described the genetic landscape of dyslipidemia in Chinese Han population, and revealed novel susceptibility genes beyond canonical lipid pathways. Genes implicated in CHD suggests extracellular matrix remodeling may mediate atherosclerotic progression in hypercholesterolemia. These findings provide novel mechanistic insights into CHD development and highlight promising targets for functional validation.