Advertisement

Impact of variants of uncertain significance of LDL receptor on phenotypes of familial hypercholesterolemia

Published:September 29, 2022DOI:https://doi.org/10.1016/j.jacl.2022.09.007

      Highlights

      • Pathogenic variants are associated with higher risk for CVD among FH patients.
      • LDL cholesterol level differs according to types of variants among FH patients.
      • VUS was significantly associated with poor outcomes in FH patients.

      Abstract

      Background

      Data on the effect of variants of uncertain significance (VUS) of LDL receptor (LDLR) on familial hypercholesterolemia (FH) phenotype is limited.

      Objective

      To investigate the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and occurrence of major adverse cardiac events (MACEs), in FH patients (N = 1050, male/female = 490/560).

      Methods

      We retrospectively assessed the data of patients with FH admitted at Kanazawa University Hospital between 1990 and 2020. Based on genotype, the patients were divided into patients without variants, with VUS of LDLR, and with pathogenic variants. Cox proportional hazard model was used to identify the factors associated with MACEs.

      Results

      The median follow-up duration was 12.6 years (interquartile range: 9.5–17.9 years). Altogether, 777 patients had FH mutation and 273 had pathogenic mutation, with 92 having VUS. Over the follow-up duration, 175 MACEs were observed. LDL cholesterol level was found to be significantly higher in patients with pathogenic variants (251 mg/dL) than in patients with VUS (225 mg/dL) and without variants (203 mg/dL). Pathogenic variants and VUS are significantly associated with MACEs (hazard ratio [HR] = 1.52, 95% confidence interval [CI] = 1.02–2.02, P = 0.033 and HR = 3.18, 95% CI = 2.00–4.36, P = 1.9 × 10−5, relative to patients without any variants, respectively), independent of classical risk factors.

      Conclusion

      VUS of LDLR was significantly associated with poor outcomes in FH patients. Genetic testing is useful for the diagnosis and risk stratification of FH patients.

      Keywords

      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:

