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Common variants in KCNN3 are associated with lone atrial fibrillation.

Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, Chung MK, Sinner MF, de Bakker PI, Mueller M, Lubitz SA, Fox E, Darbar D, Smith NL, Smith JD, Schnabel RB, Soliman EZ, Rice KM, Van Wagoner DR, Beckmann BM, van Noord C, Wang K, Ehret GB, Rotter JI, Hazen SL, Steinbeck G, Smith AV, Launer LJ, Harris TB, Makino S, Nelis M, Milan DJ, Perz S, Esko T, Köttgen A, Moebus S, Newton-Cheh C, Li M, Möhlenkamp S, Wang TJ, Kao WH, Vasan RS, Nöthen MM, MacRae CA, Stricker BH, Hofman A, Uitterlinden AG, Levy D, Boerwinkle E, Metspalu A, Topol EJ, Chakravarti A, Gudnason V, Psaty BM, Roden DM, Meitinger T, Wichmann HE, Witteman JC, Barnard J, Arking DE, Benjamin EJ, Heckbert SR, Kääb S - Nat. Genet. (2010)

Bottom Line: This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF.We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents).Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital.

View Article: PubMed Central - PubMed

Affiliation: [1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [4] These authors contributed equally to this work.

ABSTRACT
Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

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Regional plot for locus on chromosome 1 associated with lone atrial fibrillationFigures prepared using SNAP20. SNPs are plotted with the meta-analysis P-value and genomic position (NCBI Build 36). The SNP of interest is labeled. The strength of the linkage disequilibrium (LD) is indicated by gradient of red. Estimated recombination rates are shown by the blue line and gene annotations are indicated by dark green arrows. LD and recombination rates are based on the CEU HapMap release 22.
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Figure 2: Regional plot for locus on chromosome 1 associated with lone atrial fibrillationFigures prepared using SNAP20. SNPs are plotted with the meta-analysis P-value and genomic position (NCBI Build 36). The SNP of interest is labeled. The strength of the linkage disequilibrium (LD) is indicated by gradient of red. Estimated recombination rates are shown by the blue line and gene annotations are indicated by dark green arrows. LD and recombination rates are based on the CEU HapMap release 22.

Mentions: A second locus identified on chromosome 1q21 had 6 SNPs that exceeded genome-wide significance. The most significant SNP was rs13376333 with an OR of 1.56 (95%CI 1.38–1.77, P=6.3×10−12, Table 2, Figures 1 and 2, Supplemental Table 2). SNP rs13376333 is located in the intron between the first and second exon of the calcium activated potassium channel KCNN3 (NM 002249). A regional plot of the locus on chromosome 1q21 is illustrated in Figure 2. Our findings at the chromosome 1q21 locus were replicated in two studies with lone AF. First, in 977 cases from the AFNET and 3,042 controls without AF from KORA S4, rs13376333 was significantly associated with lone AF (OR 1.45,95% CI 1.26–1.66, p=8.8×10−8). Second, the association was replicated in the Vanderbilt University Lone AF Registry consisting of 187 subjects with lone AF and 565 control subjects without AF (OR 1.55 95% CI 1.19–2.03, p=0.001). In a meta-analysis combining the lone AF results of the primary GWAS and the two replication cohorts, rs13376333 had an OR of 1.52 (95%CI 1.40–1.64, p=1.83×10−21).


Common variants in KCNN3 are associated with lone atrial fibrillation.

Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, Chung MK, Sinner MF, de Bakker PI, Mueller M, Lubitz SA, Fox E, Darbar D, Smith NL, Smith JD, Schnabel RB, Soliman EZ, Rice KM, Van Wagoner DR, Beckmann BM, van Noord C, Wang K, Ehret GB, Rotter JI, Hazen SL, Steinbeck G, Smith AV, Launer LJ, Harris TB, Makino S, Nelis M, Milan DJ, Perz S, Esko T, Köttgen A, Moebus S, Newton-Cheh C, Li M, Möhlenkamp S, Wang TJ, Kao WH, Vasan RS, Nöthen MM, MacRae CA, Stricker BH, Hofman A, Uitterlinden AG, Levy D, Boerwinkle E, Metspalu A, Topol EJ, Chakravarti A, Gudnason V, Psaty BM, Roden DM, Meitinger T, Wichmann HE, Witteman JC, Barnard J, Arking DE, Benjamin EJ, Heckbert SR, Kääb S - Nat. Genet. (2010)

Regional plot for locus on chromosome 1 associated with lone atrial fibrillationFigures prepared using SNAP20. SNPs are plotted with the meta-analysis P-value and genomic position (NCBI Build 36). The SNP of interest is labeled. The strength of the linkage disequilibrium (LD) is indicated by gradient of red. Estimated recombination rates are shown by the blue line and gene annotations are indicated by dark green arrows. LD and recombination rates are based on the CEU HapMap release 22.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2871387&req=5

Figure 2: Regional plot for locus on chromosome 1 associated with lone atrial fibrillationFigures prepared using SNAP20. SNPs are plotted with the meta-analysis P-value and genomic position (NCBI Build 36). The SNP of interest is labeled. The strength of the linkage disequilibrium (LD) is indicated by gradient of red. Estimated recombination rates are shown by the blue line and gene annotations are indicated by dark green arrows. LD and recombination rates are based on the CEU HapMap release 22.
Mentions: A second locus identified on chromosome 1q21 had 6 SNPs that exceeded genome-wide significance. The most significant SNP was rs13376333 with an OR of 1.56 (95%CI 1.38–1.77, P=6.3×10−12, Table 2, Figures 1 and 2, Supplemental Table 2). SNP rs13376333 is located in the intron between the first and second exon of the calcium activated potassium channel KCNN3 (NM 002249). A regional plot of the locus on chromosome 1q21 is illustrated in Figure 2. Our findings at the chromosome 1q21 locus were replicated in two studies with lone AF. First, in 977 cases from the AFNET and 3,042 controls without AF from KORA S4, rs13376333 was significantly associated with lone AF (OR 1.45,95% CI 1.26–1.66, p=8.8×10−8). Second, the association was replicated in the Vanderbilt University Lone AF Registry consisting of 187 subjects with lone AF and 565 control subjects without AF (OR 1.55 95% CI 1.19–2.03, p=0.001). In a meta-analysis combining the lone AF results of the primary GWAS and the two replication cohorts, rs13376333 had an OR of 1.52 (95%CI 1.40–1.64, p=1.83×10−21).

Bottom Line: This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF.We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents).Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital.

View Article: PubMed Central - PubMed

Affiliation: [1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [4] These authors contributed equally to this work.

ABSTRACT
Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

Show MeSH
Related in: MedlinePlus