Analysis for Genetic Modifiers of Disease Severity in Patients with Long-QT Syndrome Type 2

Iris C R M Kolder, Michael W T Tanck, Pieter G. Postema, Julien Barc, Moritz F. Sinner, Sven Zumhagen, Anja Husemann, Birgit Stallmeyer, Tamara T. Koopmann, Nynke Hofman, Arne Pfeufer, Peter Lichtner, Thomas Meitinger, Britt M. Beckmann, Robert J Myerburg, Nanette Bishopric, Dan M. Roden, Stefan Kääb, Arthur A M Wilde, Jean Jacques SchottEric Schulze-Bahr, Connie R. Bezzina

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background - Considerable interest exists in the identification of genetic modifiers of disease severity in the long-QT syndrome (LQTS) as their identification may contribute to refinement of risk stratification. Methods and Results - We searched for single-nucleotide polymorphisms (SNPs) that modulate the corrected QT (QTc)-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, P=9.5×10<sup>-8</sup>; rs12143842, P=4.8×10<sup>-7</sup>; and rs2880058, P=8.6×10<sup>-7</sup>) were strongly associated with the QTc-interval with marked effects (>12 ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454; odds ratio, 1.85; 95% confidence interval, 1.32-2.59; P=3×10<sup>-4</sup>) and KCNQ1 (rs12576239; odds ratio, 1.84; 95% confidence interval, 1.31-2.60; P=5×10<sup>-4</sup>). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multilocus genetic risk score (GRS<inf>NOS1AP</inf>) uncovered a strong linear relationship between GRS<inf>NOS1AP</inf> and the QTc-interval (P=4.2×10<sup>-7</sup>). Furthermore, patients with a GRS<inf>NOS1AP</inf> in the lowest quartile had a lower relative risk of cardiac events compared with patients in the other quartiles combined (P=0.039). Conclusions - We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time, we linked common genetic variation at KCNQ1 with risk of long-QT syndrome.

Original languageEnglish (US)
Pages (from-to)447-456
Number of pages10
JournalCirculation: Cardiovascular Genetics
Volume8
Issue number3
DOIs
StatePublished - Jun 11 2015

Fingerprint

Long QT Syndrome
Inborn Genetic Diseases
Single Nucleotide Polymorphism
Alleles
Odds Ratio
Confidence Intervals
Population Control
Genome-Wide Association Study
Mutation
Population
Genes

Keywords

  • arrhythmias cardiac
  • ion channels
  • long-QT syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

Kolder, I. C. R. M., Tanck, M. W. T., Postema, P. G., Barc, J., Sinner, M. F., Zumhagen, S., ... Bezzina, C. R. (2015). Analysis for Genetic Modifiers of Disease Severity in Patients with Long-QT Syndrome Type 2. Circulation: Cardiovascular Genetics, 8(3), 447-456. https://doi.org/10.1161/CIRCGENETICS.114.000785

Analysis for Genetic Modifiers of Disease Severity in Patients with Long-QT Syndrome Type 2. / Kolder, Iris C R M; Tanck, Michael W T; Postema, Pieter G.; Barc, Julien; Sinner, Moritz F.; Zumhagen, Sven; Husemann, Anja; Stallmeyer, Birgit; Koopmann, Tamara T.; Hofman, Nynke; Pfeufer, Arne; Lichtner, Peter; Meitinger, Thomas; Beckmann, Britt M.; Myerburg, Robert J; Bishopric, Nanette; Roden, Dan M.; Kääb, Stefan; Wilde, Arthur A M; Schott, Jean Jacques; Schulze-Bahr, Eric; Bezzina, Connie R.

In: Circulation: Cardiovascular Genetics, Vol. 8, No. 3, 11.06.2015, p. 447-456.

