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PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes
  1. Shuji Akizuki1,
  2. Kazuyoshi Ishigaki2,
  3. Yuta Kochi3,
  4. Sze-Ming Law1,
  5. Keitaro Matsuo4,5,
  6. Koichiro Ohmura1,
  7. Akari Suzuki3,
  8. Manabu Nakayama6,
  9. Yusuke Iizuka7,
  10. Haruhiko Koseki7,
  11. Osamu Ohara8,
  12. Jun Hirata9,10,11,
  13. Yoichiro Kamatani2,12,
  14. Fumihiko Matsuda12,
  15. Takayuki Sumida13,
  16. Kazuhiko Yamamoto3,
  17. Yukinori Okada2,9,14,
  18. Tsuneyo Mimori1,
  19. Chikashi Terao1,2,15,16
  1. 1 Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  2. 2 Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  3. 3 Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  4. 4 Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
  5. 5 Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
  6. 6 Department of Frontier Research and Development, Kazusa DNA Research Institute, Chiba, Japan
  7. 7 Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  8. 8 Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  9. 9 Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
  10. 10 Pharmaceutical Discovery Research Laboratories, TEIJIN PHARMA LIMITED, Hino, Japan
  11. 11 Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  12. 12 Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
  13. 13 Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  14. 14 Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
  15. 15 Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
  16. 16 Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
  1. Correspondence to Dr Chikashi Terao, Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22, Yokohama 230-0045, Japan; a0001101{at}


Objectives Systemic 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 immune-related 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 anti-dsDNA 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.

  • systemic lupus erythematosus
  • genetic study
  • autoimmunity
  • mouse study

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  • Handling editor Mary K Crow

  • Contributors Wrote the paper: SA, S-ML, CT. Data analysis: SA, KI, CT. Performed the mouse experimental work: SA, YuK, S-ML, AS, MN, YI, HK, OO, JH, CT. Conceived and designed the study: CT. Substantial contribution to acquired samples and creation of data in 1st GWAS: KM, KO, FM, YO, TM, CT. Substantial contribution to acquired samples and creation of data in 2nd GWAS: KI, YuK, YoK, TS, KY, YO. All authors revised and approved the manuscript to be published.

  • Funding This study was supported by JSPS KAKENHI (grant nos. JP16H06251 and 16K09891), Nagao Memorial Fund and The Kato Memorial Trust for Nambyo Research.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval This study was approved by the ethical committee in each institution.

  • Provenance and peer review Not commissioned; externally peer reviewed.