Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population

Koga, Minoru; Kawasaki, Aya; Ito, Ichiaki; Furuya, Takeshi; Ohashi, Jun; Kyogoku, Chieko; Ito, Satoshi; Hayashi, Taichi; Matsumoto, Isao; Kusaoi, Makio; Takasaki, Yoshinari; Hashimoto, Hiroshi; Sumida, Takayuki; Tsuchiya, Naoyuki

doi:10.1038/jhg.2011.49

Cited by 36 publications

(26 citation statements)

References 40 publications

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“…Although each risk gene has a relatively low OR for disease susceptibility, the carriage of more risk alleles, in several risk genes, appears to increase the risk for disease susceptibility. Such cumulative associations have been shown in other autoimmune diseases [28], and now also here, by the discovery of the additive effect of alleles in C8orf13–BLK and STAT4 in increasing the risk for polymyositis/dermatomyositis.…”

Section: Discussionsupporting

confidence: 66%

Association between a C8orf13–BLK Polymorphism and Polymyositis/Dermatomyositis in the Japanese Population: An Additive Effect with STAT4 on Disease Susceptibility

et al. 2014

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BackgroundAccumulating evidence has shown that several non-HLA genes are involved in the susceptibility to polymyositis/dermatomyositis. This study aimed to investigate the involvement of C8orf13–BLK, one of the strongest candidate genes for autoimmune diseases, in susceptibility to polymyositis/dermatomyositis in the Japanese population. A possible gene–gene interaction between C8orf13–BLK and STAT4, which we recently showed to be associated with Japanese polymyositis/dermatomyositis, was also analyzed.MethodsA single-nucleotide polymorphism in C8orf13–BLK (dbSNP ID: rs13277113) was investigated in the Japanese population using a TaqMan assay in 283 polymyositis patients, 194 dermatomyositis patients, and 656 control subjects.ResultsThe C8orf13–BLK rs13277113A allele was associated with overall polymyositis/dermatomyositis (P<0.001, odds ratio [OR] 1.44, 95% confidence interval [CI] 1.19–1.73), as well as polymyositis (P = 0.011, OR 1.32, 95% CI 1.06–1.64) and dermatomyositis (P<0.001, OR 1.64, 95% CI 1.26–2.12). No association was observed between the C8orf13–BLK rs13277113A allele and either interstitial lung disease or anti-Jo-1 antibody positivity. The C8orf13–BLK rs13277113 A and STAT4 rs7574865 T alleles had an additive effect on polymyositis/dermatomyositis susceptibility. The strongest association was observed in dermatomyositis, with an OR of 3.07 (95% CI; 1.57–6.02) for the carriers of four risk alleles at the two SNP sites, namely, rs1327713 and rs7574865.ConclusionsThis study established C8orf13–BLK as a new genetic susceptibility factor for polymyositis/dermatomyositis. Both C8orf13–BLK and STAT4 exert additive effects on disease susceptibility. These observations suggested that C8orf13–BLK, in combination with STAT4, plays a pivotal role in creating genetic susceptibility to polymyositis/dermatomyositis in Japanese individuals.

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Section: Discussionsupporting

confidence: 66%

Association between a C8orf13–BLK Polymorphism and Polymyositis/Dermatomyositis in the Japanese Population: An Additive Effect with STAT4 on Disease Susceptibility

et al. 2014

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“…The cumulative number of risk alleles is reported to be significantly increased in SLE relative to healthy controls in the Japanese population [23]. We did replicate this association in Japanese childhood-onset SLE.…”

Section: Discussionmentioning

confidence: 54%

“…Recently, an association of the cumulative number of risk alleles and SLE has been reported in the United States and Japan [4], [23]. Koga et al analyzed the cumulative number of risk alleles at eight established susceptibility loci, namely HLA-DRB1 , IRF5 , STAT4 , BLK , TNFAIP3 , TNIP1 , FCGR2B and TNFSF13 , in a Japanese population.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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“…Systemic lupus erythematosus (SLE) is a chronic multisystem relapsing-remitting autoimmune disease, primarily affecting females [1], which can be influenced by hormonal, genetic and environmental factors [2][3][4][5][6][7]. Clinical studies have shown that neurologic and neuropsychiatric (NP) symptoms occur in up to 75% of patients, a condition representing a particularly severe form of the disease known as NPSLE [8].…”

Section: Introductionmentioning

confidence: 98%

Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model

Jeltsch-David

Muller

2014

Autoimmunity Reviews

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Mouse models of autoimmunity, such as (NZB×NZW)F1, MRL/MpJ-Fas(lpr) (MRL-lpr) and BXSB mice, spontaneously develop systemic lupus erythematosus (SLE)-like syndromes with heterogeneity and complexity that characterize human SLE. Despite their inherent limitations, such models have highly contributed to our current understanding of the pathogenesis of SLE as they provide powerful tools to approach the human disease at the genetic, cellular, molecular and environmental levels. They also allow novel treatment strategies to be evaluated in a complex integrated system, a favorable context knowing that very few murine models that adequately mimic human autoimmune diseases exist. As we move forward with more efficient medications to treat lupus patients, certain forms of the disease that requires to be better understood at the mechanistic level emerge. This is the case of neuropsychiatric (NP) events that affect 50-60% at SLE onset or within the first year after SLE diagnosis. Intense research performed at deciphering NP features in lupus mouse models has been undertaken. It is central to develop the first lead molecules aimed at specifically treating NPSLE. Here we discuss how mouse models, and most particularly MRL-lpr female mice, can be used for studying the pathogenesis of NPSLE in an animal setting, what are the NP symptoms that develop, and how they compare with human SLE, and, with a critical view, what are the neurobehavioral tests that are pertinent for evaluating the degree of altered functions and the progresses resulting from potentially active therapeutics.

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Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population

Cited by 36 publications

References 40 publications

Association between a C8orf13–BLK Polymorphism and Polymyositis/Dermatomyositis in the Japanese Population: An Additive Effect with STAT4 on Disease Susceptibility

Association between a C8orf13–BLK Polymorphism and Polymyositis/Dermatomyositis in the Japanese Population: An Additive Effect with STAT4 on Disease Susceptibility

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

Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model

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