Possible association of the human KCNE1 (minK) gene and QT interval in healthy subjects

Evidence from association and linkage analyses in Israeli families

Yechiel Friedlander, M. Vatta, N. Sotoodehnia, R. Sinnreich, H. Li, O. Manor, Jeffrey Towbin, D. S. Siscovick, J. D. Kark

Research output: Contribution to journalArticle

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Abstract

QT interval prolongation is associated with increased risk of sudden and non-sudden cardiac death. Potassium channel gene variants are associated with inherited long QT syndromes. Using linkage and association analyses, we investigated whether variants in the potassium channel subunit KCNE1 are associated with QTc intervals in an unselected population sample of 80 kindreds living in kibbutz settlements in Israel. Variance-component linkage analysis revealed weak evidence of linkage of KCNE1 polymorphisms with QTc intervals. Family-based association analysis showed a significant association between the G38S polymorphism and QTc interval. Further quantitative trait association analysis demonstrated a significant residual heritability component (h2 = 0.33), and that the effect of the G38S variant allele is modified by gender. Estimated maximum likelihood parameters from these models indicated that male gender, age, hypertension, diabetes, hypercholesterolemia, fibrinogen and BMI were positively associated with QTc interval; level of education and cigarette smoking showed an inverse association. Both erythrocyte membrane n-6 and n-3 fatty acids showed a significant inverse association with QTc interval. While more than 15.8% of QTc variability was contributed by covariates, another 4.7% was explained by dietary factors, the G38S polymorphism explained 2.2%, and approximately 36% was explained by polygenes. An in silico analysis showed also that the novel V80 SNP, another KCNE1 synonymous variant, abolishes the recognition for a splicing enhancer, which may lead to an increased effect of the G38S mutation. These results demonstrate that, in addition to polygenic background, dietary factors and other covariables, the KCNE1 G38S variant is involved in determining QTc levels in this population-based sample of families.

Original languageEnglish (US)
Pages (from-to)645-656
Number of pages12
JournalAnnals of Human Genetics
Volume69
Issue number6
DOIs
StatePublished - Nov 1 2005
Externally publishedYes

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Mink
Potassium Channels
Healthy Volunteers
Long QT Syndrome
Omega-3 Fatty Acids
Erythrocyte Membrane
Israel
Hypercholesterolemia
Computer Simulation
Fibrinogen
Population
Genes
Single Nucleotide Polymorphism
Smoking
Alleles
Hypertension
Education
Mutation

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Possible association of the human KCNE1 (minK) gene and QT interval in healthy subjects : Evidence from association and linkage analyses in Israeli families. / Friedlander, Yechiel; Vatta, M.; Sotoodehnia, N.; Sinnreich, R.; Li, H.; Manor, O.; Towbin, Jeffrey; Siscovick, D. S.; Kark, J. D.

In: Annals of Human Genetics, Vol. 69, No. 6, 01.11.2005, p. 645-656.

Research output: Contribution to journalArticle

Friedlander, Yechiel ; Vatta, M. ; Sotoodehnia, N. ; Sinnreich, R. ; Li, H. ; Manor, O. ; Towbin, Jeffrey ; Siscovick, D. S. ; Kark, J. D. / Possible association of the human KCNE1 (minK) gene and QT interval in healthy subjects : Evidence from association and linkage analyses in Israeli families. In: Annals of Human Genetics. 2005 ; Vol. 69, No. 6. pp. 645-656.
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abstract = "QT interval prolongation is associated with increased risk of sudden and non-sudden cardiac death. Potassium channel gene variants are associated with inherited long QT syndromes. Using linkage and association analyses, we investigated whether variants in the potassium channel subunit KCNE1 are associated with QTc intervals in an unselected population sample of 80 kindreds living in kibbutz settlements in Israel. Variance-component linkage analysis revealed weak evidence of linkage of KCNE1 polymorphisms with QTc intervals. Family-based association analysis showed a significant association between the G38S polymorphism and QTc interval. Further quantitative trait association analysis demonstrated a significant residual heritability component (h2 = 0.33), and that the effect of the G38S variant allele is modified by gender. Estimated maximum likelihood parameters from these models indicated that male gender, age, hypertension, diabetes, hypercholesterolemia, fibrinogen and BMI were positively associated with QTc interval; level of education and cigarette smoking showed an inverse association. Both erythrocyte membrane n-6 and n-3 fatty acids showed a significant inverse association with QTc interval. While more than 15.8{\%} of QTc variability was contributed by covariates, another 4.7{\%} was explained by dietary factors, the G38S polymorphism explained 2.2{\%}, and approximately 36{\%} was explained by polygenes. An in silico analysis showed also that the novel V80 SNP, another KCNE1 synonymous variant, abolishes the recognition for a splicing enhancer, which may lead to an increased effect of the G38S mutation. These results demonstrate that, in addition to polygenic background, dietary factors and other covariables, the KCNE1 G38S variant is involved in determining QTc levels in this population-based sample of families.",
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AU - Vatta, M.

