Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients


      • LDLR and PCSK9 variants detected in Japanese heterozygous FH were updated.
      • Clinical significance of LDLR and PCSK9 variants were annotated in heterozygous FH.
      • LDLR and PCSK9 pathogenic variants were found in 46% and 7.8% of FH patients, respectively.
      • The proportion of LDLR pathogenic variants decreased with increased age of CAD onset.


      Background and aims

      More than 4970 variants in the low-density lipoprotein receptor (LDLR) gene and 350 variants in the proprotein convertase subtilisin/kexin 9 (PCSK9) gene have been reported in familial hypercholesterolemia (FH) patients. However, the effects of these variants on FH pathophysiology have not been fully clarified. We aimed to update the LDLR and PCSK9 variants in Japanese heterozygous FH (HeFH) patients and annotate their clinical significance for the genetic diagnosis of HeFH.


      A genetic analysis of the LDLR and PCSK9 genes was performed in 801 clinically diagnosed HeFH patients. The association of the pathogenic variants with the clinical FH phenotype was examined.


      Pathogenic variants in the LDLR and PCSK9 genes were found in 46% (n = 296) and 7.8% (n = 51) of unrelated FH patients (n = 650), respectively. The prevalence of Achilles tendon thickness was low (44%) in patients harbouring PCSK9 pathogenic variants. Furthermore, 17% of unrelated FH patients harboured one of five frequent LDLR pathogenic variants: c.1845+2T > C, c.1012T > A: p.(Cys338Ser), c.1297G > C: p.(Asp433His), c.1702C > G: p.(Leu568Val), and c.2431A > T: p.(Lys811*). Patients harbouring the c.1845+2T > C and c.1702C > G: p.(Leu568Val) variants had significantly lower serum LDL-cholesterol levels and higher serum HDL-cholesterol levels, respectively, compared with those harbouring the other LDLR pathogenic variants. The proportion of LDLR pathogenic variants was higher in patients with a younger age of coronary artery disease (CAD) onset and significantly decreased as the age of CAD onset increased.


      This study annotated the clinical significance and characteristics of LDLR and PCSK9 pathogenic variants in Japanese HeFH patients.

