Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.
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ABSTRACT:
SUBMITTER: Benjamin EJ
PROVIDER: S-EPMC2761746 | biostudies-literature | 2009 Aug
REPOSITORIES: biostudies-literature
Publications
Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.
Benjamin Emelia J EJ Rice Kenneth M KM Arking Dan E DE Pfeufer Arne A van Noord Charlotte C Smith Albert V AV Schnabel Renate B RB Bis Joshua C JC Boerwinkle Eric E Sinner Moritz F MF Dehghan Abbas A Lubitz Steven A SA D'Agostino Ralph B RB Lumley Thomas T Ehret Georg B GB Heeringa Jan J Aspelund Thor T Newton-Cheh Christopher C Larson Martin G MG Marciante Kristin D KD Soliman Elsayed Z EZ Rivadeneira Fernando F Wang Thomas J TJ Eiríksdottir Gudny G Levy Daniel D Psaty Bruce M BM Li Man M Chamberlain Alanna M AM Hofman Albert A Vasan Ramachandran S RS Harris Tamara B TB Rotter Jerome I JI Kao W H Linda WH Agarwal Sunil K SK Stricker Bruno H Ch BH Wang Ke K Launer Lenore J LJ Smith Nicholas L NL Chakravarti Aravinda A Uitterlinden André G AG Wolf Philip A PA Sotoodehnia Nona N Köttgen Anna A van Duijn Cornelia M CM Meitinger Thomas T Mueller Martina M Perz Siegfried S Steinbeck Gerhard G Wichmann H-Erich HE Lunetta Kathryn L KL Heckbert Susan R SR Gudnason Vilmundur V Alonso Alvaro A Kääb Stefan S Ellinor Patrick T PT Witteman Jacqueline C M JC
Nature genetics 20090713 8
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)). ...[more]
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Project description:BackgroundThe gene zinc finger homeobox 3 (ZFHX3) encodes a transcription factor with cardiac expression and its genetic variants are associated with atrial fibrillation (AF). We aimed to explore the associations between single nucleotide polymorphisms (SNPs) of ZFHX3 and the risk of AF in a Chinese Han population.MethodsWe genotyped eight SNPs, including seven potentially functional SNPs and one previously reported SNP by using the middle-throughput iPLEX Sequenom MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in logistic regression models.ResultsWe enrolled a total of 1,593 Chinese Han origin individuals in the study, including 597 AF patients and 996 non-AF controls. Logistic regression analyses revealed that potentially functional SNPs rs6499600 and rs16971436 were associated with a decreased risk of AF (adjusted OR = 0.73, 95% CI: 0.63-0.86, P = 1.07×10-4; adjusted OR = 0.74, 95% CI: 0.56-0.98, P = 0.039, respectively). In addition, rs2106261 showed a robust association with an increased risk of AF (adjusted OR = 1.71, 95% CI: 1.46-2.00, P = 1.85×10-11). After multiple comparisons, rs16971436 conferred a borderline significant association with the risk of AF. Stratification analysis indicated that the risks of AF were statistically different among subgroups of age for rs2106261, and the effect for rs16971436 was more evident in subgroups of patients with coronary artery disease.ConclusionIn summary, our study investigated the role of genetic variants of ZFHX3 in AF and two SNPs (rs2106261, rs6499600) showed significant associations while rs16971436 conferred a borderline significant association with AF risk in Chinese Han populations. However, further large and functional studies are warranted to confirm our findings.
| S-EPMC4077770 | biostudies-literature
Project description:UnlabelledNonalcoholic fatty liver disease (NAFLD) is an obesity-related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African- and/or Hispanic-Americans and fine-mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African American (n = 3,124) and one Hispanic American (n = 849) cohorts. All analyses controlled for variation in age, age(2) , gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta-analyzed. Fine-mapping across African American cohorts was conducted using meta-analysis. African- and Hispanic-American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9 kg/m(2) , respectively. Hepatic steatosis was 0.20-0.34 heritable in African- and Hispanic-American families (P < 0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine-mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1.ConclusionMultiple genetic variants are associated with hepatic steatosis across ancestries. This explains a substantial proportion of the genetic predisposition in African- and Hispanic-Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries.
| S-EPMC3782998 | biostudies-literature
Project description:Expression analysis of whole tissue and cardiomyocytes of fetal and adult atrial free wall
2019-10-29 | GSE127856 | GEO
Project description:Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well-established that both common and rare sequence variants contribute to the formation of CL/P, however, the contribution of copy number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed, however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our case cohort compared to controls, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR/Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.
2022-12-01 | GSE212165 | GEO
Project description:BackgroundZFHX3 (zinc finger homeobox 3), a gene that encodes a large transcription factor, is at the second-most significantly associated locus with atrial fibrillation (AF), but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice.MethodsCRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, magnetic resonance imaging, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 loss (Zfhx3 Het and knockout, respectively). Human cardiac single-nucleus ATAC (assay for transposase-accessible chromatin)-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3.ResultsWe found single-nucleotide polymorphism (SNP) rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility with Zfhx3 knockout mice having higher incidence, frequency, and burden of AF than Zfhx3 Het and wild-type mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF.ConclusionsOur findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.
