Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome

Christian Jons; Arthur J Moss; Coeli M Lopes; Scott McNitt; Wojciech Zareba; Ilan Goldenberg; Ming Qi; Arthur A M Wilde; Wataru Shimizu; Jørgen K. Kanters; Jeffrey A Towbin; Michael J Ackerman; Jennifer L Robinson

doi:10.1111/j.1540-8167.2009.01455.x

Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome

Christian Jons, Arthur J Moss, Coeli M Lopes, Scott McNitt, Wojciech Zareba, Ilan Goldenberg, Ming Qi, Arthur A M Wilde, Wataru Shimizu, Jørgen K. Kanters, Jeffrey A Towbin, Michael J Ackerman, Jennifer L Robinson

Physiology of circulation, kidney and lung

30 Citations (Scopus)

Abstract

BACKGROUND: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac events. METHODS AND RESULTS: The study population involved 492 LQT1 patients with 54 missense mutations in the transmembrane region of the KCNQ1 channel. The amino acid sequences of the transmembrane region of 38 human voltage-gated potassium channels were aligned. An adjusted Shannon entropy score for each amino acid residue was calculated ranging from 0 (no conservation) to 1.0 (full conservation). Cox analysis was used to identify independent factors associated with the first cardiac event (syncope, aborted cardiac arrest, or death). Patients were subcategorized into tertiles by their adjusted Shannon entropy scores. The lowest tertile (score 0-0.469; n = 146) was used as a reference group; patients with intermediate tertile scores (0.470-0.665; n = 150) had no increased risk of cardiac events (HR = 1.19, P = 0.42) or aborted cardiac arrest/sudden cardiac death (HR = 1.58, P = 0.26), and those with the highest tertile scores (>0.665; n = 196) showed significantly increased risk of cardiac events (HR = 3.32, P <0.001) and aborted cardiac arrest/sudden cardiac death (HR = 2.62, P = 0.04). The increased risk in patients with the highest conservation scores was independent of QTc, gender, age, and beta-blocker therapy. CONCLUSIONS: Mutations in highly conserved amino acid residues in the KCNQ1 gene are associated with a significant risk of cardiac events independent of QTc, gender, and beta-blocker therapy
Udgivelsesdato: 2009/8

Original language	English
Journal	Cardiovascular Electrophysiology
Volume	20
Issue number	8
Pages (from-to)	859-865
Number of pages	7
ISSN	1045-3873
DOIs	https://doi.org/10.1111/j.1540-8167.2009.01455.x
Publication status	Published - 2009

Keywords

Adolescent
Adult
Amino Acid Sequence
Cardiovascular Diseases
Child
Child, Preschool
Computational Biology
Conserved Sequence
Female
Follow-Up Studies
Humans
Infant
Infant, Newborn
KCNQ1 Potassium Channel
Male
Molecular Sequence Data
Mutation, Missense
Risk Factors
Romano-Ward Syndrome
Young Adult

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10.1111/j.1540-8167.2009.01455.x

Cite this

Jons, C., Moss, A. J., Lopes, C. M., McNitt, S., Zareba, W., Goldenberg, I., Qi, M., Wilde, A. A. M., Shimizu, W., Kanters, J. K., Towbin, J. A., Ackerman, M. J., & Robinson, J. L. (2009). Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome. Cardiovascular Electrophysiology, 20(8), 859-865. https://doi.org/10.1111/j.1540-8167.2009.01455.x

Jons, C, Moss, AJ, Lopes, CM, McNitt, S, Zareba, W, Goldenberg, I, Qi, M, Wilde, AAM, Shimizu, W, Kanters, JK, Towbin, JA, Ackerman, MJ & Robinson, JL 2009, 'Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome', Cardiovascular Electrophysiology, vol. 20, no. 8, pp. 859-865. https://doi.org/10.1111/j.1540-8167.2009.01455.x

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title = "Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome",

abstract = "BACKGROUND: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac events. METHODS AND RESULTS: The study population involved 492 LQT1 patients with 54 missense mutations in the transmembrane region of the KCNQ1 channel. The amino acid sequences of the transmembrane region of 38 human voltage-gated potassium channels were aligned. An adjusted Shannon entropy score for each amino acid residue was calculated ranging from 0 (no conservation) to 1.0 (full conservation). Cox analysis was used to identify independent factors associated with the first cardiac event (syncope, aborted cardiac arrest, or death). Patients were subcategorized into tertiles by their adjusted Shannon entropy scores. The lowest tertile (score 0-0.469; n = 146) was used as a reference group; patients with intermediate tertile scores (0.470-0.665; n = 150) had no increased risk of cardiac events (HR = 1.19, P = 0.42) or aborted cardiac arrest/sudden cardiac death (HR = 1.58, P = 0.26), and those with the highest tertile scores (>0.665; n = 196) showed significantly increased risk of cardiac events (HR = 3.32, P <0.001) and aborted cardiac arrest/sudden cardiac death (HR = 2.62, P = 0.04). The increased risk in patients with the highest conservation scores was independent of QTc, gender, age, and beta-blocker therapy. CONCLUSIONS: Mutations in highly conserved amino acid residues in the KCNQ1 gene are associated with a significant risk of cardiac events independent of QTc, gender, and beta-blocker therapy Udgivelsesdato: 2009/8",