AU - Sotoodehnia, N.

AU - Sinnreich, R.

AU - Li, H.

AU - Manor, O.

AU - Towbin, Jeffrey

AU - Siscovick, D. S.

AU - Kark, J. D.

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N2 - QT interval prolongation is associated with increased risk of sudden and non-sudden cardiac death. Potassium channel gene variants are associated with inherited long QT syndromes. Using linkage and association analyses, we investigated whether variants in the potassium channel subunit KCNE1 are associated with QTc intervals in an unselected population sample of 80 kindreds living in kibbutz settlements in Israel. Variance-component linkage analysis revealed weak evidence of linkage of KCNE1 polymorphisms with QTc intervals. Family-based association analysis showed a significant association between the G38S polymorphism and QTc interval. Further quantitative trait association analysis demonstrated a significant residual heritability component (h2 = 0.33), and that the effect of the G38S variant allele is modified by gender. Estimated maximum likelihood parameters from these models indicated that male gender, age, hypertension, diabetes, hypercholesterolemia, fibrinogen and BMI were positively associated with QTc interval; level of education and cigarette smoking showed an inverse association. Both erythrocyte membrane n-6 and n-3 fatty acids showed a significant inverse association with QTc interval. While more than 15.8% of QTc variability was contributed by covariates, another 4.7% was explained by dietary factors, the G38S polymorphism explained 2.2%, and approximately 36% was explained by polygenes. An in silico analysis showed also that the novel V80 SNP, another KCNE1 synonymous variant, abolishes the recognition for a splicing enhancer, which may lead to an increased effect of the G38S mutation. These results demonstrate that, in addition to polygenic background, dietary factors and other covariables, the KCNE1 G38S variant is involved in determining QTc levels in this population-based sample of families.

AB - QT interval prolongation is associated with increased risk of sudden and non-sudden cardiac death. Potassium channel gene variants are associated with inherited long QT syndromes. Using linkage and association analyses, we investigated whether variants in the potassium channel subunit KCNE1 are associated with QTc intervals in an unselected population sample of 80 kindreds living in kibbutz settlements in Israel. Variance-component linkage analysis revealed weak evidence of linkage of KCNE1 polymorphisms with QTc intervals. Family-based association analysis showed a significant association between the G38S polymorphism and QTc interval. Further quantitative trait association analysis demonstrated a significant residual heritability component (h2 = 0.33), and that the effect of the G38S variant allele is modified by gender. Estimated maximum likelihood parameters from these models indicated that male gender, age, hypertension, diabetes, hypercholesterolemia, fibrinogen and BMI were positively associated with QTc interval; level of education and cigarette smoking showed an inverse association. Both erythrocyte membrane n-6 and n-3 fatty acids showed a significant inverse association with QTc interval. While more than 15.8% of QTc variability was contributed by covariates, another 4.7% was explained by dietary factors, the G38S polymorphism explained 2.2%, and approximately 36% was explained by polygenes. An in silico analysis showed also that the novel V80 SNP, another KCNE1 synonymous variant, abolishes the recognition for a splicing enhancer, which may lead to an increased effect of the G38S mutation. These results demonstrate that, in addition to polygenic background, dietary factors and other covariables, the KCNE1 G38S variant is involved in determining QTc levels in this population-based sample of families.

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