摘要：SummaryHomozygous familial hypercholesterolemia (HoFH) is an extremely rare metabolism disorder usually caused by low-density lipoprotein receptor (LDLR) mutations. LDLR genotype is commonly known to determine blood concentrations of LDL cholesterol. However, effects of LDLR genotype on holistic metabolome remain unclear. Herein, we present metabolomic, genetic, and clinical datasets from a large multi-center panel of 142 patients with LDLR-mutated HoFH. We found that true homozygotes and compound heterozygotes showed few differences in clinical and metabolomic phenotypes. Compared with defective/defective mutation carriers, patients carrying one or two null mutation showed profound alterations in clinical laboratory lipids and serum cholesterol esters, lysophosphocholines, bile acids, and amino acids. Importantly, these altered metabolites are implicated in multiple biochemical reactions and associated with LDL cholesterol. This study extends the first map of different LDLR genotypes influencing the metabolome and suggests that the small-molecule metabolites serve as potential targets to mitigate the deleterious impact of LDLR mutations on HoFH.Graphical abstractDisplay OmittedHighlights•Patients with TH-HoFH and DH-HoFH show few differences in sera metabolome•LDLR genotype-related metabolic network correlates with clinical phenotypes•Null and defective LDLR mutation carriers exhibit distinct metabolite profiles•Null LDLR mutations are associated with oxidative stress and cholesterol metabolismClinical genetics; Genetics; Health sciences; Human genetics; Human metabolism
