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Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.

ABSTRACT: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

SUBMITTER: Lubitz SA

PROVIDER: S-EPMC4009240 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.

Lubitz Steven A SA Lunetta Kathryn L KL Lin Honghuang H Arking Dan E DE Trompet Stella S Li Guo G Krijthe Bouwe P BP Chasman Daniel I DI Barnard John J Kleber Marcus E ME Dörr Marcus M Ozaki Kouichi K Smith Albert V AV Müller-Nurasyid Martina M Walter Stefan S Agarwal Sunil K SK Bis Joshua C JC Brody Jennifer A JA Chen Lin Y LY Everett Brendan M BM Ford Ian I Franco Oscar H OH Harris Tamara B TB Hofman Albert A Kääb Stefan S Mahida Saagar S Kathiresan Sekar S Kubo Michiaki M Launer Lenore J LJ MacFarlane Peter W PW Magnani Jared W JW McKnight Barbara B McManus David D DD Peters Annette A Psaty Bruce M BM Rose Lynda M LM Rotter Jerome I JI Silbernagel Guenther G Smith Jonathan D JD Sotoodehnia Nona N Stott David J DJ Taylor Kent D KD Tomaschitz Andreas A Tsunoda Tatsuhiko T Uitterlinden Andre G AG Van Wagoner David R DR Völker Uwe U Völzke Henry H Murabito Joanne M JM Sinner Moritz F MF Gudnason Vilmundur V Felix Stephan B SB März Winfried W Chung Mina M Albert Christine M CM Stricker Bruno H BH Tanaka Toshihiro T Heckbert Susan R SR Jukema J Wouter JW Alonso Alvaro A Benjamin Emelia J EJ Ellinor Patrick T PT

Journal of the American College of Cardiology 20140130 12

<h4>Objectives</h4>This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.<h4>Background</h4>AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.<h4>Methods</h4>We performed association testing conditioned on the most significant, independently associated genetic markers at 9 esta ...[more]

PMID: 24486271

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Project description:BackgroundAtrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke.MethodsTo determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from <1×10-3 to <1×10-8 in a prior independent genetic association study.ResultsIncident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13-1.46; P=1.5×10-4) to 1.67 (25 variants; 95% confidence interval, 1.47-1.90; P=9.3×10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39-4.58; P=2.7×10-3). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20-4.40; P=0.01).ConclusionsComprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.

Project description:ObjectiveTo investigate the correlation between KCNA5 single nucleotide polymorphism (SNP) and idiopathic atrial fibrillation (IAF).MethodsA case-control study was conducted, including 282 cases of IAF patients and 300 cases of age and sex-matched normal controls; gene sequencing method was used to detect the distribution of KCNA5 SNP (rs3741930 and rs1056468) in the two groups. The IAF patients were divided into two groups based on the different genotypes of rs1056468 and rs3741930; differences in clinical parameters between the two groups of patients were compared.ResultsFor rs3741930, the CC, CT and TT genotype frequencies in the IAF group were 16.7%, 50.0%, and 33.3% respectively; C allele frequency in IAF group was 41.7%; in the normal control group, those were 10.0%, 49.3%, 40.7% and 34.7% respectively; CC genotype frequency and C allele frequency in IAF group were significantly higher compared with the control group (P=0.019, P=0.014). For rs1056468, the AA, AT and TT genotype frequencies in the IAF group were 44.3%, 48.6%, and 7.1% respectively; in 300 cases of normal controls, those were 38.7%, 50.7%, and 10.6% respectively; A allele frequency in IAF group was 68.6 %, and it was 64.0% in normal controls. There were no significant differences in genotype and allele frequencies between control and IAF groups (P>0.05). In IAF group, among different genotypes of rs1741930 and rs1056468, there were no significant differences in age, SBP, DBP, HR, LAD and LVEF (P>0.05). While the BMI in CC and CC+TT groups of rs3741930 locus were 26.9±2.3 Kg/m(2) and 24.8±2.5 Kg/m(2) respectively. There were statistical differences between the two groups (P=0.019). BMI in AA and AA+TT groups of rs1056468 locus were 24.9±2.7 Kg/m(2) and 26.4±2.4 Kg/m(2) respectively; There was statistically significant significance between the two groups (P=0.014).ConclusionThe single nucleotide polymorphism rs3741930 locus in KCNA5 gene was related to the risk of IAF; the population carrying C allele was more susceptible to IAF; the polymorphic loci, rs3741930 and rs1056468, were correlated with the BMI of IAF patients.

