Dataset Information

Identification of TNFSF13, SPATC1L, SLC22A25 and SALL4 as novel susceptibility loci for atrial fibrillation by an exome?wide association study.

ABSTRACT: An exome?wide association study (EWAS) was performed to identify genetic variants, particularly low?frequency or rare coding variants with a moderate to large effect size, that confer susceptibility to atrial fibrillation in Japanese. The EWAS for atrial fibrillation was performed with 13,166 subjects (884 patients with atrial fibrillation and 12,282 controls) using an Illumina HumanExome?12 DNA Analysis BeadChip or Infinium Exome?24 BeadChip arrays. The association of atrial fibrillation with allele frequencies of 41,243 single nucleotide polymorphisms (SNPs) that passed quality control was examined with Fisher's exact test. Based on Bonferroni's correction, a P<1.21x10?6 was considered statistically significant. The EWAS for atrial fibrillation revealed that 122 SNPs were significantly associated with this condition. The association of the identified SNPs to atrial fibrillation was further examined by multivariable logistic regression analysis with adjustment for age, sex and the prevalence of hypertension. Eight SNPs were related (P<0.01) to atrial fibrillation, among which three polymorphisms, rs11552708 [G/A (G67R)]of TNF superfamily member 13 (TNFSF13; dominant model; P=9.36x10?9; odds ratio, 0.58), rs113710653 [C/T (E231 K)] of spermatogenesis and centriole associated 1 like (SPATC1L; dominant model; P=1.09x10?5; odds ratio, 3.27), and rs11231397 [G/C (R300T)] of solute carrier family 22 member 25 (SLC22A25; additive model; P=3.71x10?5; odds ratio, 1.77), were significantly (P<1.02x10?4) associated with this condition. The minor T allele of rs113710653 and the minor C allele of rs11231397 were risk factors for atrial fibrillation, whereas the minor A allele of rs11552708 was protective against this condition. In addition, rs77538589 [C/T (G117R)] of SALL4 exhibited a tendency to be associated with atrial fibrillation (dominant model; P=0.0002; odds ratio, 1.88), with the minor T allele representing a risk factor for this condition. TNFSF13, SPATC1L, SLC22A25 and SALL4 may thus be novel susceptibility loci for atrial fibrillation in the Japanese population.

SUBMITTER: Yamada Y

PROVIDER: S-EPMC5865780 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Identification of TNFSF13, SPATC1L, SLC22A25 and SALL4 as novel susceptibility loci for atrial fibrillation by an exome‑wide association study.

Yamada Yoshiji Y Sakuma Jun J Takeuchi Ichiro I Yasukochi Yoshiki Y Kato Kimihiko K Oguri Mitsutoshi M Fujimaki Tetsuo T Horibe Hideki H Muramatsu Masaaki M Sawabe Motoji M Fujiwara Yoshinori Y Taniguchi Yu Y Obuchi Shuichi S Kawai Hisashi H Shinkai Shoji S Mori Seijiro S Arai Tomio T Tanaka Masashi M

Molecular medicine reports 20170823 5

An exome‑wide association study (EWAS) was performed to identify genetic variants, particularly low‑frequency or rare coding variants with a moderate to large effect size, that confer susceptibility to atrial fibrillation in Japanese. The EWAS for atrial fibrillation was performed with 13,166 subjects (884 patients with atrial fibrillation and 12,282 controls) using an Illumina HumanExome‑12 DNA Analysis BeadChip or Infinium Exome‑24 BeadChip arrays. The association of atrial fibrillation with a ...[more]