Research output: Contribution to journalArticle

Kolder, ICRM, Tanck, MWT, Postema, PG, Barc, J, Sinner, MF, Zumhagen, S, Husemann, A, Stallmeyer, B, Koopmann, TT, Hofman, N, Pfeufer, A, Lichtner, P, Meitinger, T, Beckmann, BM, Myerburg, RJ, Bishopric, N, Roden, DM, Kääb, S, Wilde, AAM, Schott, JJ, Schulze-Bahr, E & Bezzina, CR 2015, 'Analysis for Genetic Modifiers of Disease Severity in Patients with Long-QT Syndrome Type 2', Circulation: Cardiovascular Genetics, vol. 8, no. 3, pp. 447-456. https://doi.org/10.1161/CIRCGENETICS.114.000785
Kolder, Iris C R M ; Tanck, Michael W T ; Postema, Pieter G. ; Barc, Julien ; Sinner, Moritz F. ; Zumhagen, Sven ; Husemann, Anja ; Stallmeyer, Birgit ; Koopmann, Tamara T. ; Hofman, Nynke ; Pfeufer, Arne ; Lichtner, Peter ; Meitinger, Thomas ; Beckmann, Britt M. ; Myerburg, Robert J ; Bishopric, Nanette ; Roden, Dan M. ; Kääb, Stefan ; Wilde, Arthur A M ; Schott, Jean Jacques ; Schulze-Bahr, Eric ; Bezzina, Connie R. / Analysis for Genetic Modifiers of Disease Severity in Patients with Long-QT Syndrome Type 2. In: Circulation: Cardiovascular Genetics. 2015 ; Vol. 8, No. 3. pp. 447-456.
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AU - Kolder, Iris C R M

AU - Tanck, Michael W T

AU - Postema, Pieter G.

AU - Barc, Julien

AU - Sinner, Moritz F.

AU - Zumhagen, Sven

AU - Husemann, Anja

AU - Stallmeyer, Birgit

AU - Koopmann, Tamara T.

AU - Hofman, Nynke

AU - Pfeufer, Arne

AU - Lichtner, Peter

AU - Meitinger, Thomas

AU - Beckmann, Britt M.

AU - Myerburg, Robert J

AU - Bishopric, Nanette

AU - Roden, Dan M.

AU - Kääb, Stefan

AU - Wilde, Arthur A M

AU - Schott, Jean Jacques

AU - Schulze-Bahr, Eric

AU - Bezzina, Connie R.

PY - 2015/6/11

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N2 - Background - Considerable interest exists in the identification of genetic modifiers of disease severity in the long-QT syndrome (LQTS) as their identification may contribute to refinement of risk stratification. Methods and Results - We searched for single-nucleotide polymorphisms (SNPs) that modulate the corrected QT (QTc)-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, P=9.5×10-8; rs12143842, P=4.8×10-7; and rs2880058, P=8.6×10-7) were strongly associated with the QTc-interval with marked effects (>12 ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454; odds ratio, 1.85; 95% confidence interval, 1.32-2.59; P=3×10-4) and KCNQ1 (rs12576239; odds ratio, 1.84; 95% confidence interval, 1.31-2.60; P=5×10-4). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multilocus genetic risk score (GRSNOS1AP) uncovered a strong linear relationship between GRSNOS1AP and the QTc-interval (P=4.2×10-7). Furthermore, patients with a GRSNOS1AP in the lowest quartile had a lower relative risk of cardiac events compared with patients in the other quartiles combined (P=0.039). Conclusions - We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time, we linked common genetic variation at KCNQ1 with risk of long-QT syndrome.

AB - Background - Considerable interest exists in the identification of genetic modifiers of disease severity in the long-QT syndrome (LQTS) as their identification may contribute to refinement of risk stratification. Methods and Results - We searched for single-nucleotide polymorphisms (SNPs) that modulate the corrected QT (QTc)-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, P=9.5×10-8; rs12143842, P=4.8×10-7; and rs2880058, P=8.6×10-7) were strongly associated with the QTc-interval with marked effects (>12 ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454; odds ratio, 1.85; 95% confidence interval, 1.32-2.59; P=3×10-4) and KCNQ1 (rs12576239; odds ratio, 1.84; 95% confidence interval, 1.31-2.60; P=5×10-4). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multilocus genetic risk score (GRSNOS1AP) uncovered a strong linear relationship between GRSNOS1AP and the QTc-interval (P=4.2×10-7). Furthermore, patients with a GRSNOS1AP in the lowest quartile had a lower relative risk of cardiac events compared with patients in the other quartiles combined (P=0.039). Conclusions - We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time, we linked common genetic variation at KCNQ1 with risk of long-QT syndrome.

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KW - ion channels

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