Familial Mediterranean Fever After Cord Blood Transplantation for Familial Hemophagocytic Lymphohistiocytosis.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder accompanied by periodic fever and sterile serositis. We report a 5-year-old boy with FMF, who underwent second unrelated cord blood transplantation (CBT) for recurrent familial hemophagocytic lymphohistiocytosis. Periodic attacks of fever and abdominal pain started 6 months after CBT. He was diagnosed with FMF according to the Tel-Hashomer criteria and treated successfully with colchicine. Genetic testing showed heterozygous p.E148Q mutation in the MEFV gene from both donor and recipient cells. Several CBT-related factors including use of an immunosuppressant can potentially be involved in the pathogenesis of FMF in our patient.

Diagnostic Rate of Autoinflammatory Diseases Evaluated by Fever Patterns in Pediatric- and Adult-Onset Patients.

OBJECTIVES: This is a noncomparative study performed to determine if fever pattern is related to a diagnosis of autoinflammatory disease (AID) in pediatric- and adult-onset patients. METHODS: The final diagnosis of patients suspected to have AID was evaluated against gene polymorphisms known to be responsible for AID, clinical manifestations, and fever pattern, in our institute from 2005 to 2016. Genomic DNA was isolated from patients' peripheral blood, and polymerase chain reaction was used to amplify the indicated exons of 12 genes: MEFV, TNFRSF1A, MVK, NLRP3, NOD2, LI1RN, IL36RN, PSMB8, NALP12, PSTPIP1, TNFAIP3, and NLRC4. Genetic polymorphisms of the above genes were examined. RESULTS: All 210 individuals (135 pediatric onset and 75 adult onset) were classified into the following 3 subgroups: (1) periodic fever (n = 74 and 25 for pediatric and adult onset, respectively), (2) recurrent fever lacking a regular period (n = 47 and 41), and (3) persistent fever (n = 14 and 9). Diagnosis of AID was highest in subgroup 1 (70.2% and 36.0% for pediatric and adult onset, respectively), followed by subgroup 2(29.8% and 17.1%), including PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) (n = 34 and 1), familial Mediterranean fever (n = 22 and 13), cryopyrin-associated periodic syndrome (n = 6 and 1), and tumor necrosis factor receptor-associated periodic syndrome (n = 3 and 1 for pediatric and adult onset, respectively). None were diagnosed with AID in subgroup 3. CONCLUSIONS: Autoinflammatory disease was more likely to be diagnosed in pediatric-onset patients compared with adult-onset patients. In both age-onset groups, AID was primarily identified in patients with periodic fever and never diagnosed in patients with persistent fever. Our findings indicate that fever pattern is a useful factor to estimate the probability of AID.

Genetic differences between type 1 diabetes with and without other autoimmune diseases.

BACKGROUND: Clusters of autoimmune diseases (ADs) are present in some people with type 1 diabetes. This clustering suggests the existence of common genetic backgrounds for abnormal autoimmunity in these individuals. However, the genetic differences between type 1 diabetes patients with and without other ADs are not well known. METHODS: To investigate the clinical background and genetic differences between type 1 diabetes patients with and without other ADs, single nucleotide polymorphisms (SNPs) in the CTLA4, SUMO4, PTPN22, IRF5, STAT4, and BLK genes were analysed by using either a TaqMan assay or direct sequencing. The frequencies of alleles, genotypes of each gene, and the human leukocyte antigen (HLA) haplotype were analysed to investigate differences among 3 groups: type 1 diabetes with systemic ADs (group A), type 1 diabetes with other organ-specific ADs (group B), and type 1 diabetes without other ADs (group C). RESULTS: The frequency of the C allele in the -1123G > C SNP in the PTPN22 gene promoter was significantly higher in groups A and B than in group C (P = .0258 and .0207, respectively). The allele frequencies of the other SNPs were comparable. The frequency of HLA DRB1*0405-DQB1*0401 was significantly higher in groups A and B than in group C (P = .021 and .0395, respectively). CONCLUSIONS: The -1123G > C SNP in the PTPN22 gene promoter and HLA DRB1*0405-DQB1*0401 might influence the concurrence of systemic and organ-specific ADs in patients with type 1 diabetes.

