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Hyperlipidemia patients carrying LDLR splicing mutation c.1187-2A>G respond favorably to rosuvastatin and PCSK9 inhibitor evolocumab

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Abstract

Mutations in the LDL receptor gene LDLR cause familial hypercholesterolemia (FH); however, the pharmacogenomics of specific LDLR mutations remains poorly understood. The goals of this study were to identify the genetic cause of a three-generation Chinese family affected with autosomal dominant FH, and to investigate the response of FH patients in the family to statin and evolocumab. Whole exome sequencing of the FH family with four patients and six unaffected members identified a heterozygous splicing mutation (c.1187-2A>G) in LDLR. The mutation co-segregated with FH in the family, providing strong genetic evidence to support its pathogenicity. The proband was a 48-year-old male FH patient who had an acute myocardial infarction (MI) and ventricular fibrillation (VF), and showed LDL-C of 5.23 mmol/L. A combination of life style modifications on food and exercise and treatment with rosuvastatin reduced his LDL-C to 2.05–2.80 mmol/L. Addition of ezetimibe did not improve rosuvastatin therapy, but addition of evolocumab further reduced LDL-C by 70% to 0.7 mmol/L at the first time and by 67% to 1.31 mmol/L at the second time. Rosuvastatin also reduced LDL-C for proband’s father and sister by 40% and 43–63%, respectively. Lovastatin alone or addition to rosuvastatin treatment did not have any effect on LDL-C for the proband and his son. Both patients carry ApoE 3/4 genotype and SLCO1B1 rs4149056 TT genotype. These results suggest that combined treatment with rosuvastatin (but not lovastatin or ezetimibe) and evolocumab can control LDL-C to meet the LDL-C treatment goal for patients with LDLR splicing mutation c.1187-2A>G.

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Acknowledgements

We sincerely appreciate the help and assistance of our patients and their family members during the entire study. We also thank other members of Center for Human Genome Research for discussion, help, advice and technical assistance. This study was supported by the China National Natural Science Foundation grants (81630002 and 32070581).

Funding

This study was supported by the China National Natural Science Foundation grants (32070581 and 81630002).

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  1. Xiaoyu Zhang, Qianqian Liu, and Hongfu Zhang contributed equally to this work

Authors and Affiliations

  1. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    Xiaoyu Zhang, Hongfu Zhang, Chengcheng Tan, Chengqi Xu & Qing K. Wang

  2. Department of Cardiology, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China

    Qianqian Liu, Qiangfeng Zhu, Saiyong Chen, Yinglong Du, Haitao Yang & Chun Wu

  3. Third People’s Hospital of Fushun County in Sichuan Province, Zigong, People’s Republic of China

    Qingli Li

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Contributions

Study design and supervision: Q.K.W and C.X.; identification and ascertainment of study subjects: Q.L., X.Z, and C.T.; collection of experimental data: X.Z. and C.T.; data analysis: all authors; draft of manuscript: X.Z. Q.L. and Q.K.W.; critical revisions of manuscript: Q.K.W., X.Z. and Q.L.; review of manuscript: all authors.

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Correspondence to Chengqi Xu, Chun Wu or Qing K. Wang.

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This study was approved by appropriate local institutional review boards on human subject research and conformed to the guidelines set forth by the Declaration of Helsinki.

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This study was approved by the Ethics Committee on Human Subject Research at Huazhong University of Science and Technology, and conformed to the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Written informed consent was obtained from all the study subjects.

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Communicated by Shuhua Xu.

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Zhang, X., Liu, Q., Zhang, H. et al. Hyperlipidemia patients carrying LDLR splicing mutation c.1187-2A>G respond favorably to rosuvastatin and PCSK9 inhibitor evolocumab. Mol Genet Genomics 297, 833–841 (2022). https://doi.org/10.1007/s00438-022-01892-4

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