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
- 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.
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