Benjamin, E. J. et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat. Genet. 41, 879-881

National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
Nature Genetics (Impact Factor: 29.35). 09/2009; 41(8):879-81. DOI: 10.1038/ng.416
Source: PubMed


We conducted meta-analyses of genome-wide association studies (GWAS) 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 novel locus for AF (ZFHX3, rs2106261, risk ratio [RR]=1.19; P=2.3×10−7), an association that was replicated in the German AF Network (odds ratio=1.44; P=1.6×10−11). Combining the discovery and replication results, rs2106261 was significantly associated with AF (RR=1.25; P=1.8×10−15).

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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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    Progress in Biophysics and Molecular Biology 08/2014; 115(2-3). DOI:10.1016/j.pbiomolbio.2014.07.012 · 2.27 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.
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    • "This common cardiac arrhythmia is associated with increased morbidity, mortality, and significant healthcare costs [18]. Numerous common genetic variants associated with atrial fibrillation risk have been identified [19-22] and rare genetic variants are expected to improve the detection of at-risk individuals [23,24]. "
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    ABSTRACT: It is often assumed that rare genetic variants will improve available risk prediction scores. We aimed to estimate the added predictive ability of rare variants for risk prediction of common diseases in hypothetical scenarios. In simulated data, we constructed risk models with an area under the ROC curve (AUC) ranging between 0.50 and 0.95, to which we added a single variant representing the cumulative frequency and effect (odds ratio, OR) of multiple rare variants. The frequency of the rare variant ranged between 0.0001 and 0.01 and the OR between 2 and 10. We assessed the resulting AUC, increment in AUC, integrated discrimination improvement (IDI), net reclassification improvement (NRI(>0.01)) and categorical NRI. The analyses were illustrated by a simulation of atrial fibrillation risk prediction based on a published clinical risk model. We observed minimal improvement in AUC with the addition of rare variants. All measures increased with the frequency and OR of the variant, but maximum increment in AUC remained below 0.05. Increment in AUC and NRI(>0.01) decreased with higher AUC of the baseline model, whereas IDI remained constant. In the atrial fibrillation example, the maximum increment in AUC was 0.02 for a variant with frequency=0.01 and OR=10. IDI and NRI showed at most minimal increase for variants with frequency greater than or equal to 0.005 and OR greater than or equal to 5. Since rare variants are present in only a minority of affected individuals, their predictive ability is generally low at the population level. To improve the predictive ability of clinical risk models for complex diseases, genetic variants must be common and have substantial effect on disease risk.
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