Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia
Zhiyong Du,
Fan Li,
Linyi Li,
Yu Wang,
Jianping Li,
Ya Yang,
Long Jiang,
Luya Wang,
Yanwen Qin
Affiliations
Zhiyong Du
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, 100191 Beijing, China
Fan Li
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China
Linyi Li
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China
Yu Wang
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China
Jianping Li
Department of Cardiology, Peking University First Hospital, 100034 Beijing, China
Ya Yang
Suzhou Municipal Hospital, Suzhou 215002, Jiangsu Province, China
Long Jiang
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China; Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
Luya Wang
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China; Corresponding author
Yanwen Qin
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China; Corresponding author
Summary: Homozygous 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.
