Rare and Deleterious Mutations in ABCG5/ABCG8 Genes Contribute to Mimicking and Worsening of Familial Hypercholesterolemia Phenotype

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  • Tada Hayato
    Department of Cardiology, Kanazawa University Graduate School of Medicine
  • Okada Hirofumi
    Department of Cardiology, Kanazawa University Graduate School of Medicine
  • Nomura Akihiro
    Department of Cardiology, Kanazawa University Graduate School of Medicine
  • Yashiro Satoshi
    Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University
  • Nohara Atsushi
    Department of Cardiology, Kanazawa University Graduate School of Medicine
  • Ishigaki Yasushi
    Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University
  • Takamura Masayuki
    Department of Cardiology, Kanazawa University Graduate School of Medicine
  • Kawashiri Masa-aki
    Department of Cardiology, Kanazawa University Graduate School of Medicine

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Abstract

<p>Background:A substantial proportion of patients clinically diagnosed as having familial hypercholesterolemia (FH) do not manifest causative mutation(s) in the FH genes such asLDLR,APOB, andPCSK9. We aimed to evaluate the effect of rare and deleterious mutation(s) inABCG5/ABCG8on hyper-low-density lipoprotein (LDL) cholesterolemia in individuals who meet the clinical criteria for FH.</p><p>Methods and Results:We compared the LDL cholesterol (LDL-C) values among 487 subjects with FH; the subjects were grouped according to the presence of mutation(s) in FH andABCG5/ABCG8genes. We identified 276 individuals with a deleterious mutation in 1 FH gene (57%, monogenic FH), but found no causative mutations in 156 individuals (32%, mutation-negative). A total of 37 individuals had deleterious mutations inABCG5orABCG8, but not in FH genes (8%,ABCG5/ABCG8mutation carriers). Among these, 3 individuals had sitosterolemia (0.6%) with double mutations. We also identified 18 individuals with deleterious mutations in an FH gene andABCG5orABCG8(4%,ABCG5/ABCG8-oligogenic FH). Subjects without mutations had significantly higher polygenic scores than those in any other groups. LDL-C levels in oligogenic FH subjects were significantly higher than in the monogenic FH subjects. Moreover, sitosterol/lathosterol levels were significantly affected by those mutations.</p><p>Conclusions:The results suggested that rare and deleterious mutations inABCG5/ABCG8contribute substantially to mimicking and exacerbation of the FH phenotype.</p>

Journal

  • Circulation Journal

    Circulation Journal 83 (9), 1917-1924, 2019-08-23

    The Japanese Circulation Society

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