      Graphical abstract


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Goldstein J.L.
        • Hobbs H.H.
        • Brown M.S.
        Familial hypercholesterolemia.
        in: Scriver B.A., C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. 8th. McGraw-Hill, Inc., New York2001: 2863-2913
        • Mabuchi H.
        • Nohara A.
        • Noguchi T.
        • et al.
        Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan.
        Atherosclerosis. 2011; 214: 404-407
        • Nordestgaard B.G.
        • Chapman M.J.
        • Humphries S.E.
        • et al.
        Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
        Eur. Heart J. 2013; 34: 3478-3490a
        • Brown M.S.
        • Goldstein J.L.
        Expression of the familial hypercholesterolemia gene in heterozygotes: mechanism for a dominant disorder in man.
        Science. 1974; 185: 61-63
        • Innerarity T.L.
        • Weisgraber K.H.
        • Arnold K.S.
        • et al.
        Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding.
        Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 6919-6923
        • Abifadel M.
        • Varret M.
        • Rabes J.P.
        • et al.
        Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
        Nat. Genet. 2003; 34: 154-156
        • Yu W.
        • Nohara A.
        • Higashikata T.
        • et al.
        Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population.
        Atherosclerosis. 2002; 165: 335-342
        • Horton J.D.
        • Cohen J.C.
        • Hobbs H.H.
        Molecular biology of PCSK9: its role in LDL metabolism.
        Trends Biochem. Sci. 2007; 32: 71-77
        • Cohen J.C.
        • Boerwinkle E.
        • Mosley Jr., T.H.
        • et al.
        Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
        N. Engl. J. Med. 2006; 354: 1264-1272
        • Iacocca M.A.
        • Chora J.R.
        • Carrie A.
        • et al.
        ClinVar database of global familial hypercholesterolemia-associated DNA variants.
        Hum. Mutat. 2018; 39: 1631-1640
        • Green R.C.
        • Berg J.S.
        • Grody W.W.
        • et al.
        ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
        Genet. Med. 2013; 15: 565-574
        • Harada-Shiba M.
        • Arai H.
        • Ishigaki Y.
        • et al.
        Guidelines for diagnosis and treatment of familial hypercholesterolemia 2017.
        J. Atheroscler. Thromb. 2018; 25: 751-770
        • Ohta N.
        • Hori M.
        • Takahashi A.
        • et al.
        Proprotein convertase subtilisin/kexin 9 V4I variant with LDLR mutations modifies the phenotype of familial hypercholesterolemia.
        J. Clin. Lipidol. 2016; 10 (e545): 547-555
        • Leigh S.
        • Futema M.
        • Whittall R.
        • et al.
        The UCL low-density lipoprotein receptor gene variant database: pathogenicity update.
        J. Med. Genet. 2017; 54: 217-223
        • Lek M.
        • Karczewski K.J.
        • Minikel E.V.
        • et al.
        Analysis of protein-coding genetic variation in 60,706 humans.
        Nature. 2016; 536: 285-291
        • Higasa K.
        • Miyake N.
        • Yoshimura J.
        • et al.
        Human genetic variation database, a reference database of genetic variations in the Japanese population.
        J. Hum. Genet. 2016; 61: 547-553
        • Nagasaki M.
        • Yasuda J.
        • Katsuoka F.
        • et al.
        Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals.
        Nat. Commun. 2015; 6: 8018
        • Hobbs H.H.
        • Brown M.S.
        • Goldstein J.L.
        Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.
        Hum. Mutat. 1992; 1: 445-466
        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of medical genetics and Genomics and the association for molecular Pathology.
        Genet. Med. 2015; 17: 405-424
        • Hori M.
        • Miyauchi E.
        • Son C.
        • et al.
        Detection of the benign c.2579C>T (p.A860V) variant of the LDLR gene in a pedigree-based genetic analysis of familial hypercholesterolemia.
        J. Clin. Lipidol. 2019; 13: 335-339
        • Cameron J.
        • Holla O.L.
        • Laerdahl J.K.
        • et al.
        Characterization of novel mutations in the catalytic domain of the PCSK9 gene.
        J. Intern. Med. 2008; 263: 420-431
        • Fasano T.
        • Sun X.M.
        • Patel D.D.
        • et al.
        Degradation of LDLR protein mediated by 'gain of function' PCSK9 mutants in normal and ARH cells.
        Atherosclerosis. 2009; 203: 166-171
        • Noguchi T.
        • Katsuda S.
        • Kawashiri M.A.
        • et al.
        The E32K variant of PCSK9 exacerbates the phenotype of familial hypercholesterolaemia by increasing PCSK9 function and concentration in the circulation.
        Atherosclerosis. 2010; 210: 166-172
        • Mabuchi H.
        Half a century tales of familial hypercholesterolemia (FH) in Japan.
        J. Atheroscler. Thromb. 2017; 24: 189-207
        • Ogura M.
        • Hori M.
        • Harada-Shiba M.
        Association between cholesterol efflux capacity and atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia.
        Arterioscler. Thromb. Vasc. Biol. 2016; 36: 181-188
        • Miyake Y.
        • Yamamura T.
        • Sakai N.
        • et al.
        Update of Japanese common LDLR gene mutations and their phenotypes: mild type mutation L547V might predominate in the Japanese population.
        Atherosclerosis. 2009; 203: 153-160
        • Funahashi T.
        • Miyake Y.
        • Yamamoto A.
        • et al.
        Mutations of the low density lipoprotein receptor in Japanese kindreds with familial hypercholesterolemia.
        Hum. Genet. 1988; 79: 103-108
        • Miyake Y.
        • Tajima S.
        • Funahashi T.
        • et al.
        A point mutation of low-density-lipoprotein receptor causing rapid degradation of the receptor.
        Eur. J. Biochem. 1992; 210: 1-7
        • Mabuchi H.
        • Nohara A.
        • Noguchi T.
        • et al.
        Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation.
        Atherosclerosis. 2014; 236: 54-61
        • Tajima T.
        • Morita H.
        • Ito K.
        • et al.
        Blood lipid-related low-frequency variants in LDLR and PCSK9 are associated with onset age and risk of myocardial infarction in Japanese.
        Sci. Rep. 2018; 8: 8107
        • Lee C.J.
        • Lee Y.
        • Park S.
        • et al.
        Rare and common variants of APOB and PCSK9 in Korean patients with extremely low low-density lipoprotein-cholesterol levels.
        PLoS One. 2017; 12e0186446
        • Paquette M.
        • Dufour R.
        • Baass A.
        The Montreal-FH-SCORE: a new score to predict cardiovascular events in familial hypercholesterolemia.
        J. Clin. Lipidol. 2017; 11: 80-86
        • Paquette M.
        • Bernard S.
        • Ruel I.
        • et al.
        Diabetes is associated with an increased risk of cardiovascular disease in patients with familial hypercholesterolemia.
        J. Clin. Lipidol. 2019; 13: 123-128
        • Talmud P.J.
        • Shah S.
        • Whittall R.
        • et al.
        Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.
        Lancet. 2013; 381: 1293-1301