Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients

Akiyoshi Nakayama, Masahiro Nakatochi, Yusuke Kawamura, Ken Yamamoto, Hirofumi Nakaoka, Seiko Shimizu, Toshihide Higashino, Teruhide Koyama, Asahi Hishida, Kiyonori Kuriki, Miki Watanabe, Toru Shimizu, Keiko Ooyama, Hiroshi Ooyama, Mitsuo Nagase, Yuji Hidaka, Daisuke Matsui, Takashi Tamura, Takeshi Nishiyama, Chisato ShimanoeSakurako Katsuura-Kamano, Naoyuki Takashima, Yuya Shirai, Makoto Kawaguchi, Mikiya Takao, Ryo Sugiyama, Yuzo Takada, Takahiro Nakamura, Hiroshi Nakashima, Masashi Tsunoda, Inaho Danjoh, Atsushi Hozawa, Kazuyoshi Hosomichi, Yu Toyoda, Yu Kubota, Tappei Takada, Hiroshi Suzuki, Blanka Stiburkova, Tanya J. Major, Tony R. Merriman, Nagato Kuriyama, Haruo Mikami, Toshiro Takezaki, Keitaro Matsuo, Sadao Suzuki, Tatsuo Hosoya, Yoichiro Kamatani, Michiaki Kubo, Kimiyoshi Ichida, Kenji Wakai, Ituro Inoue, Yukinori Okada, Nariyoshi Shinomiya, Hirotaka Matsuo

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Objectives Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. Methods Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. Results In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. Conclusions Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

Original languageEnglish
Pages (from-to)657-665
Number of pages9
JournalAnnals of the rheumatic diseases
Volume79
Issue number5
DOIs
Publication statusPublished - 2020 May 1

Keywords

  • Japanese
  • genome-wide association study (GWAS)
  • gout/hyperuricaemia
  • selection pressure analysis
  • subtype specific locus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients'. Together they form a unique fingerprint.

Cite this