PMID: 28849223

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Project description:We performed an exome-wide association study (EWAS) to identify genetic variants - in particular, low‑frequency or rare variants with a moderate to large effect size - that confer susceptibility to aortic aneurysm with 8,782 Japanese subjects (456 patients with aortic aneurysm, 8,326 control individuals) and with the use of Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The correlation of allele frequencies for 41,432 single nucleotide polymorphisms (SNPs) that passed quality control to aortic aneurysm was examined with Fisher's exact test. Based on Bonferroni's correction, a P-value of <1.21x10-6 was considered statistically significant. The EWAS revealed 59 SNPs that were significantly associated with aortic aneurysm. None of these SNPs was significantly (P<2.12x10-4) associated with aortic aneurysm by multivariable logistic regression analysis with adjustment for age, gender and hypertension, although 8 SNPs were related (P<0.05) to this condition. Examination of the correlation of these latter 8 SNPs to true or dissecting aortic aneurysm separately showed that rs1465567 [T/C (W229R)] of the EGF-like, fibronectin type III, and laminin G domains gene (EGFLAM) (dominant model; P=0.0014; odds ratio, 1.63) was significantly (P<0.0016) associated with true aortic aneurysm. We next performed EWASs for true or dissecting aortic aneurysm separately and found that 45 and 19 SNPs were significantly associated with these conditions, respectively. Multivariable logistic regression analysis with adjustment for covariates revealed that rs113710653 [C/T (E231K)] of the spermatogenesis- and centriole associated 1-like gene (SPATC1L) (dominant model; P=0.0002; odds ratio, 5.32) and rs143881017 [C/T (R140H)] of the ribonuclease A family member 13 gene (RNASE13) (dominant model; P=0.0006; odds ratio, 5.77) were significantly (P<2.78x10-4 or P<6.58x10-4, respectively) associated with true or dissecting aortic aneurysm, respectively. EGFLAM and SPATC1L may thus be susceptibility loci for true aortic aneurysm and RNASE13 may be such a locus for dissecting aneurysm in Japanese individuals.

Project description:In this study, we performed exome-wide association studies (EWASs) to identify genetic variants that confer susceptibility to ischemic stroke, intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). EWAS for ischemic stroke was performed using 1,575 patients with this condition and 9,210 controls, and EWASs for ICH and SAH were performed using 673 patients with ICH, 265 patients with SAH and 9,158 controls. Analyses were performed with Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of allele frequencies for 41,339 or 41,332 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic or hemorrhagic stroke, respectively, was examined with Fisher's exact test. Based on Bonferroni's correction, a P-value of <1.21x10-6 was considered statistically significant. EWAS for ischemic stroke revealed that 77 SNPs were significantly associated with this condition. Multivariable logistic regression analysis with adjustment for age, sex and the prevalence of hypertension and diabetes mellitus revealed that 4 of these SNPs [rs3212335 of GABRB3 (P=0.0036; odds ratio, 1.29), rs147783135 of TMPRSS7 (P=0.0024; odds ratio, 0.37), rs2292661 of PDIA5 (P=0.0054; odds ratio, 0.35) and rs191885206 of CYP4F12 (P=0.0082; odds ratio, 2.60)] were related (P<0.01) to ischemic stroke. EWASs for ICH or SAH revealed that 48 and 12 SNPs, respectively, were significantly associated with these conditions. Multivariable logistic regression analysis with adjustment for age, sex and the prevalence of hypertension revealed that rs138533962 of STYK1 (P<1.0x10-23; odds ratio, 111.3) was significantly (P<2.60x10-4) associated with ICH and that rs117564807 of COL17A1 (P=0.0009; odds ratio, 2.23x10-8) was significantly (P<0.0010) associated with SAH. GABRB3, TMPRSS7, PDIA5 and CYP4F12 may thus be novel susceptibility loci for ischemic stroke, whereas STYK1 and COL17A1 may be such loci for ICH and SAH, respectively.

Project description:BACKGROUND:Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. METHODS:Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. RESULTS:Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (P<0.001) and had fewer clinical risk factors for AF (P=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P<0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P<0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P=0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P=0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P=0.13). CONCLUSIONS:Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

Dataset Information

Identification of TNFSF13, SPATC1L, SLC22A25 and SALL4 as novel susceptibility loci for atrial fibrillation by an exome?wide association study.

Publications

Identification of TNFSF13, SPATC1L, SLC22A25 and SALL4 as novel susceptibility loci for atrial fibrillation by an exome‑wide association study.

Similar Datasets

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