Background/Purpose: The leukocyte immunoglobulin-like receptors (LILRs) are a gene family located in leukocyte receptor complex at 19q13.4. LILRs are expressed mainly in immune cells as transmembrane receptors, and some of LILRs have been shown to regulate immune cell activation. LILRA3 is the only secreted protein among LILRs, but its function remains unclear. Furthermore, LILRA3 has a 6.7-kb deletion polymorphism which lacks most of the coding region, and its frequency is especially high in the East Asian populations (71.0% in the Japanese, 18.5% in the German)(Hirayasu et al., 2006, Koch et al., 2005). Previous studies in European populations reported association of the deletion allele with multiple sclerosis (MS) (Koch et al., 2005) and Sjögren’s syndrome (SS) (Kabalak et al., 2009), while recent studies from China reported association of homozygous non-deletion genotype with rheumatoid arthritis (Du et al., 2014a), systemic lupus erythematosus (SLE) and SS (Du et al., 2014b). In this study, we examined whether LILRA3 deletion polymorphism is associated with systemic sclerosis (SSc) in a Japanese population.

Methods: 373 Japanese patients with SSc and 867 healthy Japanese controls were examined. All patients fulfilled the American College of Rheumatology criteria. 124 were classified as having diffuse cutaneous (dc) SSc, while 201 as limited cutaneous (lc) SSc from available clinical data, according to the classification by LeRoy et al. 82 were positive for anti-topoisomerase 1 antibody (ATA+) and 158 for anti-centromere antibody (ACA+). Six patients were positive for both ATA and ACA. 140 patients were classified as having interstitial lung disease (ILD) based on high resolution CT. The LILRA3 deletion was genotyped by PCR-sequence specific primers. This study was reviewed and approved by the ethics committees of each participating institute. Informed consent was provided by all subjects.

Results: We observed higher frequency of LILRA3 deletion in ATA+ SSc patients compared with healthy controls (P=0.015, OR= 1.68 under the allele model, P=0.014, OR=1.83 under the recessive model) (Table1). This association was not observed in ACA+ SSc. In the case-only analysis, the deletion allele frequency of ATA+ACA- SSc was significantly increased when compared with ATA-ACA+ SSc (P=0.0094, OR=1.93).

Conclusion: Our study demonstrated the first evidence for the association between the LILRA3 deletion and ATA+ SSc. The risk allele was in agreement with that of MS and SS in the German population, but was the opposite to that of RA and SLE in the Chinese population. This study supported the association of LILRA3 with genetic susceptibility to multiple autoimmune diseases, and its role requires further study.

Table1. Association between LILRA3 deletion polymorphism and SSc