IL-35 inhibits human osteoclastogenesis from monocytes induced by receptor-activator of NF-κB ligand.

IL-35 is known as a regulatory cytokine produced by regulatory T cells. It has also been reported that IL-35 suppresses the proliferation of Th17 cells, which is involved in the pathogenesis of many autoimmune diseases. However, in rheumatoid arthritis patients, the role of IL-35 is controversial, and the role of IL-35 in bone metabolism has not been clarified. We investigated the effect of IL-35 on human osteoclast differentiation and activation. We first evaluated the effect of rhIL-35 on human osteoclastogenesis from monocytes cultured alone, induced by soluble-RANKL. We also examined the role of IL-35 on the bone-resorption function of mature osteoclasts. Furthermore, we analysed the molecular mechanism of IL-35 function in monocytes or pre-osteoclasts using RT-PCR. rhIL-35 significantly inhibited human osteoclastogenesis in a dose-dependent manner. In addition, rhIL-35 also significantly decreased the area of pit formation by mature osteoclasts. rhIL-35 significantly decreased mRNA expression of RANK in monocytes and RANK and FOS in pre-osteoclasts. Our current findings suggest that IL-35 inhibits osteoclastogenesis and osteoclast activation by inhibiting both RANK and FOS. IL-35 also has an inhibitory effect on osteoclastic-bone resorption, suggesting that IL-35 may have a therapeutic potential for RA.

Arterial Calcification Due to Deficiency of CD73 (ACDC) As One of Rheumatic Diseases Associated With Periarticular Calcification.

In 2011, St Hilaire et al (N Engl J Med. 2011;364:432-442) identified mutations in the ecto-5'-nucleotidase (NT5E) gene, which encodes CD73, in members of 3 families with symptomatic arterial and joint calcifications. The deficiency of CD73 involves the extracellular adenosine metabolism that influences inorganic pyrophosphate and phosphate metabolism and leads to tissue calcification. Herein, we report an additional case with arterial calcification due to deficiency of CD73. Genetic analyses revealed that the patient was a compound heterozygote of mutations in the NT5E gene. The present case had intermittent monoarthritis of the finger joints and early-onset osteoarthritis in the hands. Occlusion of calcified peripheral arteries is the most important outcome of the disease. However, the rheumatic manifestations may be important clues to the diagnosis. Rheumatologists should recognize deficiency of CD73 as a rheumatic disease.

A novel peptide from TCTA protein inhibits proliferation of fibroblast-like synoviocytes of rheumatoid arthritis patients.

BACKGROUND: We have demonstrated that a peptide, which we named 'Peptide A', derived from the extracellular domain of T-cell leukemia translocation-associated gene (TCTA) protein, inhibited human osteoclastogenesis. OBJECTIVE: In the current study, we examined whether this peptide inhibits the proliferation of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) or not. MATERIAL AND METHODS: Fibroblast-like synoviocytes obtained from five RA patients were cultured in the absence or presence of 1, 5, 10 µg/ml of peptide. We used 29-mer scrambled peptide as a control. RESULTS: The peptide inhibited the proliferation of RA FLS dose-dependently. On the other hand, the scrambled peptide showed no inhibition. CONCLUSIONS: The peptide inhibits both human osteoclastogenesis and the proliferation of RA FLS. Thus, the peptide may be used for the therapy of both osteoporosis and synovitis of RA patients. This is the first report of the new peptide we discovered, which inhibits both osteoclastogenesis and synovitis. Thus, this new peptide could be a new drug for patients with both osteoporosis and RA.

Voltage-dependent anion channels (VDACs, porin) expressed in the plasma membrane regulate the differentiation and function of human osteoclasts.