Project description:ImportanceAtrial fibrillation (AF) has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts.ObjectiveTo identify rare predicted loss-of-function (pLOF) variants associated with AF and elucidate their role in risk of AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS).Design, setting, and participantsThis was a genetic association and nested case-control study. The impact of rare pLOF variants was evaluated on the risk of incident AF. HF and CM were assessed in cause-specific Cox regressions. End of follow-up was July 1, 2022. Data were analyzed from January to October 2023. The UK Biobank enrolled 502 480 individuals aged 40 to 69 years at inclusion in the United Kingdom between March 13, 2006, and October 1, 2010. UK residents of European ancestry were included. Individuals with prior diagnosis of AF were excluded from analyses of incident AF.ExposuresRare pLOF variants and an AF PRS.Main outcomes and measuresRisk of AF and incident HF or CM prior to and subsequent to AF diagnosis.ResultsA total of 403 990 individuals (218 489 [54.1%] female) with a median (IQR) age of 58 (51-63) years were included; 24 447 were diagnosed with incident AF over a median (IQR) follow-up period of 13.3 (12.4-14.0) years. Rare pLOF variants in 6 genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were associated with AF. Of these, TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicated in an external cohort. Combined with high PRS, rare pLOF variants conferred an odds ratio of 7.08 (95% CI, 6.03-8.28) for AF. Carriers with high PRS also had a substantial 10-year risk of AF (16% in female individuals and 24% in male individuals older than 60 years). Rare pLOF variants were associated with increased risk of CM both prior to AF (hazard ratio [HR], 3.13; 95% CI, 2.24-4.36) and subsequent to AF (HR, 2.98; 95% CI, 1.89-4.69).Conclusions and relevanceRare and common genetic variation were associated with an increased risk of AF. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk stratification.

Project description:ImportanceDespite the development of risk stratification schemes that have been widely used to determine the risk for thromboembolism in patients with nonvalvular atrial fibrillation (NVAF), risk stratification schemes in Asian patients with NVAF remain undetermined.ObjectiveTo determine risk factors for ischemic stroke in Japanese patients with NVAF.Design, setting, and participantsThis cohort study analyzed individual patient data from 5 AF registries in Japan: J-RHYTHM (Japanese Rhythm Management Trial for Atrial Fibrillation) Registry, Fushimi AF Registry, Shinken Database, Keio Interhospital Cardiovascular Studies (Keio Study), and Hokuriku-Plus AF Registry. Patients with atrial fibrillation were registered from 158 institutions in the J-RHYTHM Registry, 80 in the Fushimi AF Registry, a single hospital in Shinken Database, 11 in the Keio Study, and 19 in the Hokuriku-Plus AF Registry. Patients with valvular AF or lacking data were excluded. Data were collected and integrated in March 2016, and those from the Keio Study were updated in April 2018. Data were analyzed from April 2018 to February 2020.Main outcomes and measuresSignificant risk factors for ischemic stroke were determined by adjusted Cox proportional hazards analysis.ResultsIn total, 12 289 patients with NVAF (3758 [31%] female; mean [SD] age 70.2 [11] years) were analyzed with a mean (SD) follow-up period of 649 (181) days (1.8 [0.5] years). During 21 820 person-years of follow-up, 241 cases of ischemic stroke were reported. Risk factors associated with ischemic stroke after adjustment for oral anticoagulant use at enrollment were age (75-84 years: hazard ratio [HR], 1.74; 95% CI, 1.32-2.30; P < .001; and ≥85 years: HR, 2.41; 1.63-3.56; P < .001), hypertension (HR, 1.60; 95% CI, 1.15-2.23; P = .006), previous stroke (HR, 2.75; 95% CI, 2.09-3.62; P < .001), persistent or permanent AF (HR, 1.59; 95% CI, 1.21-2.10; P = .001), and body mass index less than 18.5 (HR, 1.55; 95% CI, 1.05-2.29; P = .03). Neither diabetes nor heart failure were identified as risk factors for ischemic stroke.Conclusions and relevancePrevious stroke, advanced age, hypertension, persistent or permanent AF, and low body mass index were independent risk factors associated with ischemic stroke in Japanese patients with NVAF.

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Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.

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Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.

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