| S-EPMC10527554 | biostudies-literature
Project description:BackgroundAtrial fibrillation (AF) is a common, sustained cardiac arrhythmia. Recent studies have reported an association between ZFHX3/PRRX1 polymorphisms and AF. In this study, a meta-analysis was conducted to confirm these associations. Objective and Methods. The PubMed, Embase, and Wanfang databases were searched, covering all publications before July 20, 2020.ResultsOverall, seven articles including 3,674 cases and 8,990 healthy controls for ZFHX3 rs2106261 and 1045 cases and 1407 controls for PRRX1 rs3903239 were included. The odds ratio (OR) (95% confidence interval (CI)) was used to assess the associations. Publication bias was calculated using Egger's and Begg's tests. We found that the ZFHX3 rs2106261 polymorphism increased AF risk in Asians (for example, allelic contrast: OR [95% CI]: 1.39 [1.31-1.47], P < 0.001). Similarly, strong associations were detected through stratified analysis using source of control and genotype methods (for example, allelic contrast: OR [95% CI]: 1.51 [1.38-1.64], P < 0.001 for HB; OR [95% CI]: 1.31 [1.21-1.41], P < 0.001 for PB; OR [95% CI]: 1.55 [1.33-1.80], P < 0.001 for TaqMan; and OR [95% CI]: 1.31 [1.21-1.41], P < 0.001 for high-resolution melt). In contrast, an inverse relationship was observed between the PRRX1 rs3903239 polymorphism and AF risk (C-allele vs. T-allele: OR [95% CI]: 0.83 [0.77-0.99], P=0.036; CT vs. TT: OR [95% CI]: 0.79 [0.67-0.94], P=0.006). No obvious evidence of publication bias was observed.ConclusionsIn summary, our study suggests that the ZFHX3 rs2106261 and PRRX1 rs3903239 polymorphisms are associated with AF risk, and larger case-controls must be carried out to confirm the abovementioned conclusions.
| S-EPMC8692054 | biostudies-literature
Project description:Background: Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC), and Crohn's disease (CD), has been reported to be associated with an increased risk of atrial fibrillation (AF). However, the causal role of the chronic intestinal inflammation (CII) in the development of AF remains controversial. We use Mendelian randomization (MR) analysis to explore the causal inference of CII on AF. Methods: A two-sample MR analysis was performed to estimate the potential causal effect of CII on AF. Statistical summaries for the associations between single nucleotide polymorphisms (SNPs) and phenotypes of CII were obtained from genome-wide association studies (GWAS) with cohorts of CD (n = 51,874), UC (n = 47,745), and IBD (n = 65,642) of European descent. The GWAS of 1,030,836 people of European ancestry, including 60,620 AF cases and 970,216 controls was collected to identify genetic variants underlying AF. The causal inference was estimated using the multiplicative random effects inverse-variance weighted method (IVW). The methods of MR-Egger, simple median, and weighted median were also employed to avoid the bias of pleiotropy effects. Results: Using three sets of SNPs (75 SNPs of CD, 60 SNPs of UC, and 95 SNPs of IBD), multiplicative random-effect IVW model estimated a universal null effect of CII on AF (CD: OR = 1.0059, 95% CI: 0.9900, 1.0220, p = 0.47; UC: OR = 1.0087, 95% CI: 0.9896, 1.0281, p = 0.38; IBD: OR = 1.0080, 95% CI: 0.9908, 1.0255, p = 0.37). Similar results were observed using the MR-Egger, simple median, weighted median methods. Conclusion: As opposing to the traditional observational studies, our two-sample MR analysis did not find enough evidence to support a causal role of either CD or UC in the development of AF.
| S-EPMC8141578 | biostudies-literature
Project description:We expanded our genome-wide association study on atrial fibrillation (AF) in Iceland, which previously identified risk variants on 4q25, and tested the most significant associations in samples from Iceland, Norway and the United States. A variant in the ZFHX3 gene on chromosome 16q22, rs7193343-T, associated significantly with AF (odds ratio OR = 1.21, P = 1.4 x 10(-10)). This variant also associated with ischemic stroke (OR = 1.11, P = 0.00054) and cardioembolic stroke (OR = 1.22, P = 0.00021) in a combined analysis of five stroke samples.
| S-EPMC2740741 | biostudies-literature
Project description:The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p < 1 × 10-4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y, and ACER3) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 (p = 9.5 × 10-4) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 (p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p = 2.2 × 10-7). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.
| S-EPMC8277572 | biostudies-literature
Project description:BackgroundOsteoarthritis (OA) is a degenerative disease with high prevalence. Some observational studies have shown that patients with osteoarthritis often have co-existing cardiovascular diseases (CVD) such as atrial fibrillation (AF) and coronary atherosclerosis (CA). However, there is still a lack of stronger evidence confirming the association between osteoarthritis and cardiovascular disease. In this study, we used a bidirectional two-sample Mendelian randomization study to investigate the relationship between OA with AF and CA.MethodsOA data from the UK Biobank and arcOGEN (Arthritis Research UK Osteoarthritis Genetics, a study that aimed to find genetic determinants of osteoarthritis and elucidate the genetic architecture of the disease) integration were selected for the study (n = 417,596), AF data were obtained from six studies (n = 1,030,836), and coronary atherosclerosis data were derived from the FinnGen (n = 218,792). MR analysis was performed primarily using the Inverse variance weighted (IVW) method, with MR Egger, weighted median, simple mode, weighted mode as supplements, sensitivity analysis was performed using Cochran Q statistic, and leave-one-out analysis.ResultsWe found that OA and AF were positively associated [IVW: OR (95% CI): 1.11 (1.04, 1.19), P = 0.002], while OA and CA were negatively associated [IVW: OR (95% CI): 0.88 (0.79, 0.98), P = 0.02]. In the reverse MR analysis, no effect of AF on OA was found [IVW: OR (95% CI): 1.00 (0.97, 1.03), P = 0.84], meanwhile, CA and OA were found to be associated negatively [IVW: OR (95% CI): 0.95 (0.92, 0.99), P = 0.01]. No violations of MR assumptions were found in the sensitivity analysis.ConclusionThis research confirms that OA is a risk factor for AF, and there is a mutual protective factor between OA and CA. However, further studies are still necessary to elucidate the underlying mechanisms.
| S-EPMC10424699 | biostudies-literature