Fewer molecules have been identified on human than murine osteoclasts, the former differing from murine osteoclasts in many ways. We show that voltage-dependent anion channels (VDACs, porin) are expressed in the plasma membrane of human osteoclasts. A search for novel proteins expressed in the plasma membrane of human osteoclasts identified VDAC. Anti-VDAC antibodies inhibited human osteoclastogenesis in vitro. VDAC expression was detected in membranes by immunoelectron microscopy and immunocytochemical double staining. The VDAC protein functions as a Cl(-) channel. VDACs regulate bone resorption, which show using Osteologic™ plates. The epitope of the antibody lay within a 10-amino acid sequence in the VDAC. The findings suggest that the VDAC is, at least partly, a novel Cl(-) channel regulating the differentiation and function of human osteoclasts. VDACs may play a crucial role in acidifying the resorption lacunae between osteoclasts and bone. Inhibitors of VDACs could be used to treat diseases involving increased resorption, such as osteoporosis, rheumatoid arthritis, and Paget's disease.

Tacrolimus potently inhibits human osteoclastogenesis induced by IL-17 from human monocytes alone and suppresses human Th17 differentiation.

Tacrolimus (FK506, Prograf®) is an orally available, T cell specific and anti-inflammatory agent that has been proposed as a therapeutic drug in rheumatoid arthritis (RA) patients. It has been known that T cells have a critical role in the pathogenesis of RA. Recent studies suggest that Th17 cells, which mainly produce IL-17, are involved in many autoimmune inflammatory disease including RA. The present study was undertaken to assess the effect of tacrolimus on IL-17-induced human osteoclastogenesis and human Th17 differentiation. Human CD14(+) monocytes were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and IL-17. From day 4, tacrolimus was added to these cultures. Osteoclasts were immunohistologically stained for vitronectin receptor 10days later. IL-17 production from activated T cells stimulated with IL-23 was measured by enzyme-linked immunosorbent assay (ELISA). Th17 differentiation from naïve T cells was assayed by flow cytometry. Tacrolimus potently inhibited IL-17-induced osteoclastogenesis from human monocytes and osteoclast activation. Addition of tacrolimus also reduced production of IL-17 in human activated T cells stimulated with IL-23. Interestingly, the population of human IL-17(+)IFN-γ(-) CD4 T cells or IL-17(+)TNF-α(+) CD4 T cells were decreased by adding of tacrolimus. The present study demonstrates that the inhibitory effect of tacrolimus on IL-17-induced osteoclastogenesis from human monocytes. Tacrolimus also inhibited expression of IL-17 or TNF-α by reducing the proportion of Th17, suggesting that therapeutic effect on Th17-associated disease such as RA, inflammatory bowel disease, multiple sclerosis, psoriasis, or allograft rejection.

The role of T-cell leukemia translocation-associated gene protein in human tumorigenesis and osteoclastogenesis.

Synovial tissues of patients with rheumatoid arthritis (RA) include factors regulating bone resorption, such as receptor activator NF-κB ligand (RANKL), TNF-α, IL-6, IL-17, and IFN-γ. However, in addition to these cytokines, other factors expressed in synovial tissues may play a role in regulating bone resorption. In 2009, we demonstrated that novel peptides from T-cell leukemia translocation-associated gene (TCTA) protein expressed in synovial tissues from patients with RA inhibit human osteoclastogenesis, preventing cellular fusion via the interaction between TCTA protein and a putative counterpart molecule. Only a few studies on the role of TCTA protein have been reported. Genomic Southern blots demonstrated a reduced TCTA signal in three of four small cell lung cancer cell lines, suggesting the loss of one of the two copies of the gene. In the current paper, we reviewed the roles of TCTA protein in lung cancer cell lines and human osteoclastogenesis.

Role of osteoclasts and interleukin-17 in the pathogenesis of rheumatoid arthritis: crucial 'human osteoclastology'.

