PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population

Abstract

Objective. Systemic sclerosis (SSc) is an autoimmune disease for which multiple susceptibility genes have been reported. Genome-wide association studies have shown that large numbers of susceptibility genes are shared among autoimmune diseases. Recently, our group identified 9 novel susceptibility genes associated with rheumatoid arthritis (RA) in a Japanese population. The aim of this study was to elucidate whether the 18 genes that displayed associations or suggestive associations for RA in our previous study are associated with SSc in Japanese.Methods. We performed an association study that included 415 patients with SSc and 16,891 control subjects, followed by a replication study that included 315 patients and 21,054 control subjects. The 18 markers reported to display association with RA were analyzed for their associations with SSc in the first study, and 5 markers were further analyzed in the replication study. The inverse variance method was used to evaluate the associations of these markers with SSc in a combined study.Results. In the phospholipase D4 gene (PLD4), rs2841277 displayed a significant association with SSc in Japanese patients (P ‫؍‬ 0.00017). We observed that rs2841280 in exon 2 of PLD4 was in strong linkage disequilibrium with rs2841277 and introduced an amino acid alteration. We also observed associations between SSc and rs6932056 in TNFAIP3 and rs2280381 in IRF8 (P ‫؍‬ 0.0000095 and P ‫؍‬ 0.0030, respectively), both of which displayed associations with SSc in a European population.Conclusion. We determined that PLD4 is a novel susceptibility gene for SSc in Japanese, thus confirming the involvement of PLD4 in autoimmunity. Associations between SSc and TNFAIP3 or IRF8 were also detected in our Japanese population. SSc and RA appear to share relatively large proportions of their genetic backgrounds.

Exome-wide association study identifies four novel loci for systemic lupus erythematosus in Han Chinese population

“…The expression of AHNAK2 is significantly upregulated in F4/80 hi mononuclear cells in murine SLE nephritis, suggesting AHNAK2 is a potential effector gene 33. However, we note that SNP rs4465542 links strongly with two proximal SNPs that have been reported for the risk of systemic sclerosis in Japanese samples within the PLD4 gene 34. Though the function of the PLD4 gene is poorly understood, we cannot rule out its possibility as a susceptibility gene for SLE.…”

PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells

“…Recent studies showed two autoimmune diseases, sclerosis and rheumatoid arthritis, were related to PLD4 mutation (16,17). Although PLD4 seemed to have some immunological functions, little was known about its function in cells.…”

“…After treated with LPS, the expression of the PLD4 in microglia was increased which could promote the function of phagocytosis (15). Recent studies have indicated mutation in PLD4 gene was associated with two autoimmune diseases, named systemic sclerosis (16) and rheumatoid arthritis (17), both had abnormal inflammatory skin lesions symptoms (18). Although PLD4 was involved in microglia phagocytosis, there is little known on its function and the mechanism, thus PLD4 needed to be explored.…”

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

“…A nonsense mutation in PLD4 (W215X) in Fleckvieh cattle causes severe skin lesions, generally poor health, and decreased survival ( 99 ). PLD4 defi ciency in humans has been linked through genome-wide association studies to syndromes such as rheumatoid arthritis ( 100 ) and the autoimmune disease systemic sclerosis ( 101 ). Taken together, these fi ndings suggest that PLD4 defi ciency results in hyper-activation of the immune system, causing a variety of autoimmune-like syndromes.…”