Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.

National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
Nature Genetics (Impact Factor: 29.65). 09/2009; 41(8):879-81. DOI: 10.1038/ng.416
Source: PubMed

ABSTRACT We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).

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Available from: Thor Aspelund, Jul 30, 2015
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    • "Although good progress has been made in the characterisation of factors that cause AF (Camm et al., 2012a,b; Schotten et al., 2011; Wakili et al., 2011), there is still an unmet need for better therapies to prevent incident and recurrent AF (Camm et al., 2012a,b; Kirchhof et al., 2013). Unravelling the mechanisms conveying the genetic basis of atrial fibrillation (Benjamin et al., 2009; Ellinor et al., 2012; Gudbjartsson et al., 2007) is a promising and relatively new avenue to novel preventive and therapeutic targets. Genetically altered murine models are popular tools for the study of molecular disease mechanisms, including of atrial fibrillation. "
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    ABSTRACT: We developed and validated a new optical mapping system for quantification of electrical activation and repolarisation in murine atria. The system makes use of a novel 2(nd) generation complementary metal-oxide-semiconductor (CMOS) camera with deliberate oversampling to allow both assessment of electrical activation with high spatial and temporal resolution (128 x 2048 pixels) and reliable assessment of atrial murine repolarisation using post-processing of signals. Optical recordings were taken from isolated, superfused and electrically stimulated murine left atria. The system reliably describes activation sequences, identifies areas of functional block, and allows quantification of conduction velocities and vectors. Furthermore, the system records murine atrial action potentials with comparable duration to both monophasic and transmembrane action potentials in murine atria.
    Progress in Biophysics and Molecular Biology 08/2014; 115(2-3). DOI:10.1016/j.pbiomolbio.2014.07.012 · 3.38 Impact Factor
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    • "The AT-motif binding factor 1/zinc finger homeobox 3 (ATBF1/ ZFHX3) gene encodes a large protein structurally characterized by multiple zinc-finger motifs and four homeodomains [1]. ATBF1 appears to play a role in neuronal differentiation and cell death [2] [3] [4], atrial fibrillation [5] [6], and embryonic development [7]. ATBF1 could be a tumor suppressor in several organs including the prostate, "
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    ABSTRACT: The ATBF1/ZFHX3 gene at 16q22 is the second most frequently mutated gene in human prostate cancer and has reduced expression or mislocalization in several types of human tumors. Nonetheless, the hypothesis that ATBF1 has a tumor suppressor function in prostate cancer has not been tested. In this study, we examined the role of ATBF1 in prostatic carcinogenesis by specifically deleting Atbf1 in mouse prostatic epithelial cells. We also examined the effect of Atbf1 deletion on gene expression and signaling pathways in mouse prostates. Histopathologic analyses showed that Atbf1 deficiency caused hyperplasia and mouse prostatic intraepithelial neoplasia (mPIN) primarily in the dorsal prostate but also in other lobes. Hemizygous deletion of Atbf1 also increased the development of hyperplasia and mPIN, indicating a haploinsufficiency of Atbf1. The mPIN lesions expressed luminal cell markers and harbored molecular changes similar to those in human PIN and prostate cancer, including weaker expression of basal cell marker cytokeratin 5 (Ck5), cell adhesion protein E-cadherin, and the smooth muscle layer marker Sma; elevated expression of the oncoproteins phospho-Erk1/2, phospho-Akt and Muc1; and aberrant protein glycosylation. Gene expression profiling revealed a large number of genes that were dysregulated by Atbf1 deletion, particularly those that encode for secretory and cell membrane proteins. The four signaling networks that were most affected by Atbf1 deletion included those centered on Erk1/2 and IGF1, Akt and FSH, NF- k B and progesterone and β-estradiol. These findings provide in vivo evidence that ATBF1 is a tumor suppressor in the prostate, suggest that loss of Atbf1 contributes to tumorigenesis by dysregulating membrane and secretory proteins and multiple signaling pathways, and provide a new animal model for prostate cancer.
    Neoplasia (New York, N.Y.) 05/2014; In press(5). DOI:10.1016/j.neo.2014.05.001 · 5.40 Impact Factor
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    ABSTRACT: Objectives: The aim of this study was to screen lone atrial fibrillation (AF) patients for mutations in the genes KCNJ2, KCNJ3 and KCNJ5, all encoding potassium channels. Furthermore, we wanted to replicate the prior association of two single-nucleotide polymorphisms (SNPs) in KCNJ5, C171T (rs6590357) and G810T (rs7118824), with lone AF in Han Chinese. Methods: We sequenced the coding region and splice site of KCNJ2, KCNJ3 and KCNJ5 in 187 early-onset lone-AF patients screening for mutations and counting SNP frequencies for the two noted SNPs in KCNJ5. Results: No mutations were found in KCNJ2, KCNJ3 or KCNJ5. Both genotype distribution and allele frequencies of the SNPs rs6590357 and rs7118824 significantly differed between the AF and control group (pgenotype = 0.0067, pallele = 0.0021 and pgenotype = 0.014, pallele = 0.0101, respectively). On allele level, the OR for lone AF for rs6590357 was 1.77 (95% CI 1.16–2.73, p = 0.009) and for rs7118824 it was 1.71 (95% CI 1.13–2.57, p = 0.01) in a model adjusted for age and gender. Conclusions: Our findings indicate that rs6590357 and rs7118824 in KCNJ5 are associated with early-onset lone AF in Caucasians. No mutations were found in the exon or splice site of KCNJ2, KCNJ3 or KCNJ5.
    Cardiology 01/2011; 118(2):116-120. DOI:10.1159/000323840 · 2.04 Impact Factor
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