Many papers have reported that osteoclasts play an important role in the pathogenesis of rheumatoid arthritis (RA); however, when we started to investigate the pathogenesis of RA, the roles of osteoclasts were not highlighted in RA bone resorption. In recent years, the number of articles on the roles of osteoclasts and interleukin (IL)-17 in the pathogenesis of RA has increased exponentially. In this review article, we describe our articles on the roles of osteoclasts and IL-17 in joint destruction in RA, from 1990 to 2011, and highlight a novel term, 'human osteoclastology', which we have used since 2008.

Anti-C1q antibodies are associated with systemic lupus erythematosus global activity but not specifically with nephritis: a controlled study of 126 consecutive patients.

OBJECTIVE: Several studies have shown that anti-C1q antibodies correlate with the occurrence and activity of nephritis in systemic lupus erythematosus (SLE). However, the significance of anti-C1q antibodies in SLE has not been fully characterized. The aim of this study was to investigate associations between anti-C1q antibodies and clinical and serologic parameters of SLE. METHODS: An enzyme-linked immunosorbent assay kit was used to measure anti-C1q antibodies in the sera of 126 consecutive patients with active SLE who were admitted to our university hospital from 2007 through 2009. Sera obtained from patients with high titers of anti-C1q antibodies at the initial evaluation (n = 20) were reevaluated following treatment. Control sera were obtained from patients with other autoimmune diseases and from normal healthy control subjects (n = 20 in each group). Associations between anti-C1q antibodies and clinical and serologic parameters of SLE were statistically analyzed. RESULTS: Anti-C1q antibodies were detected in the sera of 79 of 126 patients with SLE. The prevalence and titers of anti-C1q antibodies were significantly (P < 0.0001) higher in SLE patients than in patients with rheumatoid arthritis, patients with systemic sclerosis, and normal healthy control subjects. The prevalence and titers of anti-C1q antibodies were not significantly associated with active lupus nephritis (P = 0.462 and P = 0.366, respectively). Anti-C1q antibody titers were significantly correlated with SLE Disease Activity Index 2000 scores and the levels of anti-double-stranded DNA antibodies, C3, C4, CH50, and C1q (P < 0.0001 for all comparisons). Moreover, anti-C1q antibody titers significantly decreased as clinical disease was ameliorated following treatment (P = 0.00097). CONCLUSION: These findings indicate that anti-C1q antibodies are associated with SLE global activity but not specifically with active lupus nephritis.

Activation of the activin A-ALK-Smad pathway in systemic sclerosis.

Systemic sclerosis (SSc) is a chronic disease of unknown etiology that is characterized by multiple tissue fibrosis. Transforming Growth Factor-beta (TGF-ß) is thought to be the most important mediator that induces fibrosis. However, the molecular mechanisms by which fibrosis is induced have not been fully elucidated. In this study, the role of activin, a member of the TGF-ß superfamily, was investigated in the pathogenesis of fibrosis in SSc. Serum activin A levels in patients with SSc were measured by ELISA, and the expression of the activin receptor type IB (ACVRIB/ALK4) and the activity of the signaling pathway via ACVRIB/ALK4 were investigated using western blotting. To evaluate a potential therapeutic strategy for SSc, we also attenuated the ACVRIB/ALK4 pathway using an inhibitor. Serum activin A levels were significantly higher in SSc patients than in normal controls. Activin A and ACVRIB/ALK4 expression were also higher in cultured SSc fibroblasts. Activin A stimulation induced phosphorylation of Smad2/3 and CTGF expression in SSc fibroblasts. Procollagen production and Col1α mRNA also increased upon stimulation by activin A. The basal level of Smad2/3 phosphorylation was higher in cultured SSc fibroblasts than in control cells, and treatment with the ALK4/5 inhibitor SB431542 prevented phosphorylation of Smad2/3 and CTGF expression. Furthermore, production of collagen was also induced by activin A. Activin A-ACVRIB/ALK4-Smad-dependent collagen production was augmented in SSc fibroblasts, suggesting the involvement of this signaling mechanism in SSc. Inhibition of the activin A-ACVRIB/ALK4-Smad pathway would be a new approach for the treatment of SSc.

Association of the FAM167A-BLK region with systemic sclerosis.

