Phenotypic Variability in Caucasian and Japanese Patients with Matched LQT1 Mutations

Authors

  • Judy F. Liu M.S.,

    1. Cardiology Division of the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
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  • Ilan Goldenberg M.D.,

    1. Cardiology Division of the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
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  • Arthur J. Moss M.D.,

    1. Cardiology Division of the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
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  • Wataru Shimizu M.D., Ph.D.,

    1. the Division of Cardiology, Department of Internal Medicine and Laboratory of Molecular Genetics, National Cardiovascular Center, Suita, Japan
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  • Arthur A. Wilde M.D., Ph.D.,

    1. the Experimental and Molecular Cardiology Group and the Department of Clinical Genetics, Academic Medical Center, AZ Amsterdam, The Netherlands
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  • Nynke Hofman M.Sc.,

    1. the Experimental and Molecular Cardiology Group and the Department of Clinical Genetics, Academic Medical Center, AZ Amsterdam, The Netherlands
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  • Scott McNitt M.S.,

    1. Cardiology Division of the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
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  • Wojciech Zareba M.D., Ph.D.,

    1. Cardiology Division of the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
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  • Yoshihiro Miyamato M.D., Ph.D.,

    1. the Division of Cardiology, Department of Internal Medicine and Laboratory of Molecular Genetics, National Cardiovascular Center, Suita, Japan
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  • Jennifer L. Robinson M.S.,

    1. Cardiology Division of the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
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  • Mark L. Andrews B.B.A.

    1. Cardiology Division of the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
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  • Financial support: This study was supported in part by research grants HL-33843 and HL-51618 from the National Institutes of Health, Bethesda, Maryland.

Address for reprints: Ilan Goldenberg, M.D., Heart Research Follow-Up Program, Box 653, University of Rochester Medical Center, Rochester, NY 14642. Fax: 585-273-5283; E-mail: Ilan.Goldenberg@heart.rochester.edu

Abstract

Background: Ethnic differences may affect the phenotypic expression of genetic disorders. However, data regarding the effect of ethnicity on outcome in patients with genetic cardiac disorders are limited. We compared the clinical course of Caucasian and Japanese long QT type-1 (LQT1) patients who were matched for mutations in the KCNQ1 gene.

Methods: The study population comprised 62 Caucasian and 38 Japanese LQT1 patients from the International LQTS Registry who were identified as having six identical KCNQ1 mutations. The biophysical function of the mutations was categorized into dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. The primary end point of the study was the occurrence of a first cardiac event from birth through age 40 years.

Results: Japanese patients had a significantly higher cumulative rate of cardiac events (67%) than Caucasian patients (39%; P = 0.01). The respective frequencies of dominant negative mutations in the two ethnic groups were 63% and 28% (P < 0.001). In multivariate analysis, Japanese patients had an 81% increase in the risk of cardiac events (P = 0.06) as compared with Caucasians. However, when the biophysical function of the mutations was included in the multivariate model, the risk associated with Japanese ethnicity was no longer evident (HR = 1.05; P = 0.89). Harboring a dominant negative mutation was shown to be the most powerful and significant predictor of outcome (HR = 3.78; P < 0.001).

Conclusions: Our data indicate that ethnic differences in the clinical expression of LQTS can be attributed to the differences in frequencies of the specific mutations within the two populations.

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