      Subscribe to Journal of Clinical Lipidology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Mabuchi H
        Half a century tales of familial hypercholesterolemia (FH) in Japan.
        J Atheroscler Thromb. 2017; 24: 189-207
        • Beheshti SO
        • Madsen CM
        • Varbo A
        • Nordestgaard BG
        Worldwide prevalence of familial hypercholesterolemia: meta-analyses of 11 million subjects.
        J Am Coll Cardiol. 2020; 75: 2553-2566
        • Hu P
        • Dharmayat KI
        • Stevens CAT
        • Sharabiani MTA
        • Jones RS
        • Watts GF
        • Genest J
        • Ray KK
        • Vallejo-Vaz AJ
        Prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease: a systematic review and meta-analysis.
        Circulation. 2020; 141: 1742-1759
        • Khera AV
        • Won HH
        • Peloso GM
        • Lawson KS
        • Bartz TM
        • Deng X
        • van Leeuwen EM
        • Natarajan P
        • Emdin CA
        • Bick AG
        • Morrison AC
        • Brody JA
        • Gupta N
        • Nomura A
        • Kessler T
        • Duga S
        • Bis JC
        • van Duijn CM
        • Cupples LA
        • Psaty B
        • Rader DJ
        • Danesh J
        • Schunkert H
        • McPherson R
        • Farrall M
        • Watkins H
        • Lander E
        • Wilson JG
        • Correa A
        • Boerwinkle E
        • Merlini PA
        • Ardissino D
        • Saleheen D
        • Gabriel S
        • Kathiresan S
        Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.
        J Am Coll Cardiol. 2016; 67: 2578-2589
        • Tada H
        • Kawashiri MA
        • Nohara A
        • Inazu A
        • Mabuchi H
        • Yamagishi M
        Impact of clinical signs and genetic diagnosis of familial hypercholesterolaemia on the prevalence of coronary artery disease in patients with severe hypercholesterolaemia.
        Eur Heart J. 2017; 38: 1573-1579
        • Tada H
        • Okada H
        • Nohara A
        • Yamagishi M
        • Takamura M
        • Kawashiri MA
        Effect of cumulative exposure to low-density lipoprotein-cholesterol on cardiovascular events in patients with familial hypercholesterolemia.
        Circ J. 2021; 85: 2073-2078
        • Luirink IK
        • Wiegman A
        • Kusters DM
        • Hof MH
        • Groothoff JW
        • de Groot E
        • Kastelein JJP
        • Hutten BA
        20-year follow-up of statins in children with familial hypercholesterolemia.
        N Engl J Med. 2019; 381: 1547-1556
        • Tada H
        • Okada H
        • Nomura A
        • Nohara A
        • Yamagishi M
        • Takamura M
        • Kawashiri MA
        Prognostic impact of cascade screening for familial hypercholesterolemia on cardiovascular events.
        J Clin Lipidol. 2021; 15: 358-365
        • Nagahara K
        • Nishibukuro T
        • Ogiwara Y
        • Ikegawa K
        • Tada H
        • Yamagishi M
        • Kawashiri MA
        • Ochi A
        • Toyoda J
        • Nakano Y
        • Adachi M
        • Mizuno K
        • Hasegawa Y
        • Dobashi K
        Genetic analysis of Japanese children clinically diagnosed with familial hypercholesterolemia.
        J Atheroscler Thromb. 2022; (in press)
        • Ma N
        • Zhang JZ
        • Itzhaki I
        • Zhang SL
        • Chen H
        • Haddad F
        • Kitani T
        • Wilson KD
        • Tian L
        • Shrestha R
        • Wu H
        • Lam CK
        • Sayed N
        • Wu JC
        Determining the pathogenicity of a genomic variant of uncertain significance using CRISPR/Cas9 and human-induced pluripotent stem cells.
        Circulation. 2018; 138: 2666-2681
        • Di Costanzo A
        • Minicocci I
        • D'Erasmo L
        • Commodari D
        • Covino S
        • Bini S
        • Ghadiri A
        • Ceci F
        • Maranghi M
        • Catapano AL
        • Gazzotti M
        • Casula M
        • Montali A
        • Arca M
        Refinement of pathogenicity classification of variants associated with familial hypercholesterolemia: implications for clinical diagnosis.
        J Clin Lipidol. 2021; 15: 822-831
        • Richards S
        • Aziz N
        • Bale S
        • Bick D
        • Das S
        • Gastier-Foster J
        • Grody WW
        • Hegde M
        • Lyon E
        • Spector E
        • Voelkerding K
        • Rehm HL
        ACMG Laboratory Quality Assurance Committee: 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
        • Harada-Shiba M
        • Arai H
        • Ishigaki Y
        • Ishibashi S
        • Okamura T
        • Ogura M
        • Dobashi K
        • Nohara A
        • Bujo H
        • Miyauchi K
        • Yamashita S
        • Yokote K
        Working Group by Japan Atherosclerosis Society for Making Guidance of Familial Hypercholesterolemia: Guidelines for diagnosis and treatment of familial hypercholesterolemia.
        J Atheroscler Thromb. 2018; 25: 751-770
        • Araki E
        • Goto A
        • Kondo T
        • Noda M
        • Noto H
        • Origasa H
        • Osawa H
        • Taguchi A
        • Tanizawa Y
        • Tobe K
        • Yoshioka N
        Japanese clinical practice guideline for diabetes 2019.
        J Diabetes Investig. 2020; 11: 1020-1076
        • Tada H
        • Kawashiri MA
        • Nomura A
        • Teramoto R
        • Hosomichi K
        • Nohara A
        • Inazu A
        • Mabuchi H
        • Tajima A
        • Yamagishi M
        Oligogenic familial hypercholesterolemia, LDL cholesterol, and coronary artery disease.
        J Clin Lipidol. 2018; 12: 1436-1444
        • Yamamoto T
        • Shimojima K
        • Ondo Y
        • Imai K
        • Chong PF
        • Kira R
        • Amemiya M
        • Saito A
        • Okamoto N
        Challenges in detecting genomic copy number aberrations using next-generation sequencing data and the eXome Hidden Markov Model: a clinical exome-first diagnostic approach.
        Hum Genome Var. 2016; 3: 16025
        • Nohara A
        • Tada H
        • Ogura M
        • Okazaki S
        • Ono K
        • Shimano H
        • Daida H
        • Dobashi K
        • Hayashi T
        • Hori M
        • Matsuki K
        • Minamino T
        • Yokoyama S
        • Harada-Shiba M
        Homozygous familial hypercholesterolemia.
        J Atheroscler Thromb. 2021; 28: 665-678
        • Yamashita S
        • Masuda D
        • Harada-Shiba M
        • Arai H
        • Bujo H
        • Ishibashi S
        • Daida H
        • Koga N
        • Oikawa S
        Effectiveness and safety of lipid-lowering drug treatments in Japanese patients with familial hypercholesterolemia: familial hypercholesterolemia expert forum (FAME) study.
        J Atheroscler Thromb. 2022; 29: 608-638
        • 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
        • Tada H
        • Kojima N
        • Yamagami K
        • Nomura A
        • Nohara A
        • Usui S
        • Sakata K
        • Fujino N
        • Takamura M
        • Kawashiri MA
        Effects of different types of pathogenic variants on phenotypes of familial hypercholesterolemia.
        Front Genet. 2022; 13872056