OBJECTIVE: An association of single-nucleotide polymorphisms (SNPs) in the FAM167A (previously referred to as C8orf13)-BLK region with systemic lupus erythematosus (SLE) has been demonstrated in Caucasians and in Asians. Recent studies have shown that many genes, including IRF5, STAT4, and PTPN22, are shared susceptibility genes in multiple autoimmune diseases. We undertook the current study to examine whether the FAM167A-BLK region is also associated with susceptibility to systemic sclerosis (SSc). METHODS: Japanese patients with SSc (n = 309) and healthy controls (n = 769) were enrolled in a 2-tiered case-control association study. In tier 1, 124 patients and 412 controls were tested to determine association of 16 tag SNPs encompassing the FAM167A-BLK region with SSc. In tier 2, an additional 185 patients and 357 controls were analyzed for SNP rs13277113. RESULTS: Two haplotype blocks that correspond approximately to FAM167A and BLK were observed. In tier 1 of the study, the rs13277113A allele in the BLK block exhibited the most significant association with SSc after correction for multiple testing (permutated P = 0.024). Two SNP haplotypes formed by rs13277113 and the most significant SNP in the FAM167A block did not exhibit stronger association. When samples from tier 1 and tier 2 were combined, the rs13277113A allele was significantly associated with SSc (odds ratio 1.45 [95% confidence interval 1.17-1.79], P = 6.1 x 10(-4)). Association or a tendency toward association of rs13277113A with SSc was observed regardless of a patient's autoantibody profile or whether a patient had diffuse cutaneous or limited cutaneous SSc. CONCLUSION: Our findings indicate that the rs13277113A allele is associated not only with SLE but also with SSc and that the FAM167A-BLK region is a common genetic risk factor for both SLE and SSc.

Interleukin-18 promoter polymorphisms in Japanese patients with rheumatoid arthritis: protective effect of the T allele and T/T genotype at rs360722.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with a strong genetic contribution to its pathogenesis. Among numerous candidate genes, cytokine gene polymorphisms have been implicated. Interleukin-18 (IL-18) induces production of tumor necrosis factor-α and promotes T helper (Th)1-type immune responses. This study investigates the association between IL-18 promoter polymorphisms and RA susceptibility. A total of 2471 Japanese case-control samples (1493 RA patients and 978 healthy controls) were examined. Three haplotype tag single-nucleotide polymorphisms, rs1946518A/C, rs360718T/G, and rs360722T/C, spanning from the 5'UTR to intron 1 were genotyped using allelic discrimination with the use of specific TaqMan probes, and three haplotypes (A-T-T, C-T-C, and A-G-C) were determined. Among these polymorphisms, the frequency of the T allele at rs360722, which tags the A-T-T haplotype, was significantly lower in the RA patient group compared with the normal subjects [0.46 versus 0.49, P = 0.0061, Fisher's exact probability test, odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75-0.95]. Having the T/T genotype further increased the significance (0.20 versus 0.27, P = 0.0006, OR = 0.72, 95% CI = 0.58-0.86). Therefore, presence of the T allele and T/T genotype at rs360722 reduces the susceptibility of Japanese people to RA.

Characteristics of Japanese patients with systemic sclerosis complicated with calcinosis.

AIM: Calcinosis is often observed in systemic sclerosis (SSc), but its pathogenesis remains unclear. The aim of the present study was to explore the association of clinical features with calcinosis in patients with SSc. METHODS: A retrospective cohort study was performed analyzing 416 SSc patients from our SSc database. We examined the clinical features with relation to calcinosis and SSc. RESULTS: Calcinosis was observed in 24.0% of patients with SSc. The group with calcinosis comprised more female patients (P < 0.05) and diffuse cutaneous types (P < 0.001) than the group without calcinosis. Complications of Raynaud's phenomenon (P < 0.05), nail fold bleeding (NFB) (P < 0.001), peripheral bone resorption (P < 0.001), myositis (P < 0.001), and pulmonary hypertension (P < 0.05) were more frequently observed in patients with calcinosis compared with those without calcinosis. The group with calcinosis had a higher modified Rodnan total skin-thickness score (mRSS) than the group without calcinosis (P < 0.001). The factors that affected calcinosis in multivariable analysis were peripheral bone resorption (partial correlation coefficient 0.46, 34%), anti-Scl-70 antibody (partial correlation coefficient 0.29, 20%), diffuse type (partial correlation coefficient 0.34, 16%) and NFB (partial correlation coefficient 0.23, 11.2%). CONCLUSIONS: Calcinosis in SSc is associated with Raynaud's phenomenon, NFB, and pulmonary hypertension, so peripheral circulatory insufficiency seems to be one of the causes of calcinosis. Furthermore, as it is related to mRSS and the diffuse cutaneous type, common factors related to skin fibrosis are considered to be involved.

