PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes

Shuji Akizuki, Kazuyoshi Ishigaki, Yuta Kochi, Sze Ming Law, Keitaro Matsuo, Koichiro Ohmura, Akari Suzuki, Manabu Nakayama, Yusuke Iizuka, Haruhiko Koseki, Osamu Ohara, Jun Hirata, Yoichiro Kamatani, Fumihiko Matsuda, Takayuki Sumida, Kazuhiko Yamamoto, Yukinori Okada, Tsuneyo Mimori, Chikashi Terao

研究成果: Article査読

33 被引用数 (Scopus)

抄録

Objectives S ystemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by autoantibody production and widespread inflammation damaging many organs. Previous genome-wide association studies (GWASs) have revealed over 80 genetic determinants of SLE, but they collectively explain a fraction of the heritability, and only a few were proven in vivo for the involvement in SLE. We conducted a meta-analysis of SLE GWAS in the Japanese population, followed by functional analyses of a susceptibility gene with use of mutant mice. Methods We conducted a meta-analysis of two GWASs comprising a total of 1363 cases and 5536 controls using the 1000 Genome Project data as an imputation reference. Enrichment analyses for functional annotations were conducted. We examined Phospholipase D4 (Pld4) mutant mice to assess functional involvement of a genetic determinant. Results We found a total of 14 significant loci, which included rs2582511 in AHNAK2/PLD4 recently reported in a Chinese study and a novel locus of rs143181706 in MAMLD1 (p=7.9×10 -11 and 3.7×10 -8 , respectively). PLD4 risk allele was associated with anti-dsDNA antibody production. Enrichment analysis of genetic signals revealed involvement of a wide range of immunerelated cells and pathways. Pld4 mutant mice revealed remarkably low body weight. The mice demonstrated autoimmune phenotypes compatible with SLE, including splenomegaly and lymphadenopathy, expansion of B cells and hypersecretion of BAFF and production of autoantibodies especially anti-nuclear antibody and antidsDNA antibody. Conclusions We found a novel susceptibility gene to SLE. Pld4 mutant mice revealed autoimmune phenotypes suggesting functional involvement of PLD4 with the basics of SLE.

本文言語English
ページ(範囲)509-518
ページ数10
ジャーナルAnnals of the rheumatic diseases
78
4
DOI
出版ステータスPublished - 2019 4月 1
外部発表はい

ASJC Scopus subject areas

  • リウマチ学
  • 免疫アレルギー学
  • 免疫学
  • 生化学、遺伝学、分子生物学一般

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