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

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.
Yoshiji Yamada 1,  Jun Sakuma 2,  Ichiro Takeuchi 2,  Yoshiki Yasukochi 1,  Kimihiko Kato 1,  Mitsutoshi Oguri 1,  Tetsuo Fujimaki 3,  Hideki Horibe 4,  Masaaki Muramatsu 5,  Motoji Sawabe 6,  Yoshinori Fujiwara 7,  Yu Taniguchi 7,  Shuichi Obuchi 8,  Hisashi Kawai 8,  Shoji Shinkai 9,  Seijiro Mori 10,  Tomio Arai 11,  Masashi Tanaka 12
Affiliations

Affiliations

  • 1 Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu 514‑8507, Japan.
  • 2 CREST, Japan Science and Technology Agency, Kawaguchi 332‑0012, Japan.
  • 3 Department of Cardiovascular Medicine, Inabe General Hospital, Inabe 511‑0428, Japan.
  • 4 Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi 507‑8522, Japan.
  • 5 Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101‑0062, Japan.
  • 6 Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo 113‑8510, Japan.
  • 7 Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo 173‑0015, Japan.
  • 8 Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo 173‑0015, Japan.
  • 9 Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo 173‑0015, Japan.
  • 10 Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo 173‑0015, Japan.
  • 11 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173‑0015, Japan.
  • 12 Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo 173‑0015, Japan.
PMID: 28849223 DOI: 10.3892/mmr.2017.7334
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.

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