keywords = "Adolescent, Adult, Amino Acid Sequence, Cardiovascular Diseases, Child, Child, Preschool, Computational Biology, Conserved Sequence, Female, Follow-Up Studies, Humans, Infant, Infant, Newborn, KCNQ1 Potassium Channel, Male, Molecular Sequence Data, Mutation, Missense, Risk Factors, Romano-Ward Syndrome, Young Adult",

author = "Christian Jons and Moss, {Arthur J} and Lopes, {Coeli M} and Scott McNitt and Wojciech Zareba and Ilan Goldenberg and Ming Qi and Wilde, {Arthur A M} and Wataru Shimizu and Kanters, {J{\o}rgen K.} and Towbin, {Jeffrey A} and Ackerman, {Michael J} and Robinson, {Jennifer L}",

year = "2009",

doi = "10.1111/j.1540-8167.2009.01455.x",

language = "English",

volume = "20",

pages = "859--865",

journal = "Journal of Cardiovascular Electrophysiology",

issn = "1045-3873",

publisher = "Wiley-Blackwell",

number = "8",

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TY - JOUR

T1 - Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome

AU - Jons, Christian

AU - Moss, Arthur J

AU - Lopes, Coeli M

AU - McNitt, Scott

AU - Zareba, Wojciech

AU - Goldenberg, Ilan

AU - Qi, Ming

AU - Wilde, Arthur A M

AU - Shimizu, Wataru

AU - Kanters, Jørgen K.

AU - Towbin, Jeffrey A

AU - Ackerman, Michael J

AU - Robinson, Jennifer L

PY - 2009

Y1 - 2009

N2 - BACKGROUND: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac events. METHODS AND RESULTS: The study population involved 492 LQT1 patients with 54 missense mutations in the transmembrane region of the KCNQ1 channel. The amino acid sequences of the transmembrane region of 38 human voltage-gated potassium channels were aligned. An adjusted Shannon entropy score for each amino acid residue was calculated ranging from 0 (no conservation) to 1.0 (full conservation). Cox analysis was used to identify independent factors associated with the first cardiac event (syncope, aborted cardiac arrest, or death). Patients were subcategorized into tertiles by their adjusted Shannon entropy scores. The lowest tertile (score 0-0.469; n = 146) was used as a reference group; patients with intermediate tertile scores (0.470-0.665; n = 150) had no increased risk of cardiac events (HR = 1.19, P = 0.42) or aborted cardiac arrest/sudden cardiac death (HR = 1.58, P = 0.26), and those with the highest tertile scores (>0.665; n = 196) showed significantly increased risk of cardiac events (HR = 3.32, P <0.001) and aborted cardiac arrest/sudden cardiac death (HR = 2.62, P = 0.04). The increased risk in patients with the highest conservation scores was independent of QTc, gender, age, and beta-blocker therapy. CONCLUSIONS: Mutations in highly conserved amino acid residues in the KCNQ1 gene are associated with a significant risk of cardiac events independent of QTc, gender, and beta-blocker therapy Udgivelsesdato: 2009/8

AB - BACKGROUND: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac events. METHODS AND RESULTS: The study population involved 492 LQT1 patients with 54 missense mutations in the transmembrane region of the KCNQ1 channel. The amino acid sequences of the transmembrane region of 38 human voltage-gated potassium channels were aligned. An adjusted Shannon entropy score for each amino acid residue was calculated ranging from 0 (no conservation) to 1.0 (full conservation). Cox analysis was used to identify independent factors associated with the first cardiac event (syncope, aborted cardiac arrest, or death). Patients were subcategorized into tertiles by their adjusted Shannon entropy scores. The lowest tertile (score 0-0.469; n = 146) was used as a reference group; patients with intermediate tertile scores (0.470-0.665; n = 150) had no increased risk of cardiac events (HR = 1.19, P = 0.42) or aborted cardiac arrest/sudden cardiac death (HR = 1.58, P = 0.26), and those with the highest tertile scores (>0.665; n = 196) showed significantly increased risk of cardiac events (HR = 3.32, P <0.001) and aborted cardiac arrest/sudden cardiac death (HR = 2.62, P = 0.04). The increased risk in patients with the highest conservation scores was independent of QTc, gender, age, and beta-blocker therapy. CONCLUSIONS: Mutations in highly conserved amino acid residues in the KCNQ1 gene are associated with a significant risk of cardiac events independent of QTc, gender, and beta-blocker therapy Udgivelsesdato: 2009/8

KW - Adolescent

KW - Adult

KW - Amino Acid Sequence

KW - Cardiovascular Diseases

KW - Child

KW - Child, Preschool

KW - Computational Biology

KW - Conserved Sequence

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - KCNQ1 Potassium Channel

KW - Male

KW - Molecular Sequence Data

KW - Mutation, Missense

KW - Risk Factors

KW - Romano-Ward Syndrome

KW - Young Adult

U2 - 10.1111/j.1540-8167.2009.01455.x

DO - 10.1111/j.1540-8167.2009.01455.x

M3 - Journal article

C2 - 19490272

SN - 1045-3873

VL - 20

SP - 859

EP - 865

JO - Journal of Cardiovascular Electrophysiology

JF - Journal of Cardiovascular Electrophysiology

IS - 8

ER -