Patients with ldlr and pcsk9 gene variants experienced higher incidence of cardiovascular outcomes in heterozygous familial hypercholesterolemia

Takahito Doi, Mika Hori, Mariko Harada-Shiba, Yu Kataoka, Daisuke Onozuka, Kunihiro Nishimura, Ryo Nishikawa, Kosuke Tsuda, Masatsune Ogura, Cheol Son, Yoshihiro Miyamoto, Teruo Noguchi, Hiroaki Shimokawa, Satoshi Yasuda

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14 Citations (Scopus)


BACKGROUND: Patients with familial hypercholesterolemia who harbored both low-density lipoprotein receptor (LDLR) and PCSK9 (proprotein convertase subtilisin/kexin type 9) gene variants exhibit severe phenotype associated with substantially high levels of low-density lipoprotein cholesterol. In this study, we investigated the cardiovascular outcomes in patients with both LDLR and PCSK9 gene variants. METHODS AND RESULTS: A total of 232 unrelated patients with LDLR and/or PCSK9 gene variants were stratified as follows: patients with LDLR and PCSK9 (LDLR/PCSK9) gene variants, patients with LDLR gene variant, and patients with PCSK9 gene variant. Clinical demographics and the occurrence of primary outcome (nonfatal myocardial infarction) were compared. The observation period of primary outcome started at the time of birth and ended at the time of the first cardiac event or the last visit. Patients with LDLR/PCSK9 gene variants were identified in 6% of study patients. They had higher levels of low-density lipoprotein cholesterol (P=0.04) than those with LDLR gene variants. On multivariate Cox regression model, they experienced a higher incidence of nonfatal myocardial infarction (hazard ratio, 4.62; 95% CI, 1.66–11.0; P=0.003 versus patients with LDLR gene variant). Of note, risk for nonfatal myocardial infarction was greatest in male patients with LDLR/PCSK9 gene variants compared with those with LDLR gene variant (86% versus 24%; P<0.001). CONCLUSIONS: Patients with LDLR/PCSK9 gene variants were high-risk genotype associated with atherogenic lipid profiles and worse cardiovascular outcomes. These findings underscore the importance of genetic testing to identify patients with LDLR/ PCSK9 gene variants, who require more stringent antiatherosclerotic management.

Original languageEnglish
Article numbere018263
Pages (from-to)1-11
Number of pages11
JournalJournal of the American Heart Association
Issue number4
Publication statusPublished - 2021 Feb 16


  • Cardiovascular outcome
  • Familial hypercholesterolemia
  • LDLR gene
  • PCSK9 gene


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