Increased HGF and c-Met in muscle tissues of polymyositis and dermatomyositis patients: beneficial roles of HGF in muscle regeneration.

We investigated the expression of hepatocyte growth factor (HGF), which has mitogenic and anti-fibrotic activities, in muscle tissue of polymyositis/dermatomyositis (PM/DM) patients, as well as its functional roles in cultured myoblasts. Immunohistochemistry in muscle from PM/DM patients revealed that HGF was expressed predominantly on infiltrating mononuclear cells and that muscle cells expressed the receptor c-met. Cultured myoblasts produced HGF; which was increased by IL-1alpha but suppressed by TGF-beta and dexamethasone. Exogenous HGF induced myoblast proliferation and reduced procollagen type I production. Furthermore, HGF enhanced the gene expression of muscle regulatory factors MyoD and Myf5, while suppressing expression of fibrosis-related genes, connective tissue growth factor and alpha-smooth muscle actin. Although dexamethasone showed contrasting effects to HGF on the expression of these genes, co-treatment with HGF ameliorated the effects of dexamethasone. Taking the beneficial roles of HGF into consideration, administration of HGF might contribute to muscle regeneration in PM/DM especially under corticosteroid treatment.

Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and their effect on visceral fat area in the Japanese population.

The predominant risk factor of metabolic syndrome is intra-abdominal fat accumulation, which is determined by waist circumference and waist-hip ratio measurements and visceral fat area (VFA) that is measured by computed tomography (CT). There is evidence that waist circumference and waist-hip ratio in the Caucasian population are associated with variations in several genes, including neurexin 3 (NRXN3), transcription factor AP-2ß (TFAP2B), methionine sulfoxide reductase A (MSRA), lysophospholipase-like-1 (LYPLAL1), fat mass and obesity associated (FTO) and melanocortin 4 receptor (MC4R) genes. To investigate the relationship between VFA and subcutaneous fat area (SFA) and these genes in the recruited Japanese population, we genotyped 8 single-nucleotide polymorphisms (SNPs) in these 6 genes from 1228 subjects. Multiple regression analysis revealed that gender, age, and rs1558902 and rs1421085 genotypes (additive model) in FTO were significantly associated with body mass index (BMI; P=0.0039 and 0.0039, respectively), SFA (P=0.0027 and 0.0023, respectively) and VFA (P=0.045 and 0.040, respectively). However, SNPs in other genes, namely, NRXN3, TFAP2B, MSRA, LYPLAL1 and MC4R were not significantly associated with BMI, SFA or VFA. Our data suggest that some SNPs, which were identified in genome-wide studies in the Caucasians, also confer susceptibility to fat distribution in the Japanese subjects.

Excessive production of IFN-gamma in patients with systemic lupus erythematosus and its contribution to induction of B lymphocyte stimulator/B cell-activating factor/TNF ligand superfamily-13B.

