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

Mol Med Rep. 2017 Nov;16(5):5823-5832. doi: 10.3892/mmr.2017.7334. Epub 2017 Aug 23.

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.

MeSH terms

  • Aged
  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / physiopathology
  • Case-Control Studies
  • Cytoskeletal Proteins / genetics*
  • Exome / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Organic Cation Transport Proteins / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors
  • Solute Carrier Proteins
  • Transcription Factors / genetics*
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / genetics*

Substances

  • Cytoskeletal Proteins
  • Organic Cation Transport Proteins
  • SALL4 protein, human
  • SLC22A25 protein, human
  • SPATC1L protein, human
  • Solute Carrier Proteins
  • TNFSF13 protein, human
  • Transcription Factors
  • Tumor Necrosis Factor Ligand Superfamily Member 13