Analysis of Gender Differences in Genetic Risk: Association of TNFAIP3 Polymorphism with Male Childhood-Onset Systemic Lupus Erythematosus in the Japanese Population

Abstract

BackgroundSystemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs) in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies.Methodology/Principal FindingsThe 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027). The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041). Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G) risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46–11.2 P<0.05).ConclusionsAssociations of polymorphisms in STAT4 and SPP1 with childhood-onset SLE were confirmed in a Japanese population. Although these are preliminary results for a limited number of cases, TNFAIP3 rs2230926G may be an important predictor of disease onset in males. We also replicated findings that the cumulative number of risk alleles was significantly increased in childhood-onset SLE.

Associations between TNFAIP3 gene polymorphisms and systemic lupus erythematosus risk: an updated meta‐analysis

“…Among these, 13 did not study the association of TNFAIP3 gene polymorphisms with SLE, 1 article for data duplication (31). Thus, 20 articles met our inclusion criteria (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Among the eligible articles, two articles (22,24) contained data on two or more different groups, and these groups were analyzed independently.…”

“…Among the eligible articles, two articles (22,24) contained data on two or more different groups, and these groups were analyzed independently. Finally, a total of 23 studies in 20 articles including 18,501 patients with SLE and 30,435 healthy controls were considered in our meta-analysis (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). There were 20 studies on rs2230926 (12-27, 30), 10 studies on rs5029939 (11,13,17,22,23,26,(28)(29)(30), 8 studies on rs3757173 (16,17,22,27,30), 5 studies on rs5029937 (20,22,26,30).…”

“…This is the first identified with rheumatoid arthritis . Over the last decade, numerous studies have investigated the relationship between TNFAIP3 gene polymorphisms association with SLE .…”

“…Fan et al (33) and Lee and Song (34) both performed meta-analysis to assess the association between TNFAIP3 gene polymorphisms and SLE risk, but these meta-analysis included only two and eight studies, respectively. More studies concerning the association between SNPs and SLE risk have been reported in recent years (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Thus, it seems necessary to perform a meta-analysis that includes the most updated data to investigate the relationships between TNFAIP3 gene polymorphisms and the risk of SLE.…”

Systemic Lupus Erythematosus (SLE) with Lupus Nephritis in a 15 Year-Old Male – A Case Report

“…Other studies of clinical characteristics indicated that men younger than 33 at the time of diagnosis were more likely to develop lupus nephritis, and that patients of Asian descent tend to have more severe disease, including the renal manifestations. [15] The patient was diagnosed with SLE based on the classification of the American College of Rheumatology. The serology examination of SLE shows high titre of ANA and Anti-dsDNA.…”