Expression and immunological significance of IFN-gamma, a pivotal cytokine in murine lupus, have not been clearly demonstrated in human systemic lupus erythematosus (SLE). In the present study we investigated the expression of IFN-gamma in peripheral blood T cells from patients with SLE and its role in the production of the soluble B lymphocyte stimulator (sBLyS). Peripheral blood T cells from patients with SLE expressed significantly larger amounts of IFN-gamma in response to stimulation with anti-CD3 mAb plus anti-CD28 mAb than those from normal controls as shown by three analytical methods, including ELISA, flow cytometry, and quantitative RT-PCR. The ratio of IFN-gamma-producing T cells to effector memory T cells in CD3(+)CD4(+) and CD3(+)CD8(+) populations in patients with SLE was significantly higher than that of normal controls. The T-box expressed in T cells (T-bet) mRNA/GATA-binding protein-3 (GATA-3) mRNA ratio was significantly higher in patients with SLE than in normal controls. T cell culture supernatants from patients with SLE contained significantly higher sBLyS-inducing activity than normal controls; this was almost completely inhibited by the addition of anti-human IFN-gamma mAb. Percentages of BLyS-expressing peripheral blood monocytes in patients with SLE were significantly higher than those of normal controls. Monocytes from patients with SLE produced significantly larger amounts of sBLyS in response to IFN-gamma than those from normal controls. Taken together, these data strongly indicate that the overexpression of IFN-gamma in peripheral blood T cells contributes to the immunopathogenesis of SLE via the induction of sBLyS by monocytes/macrophages, which would promote B cell activation and maturation.

Interferon-induced helicase (IFIH1) polymorphism with systemic lupus erythematosus and dermatomyositis/polymyositis.

The aim of the present study was to evaluate whether the interferon-induced helicase (IFIH1) Ala946Thr (rs1990760 A>G) polymorphism is associated with susceptibility to systemic lupus erythematosus (SLE) and dermatomyositis (DM) or polymyositis (PM) in the Japanese population. The study population consisted of 243 SLE patients, 125 DM/PM patients, and 268 healthy controls from Japan. A Taqman single nucleotide polymorphism genotyping assay was designed for rs1990760 by Applied Biosystems. There were no significant differences between SLE and DM/PM patients and healthy controls regarding the frequency of each genotype and allele. However, the frequency of the AA genotype and the A allele tended to be higher in PM patients with interstitial lung disease (ILD). Additionally, when comparing the AA and AG + GG genotypes at rs1990760, the AA genotype was significantly more frequent in PM patients with ILD than in healthy controls [odds ratio, 3.23 (95% confidence interval, 1.06-9.81); P = 0.04] or in PM patients without ILD [odds ratio, 5.40 (95% confidence interval, 1.37-21.26); P = 0.027]. Our observations suggest that the G allele protects against the onset of ILD and that the AA genotype is a risk factor for lung injury in PM patients.

Single nucleotide polymorphisms of CD244 gene predispose to renal and neuropsychiatric manifestations with systemic lupus erythematosus.

The objective of this study was to explore the association of single nucleotide polymorphisms (SNPs) of the CD244 gene with several clinical features of systemic lupus erythematosus (SLE). Two hundred and forty-three patients with SLE and 369 healthy controls were enrolled. Two SNPs (rs6682654 and rs3766379) in the CD244 gene were determined by allelic discrimination using a specific TaqMan probe. Only SNP rs3766379 was significantly associated with susceptibility to SLE [P = 0.009; odds ratio (OR) 1.28; 95% confidence interval (CI) 1.04-1.57]. The association was preferentially observed in subsets of SLE patients with nephritis and neuropsychiatric lupus. The frequency of the rs6682654 C allele was strongly associated with nephritis and neuropsychiatric lupus (P = 0.00065; OR 1.99; 95% CI 1.34-2.95, and P = 1.6 × 10(-7); OR 3.47; 95% CI 2.12-5.70, respectively), as was the frequency of the rs3766379 T allele (P = 0.0014; OR 1.86; 95% CI 1.27-2.71, and P = 2.6 × 10(-7); OR 3.15; 95% CI 2.00-4.96, respectively). In this study, an SNP of the CD244 gene was associated with susceptibility to SLE. There was a strikingly strong association in SLE patients with nephritis and neuropsychiatric lupus, suggesting that this genetic marker could predict involvement of those severe complications.