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Objective: The aim of this study is to determine whether the functional interferon regulatory factor 5 ( IRF5) polymorphism rs2004640 is associated with susceptibility to systemic lupus erythematosus (SLE) in multiple ethnic populations., Methods: A meta-analysis was conducted on the T allele of the IRF5 rs2004640 polymorphism in all study participants as well as each ethnic population., Results: Twenty research articles that included 28 comparative studies of 20,892 patients and 24,930 controls were included in the meta-analysis. The Asian population had a much lower prevalence of the T allele than any other study population at 28%, and the European population had the highest prevalence of the T allele at 52%. Meta-analysis showed an association between the IRF5 rs2004640 polymorphism and SLE in all participants (odds ratio = 1.472, 95% confidence interval = 1.370-1.582, p < 0.001). Analysis after stratification by ethnicity indicated that the IRF5 rs2004640 T allele is significantly associated with SLE in Europeans, Asians, Latin Americans and Arabs., Conclusions: This meta-analysis confirms that the IRF5 rs2004640 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: To systematically review evidence regarding the relationship between circulating macrophage migration inhibitory factor (MIF) levels and rheumatoid arthritis (RA), and the association between MIF gene polymorphisms and RA susceptibility., Design: We performed a meta-analysis on data of serum/plasma MIF levels in patients with RA and in controls, and on associations between the MIF -173 C/G and -794CATT 5-8 polymorphisms and RA susceptibility., Patients: Twelve studies, comprising a total of 362 RA cases and 531 controls evaluated for MIF levels, and 2367 RA cases and 2395 controls evaluated for MIF polymorphisms, were included., Results: MIF levels were significantly higher in the RA group than in the control group (standardised mean difference (95% CI) 0.923 (0.766 to 1.080), p<0.001). Stratification by ethnicity revealed significantly higher MIF levels in the RA group in Caucasian, Asian and Latin American populations. MIF levels were significantly higher in patients with RA, regardless of adjustment, sample size or data type evaluated. RA was identified to be significantly associated with the MIF -173 C allele (OR (95% CI) 1.271 (1.141 to 1.416), p<0.001), as well as with the -794CATT 7 allele (OR (95% CI) 1.229 (1.084 to 1.415), p=0.002) and the -794CATT 7 - MIF -173C haplotype RA (OR (95% CI) 1.433 (1.138 to 1.805), p=0.002)., Conclusions: Our meta-analyses revealed significantly higher circulating MIF levels in patients with RA, and found evidence of associations between the MIF -173 C/G and -794CATT 5-8 polymorphisms and RA susceptibility., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: The aim of this study was to determine whether endothelial nitric oxide synthase (eNOS) polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)., Methods: A meta-analysis was conducted on associations between the 4b/a, T786C, and G894T polymorphisms of eNOS and SLE or RA using the following methods: (1) allele contrast, (2) recessive model, (3) dominant model, and (4) homozygous contrast., Results: Nineteen studies were included in this meta-analysis, comprising eleven studies on SLE (1561 patients and 1565 controls) and eight on RA (1624 patients and 2118 controls). Meta-analysis showed a significant association between SLE and the 4b/a polymorphism using the recessive model and the homozygous contrast (odds ratio [OR] = 1.836, 95 % confidence interval [CI] = 1.171-2.878, p = 0.008; OR = 2.055, 95 % CI = 1.302-3.243, p = 0.002). Ethnicity-specific meta-analysis showed a significant association between the aa vs. bb of the 4b/a polymorphism and SLE in European populations (OR = 2.096, 95 % CI = 1.288-4.0, p = 0.027), but not in Arab populations. Stratification by presence of lupus nephritis (LN) indicated a significant association between the a allele and the aa + ab genotype of the 4b/a polymorphism and LN in SLE patients (OR = 2.125, 95 % CI = 1.289-3.054, p = 0.003; OR = 2.655, 95 % CI = 1.509-4.671, p = 0.001). Meta-analysis indicated no association between SLE and the T786C and G894T polymorphisms. No association was found between the eNOS 4b/a, T786C, and G894T polymorphisms and RA CONCLUSIONS: This meta-analysis of published studies shows that the eNOS 4b/a polymorphism may be associated with the development of SLE, but the 4b/a, T786C, and G894T polymorphisms may be not associated with RA susceptibility.

This study investigated whether the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene (ATIC) 347 C/G polymorphism can predict the response to or toxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA). We conducted a meta-analysis of studies on the association between ATIC 347 C/G polymorphism and non-responsiveness to or toxicity of MTX in RA patients, using PUBMED, EMBASE, and COCHRANE. Nine comparative studies from 6 articles including 1056 RA patients met our inclusion criteria. This final group of studies comprised 5 studies on response to MTX and 4 on toxicity of MTX in RA patients in relation to the ATIC 347 C/G polymorphism status. Meta-analysis showed association between the ATIC 347 GG + GC genotype and non-response to MTX therapy (OR = 1.572, 95 % CI 1.146-2.156, p = 0.005). Stratification by ethnicity indicated significant association between the ATIC 347 GG + GC genotype and non-response to MTX in Caucasians (OR = 1.884, 95 % CI 1.236-2.873, p = 0.003), but not in Asian patients. Similarly, associations were noted for the ATIC 347 C/G polymorphism through analysis using recessive and overdominant models. Meta-analysis revealed association between the ATIC 347 GG + GC genotype and MTX toxicity (OR = 1.454 95 % CI 1.034-2.044, p = 0.032). Stratification by ethnicity indicated significant association between the ATIC 347 GG + GC genotype and MTX toxicity in Caucasians (OR = 1.741, 95 % CI 1.080-2.806, p = 0.023), but not in Asian patients. The ATIC 347 C/G polymorphism may be associated with non-responsiveness to and or toxicity of MTX in Caucasian RA patients.

We aimed to investigate whether the PTPRC rs10919563 A/G and Fc gamma receptor 2A (FCGR2A) R131H polymorphisms can predict the response to anti-TNF therapy in rheumatoid arthritis (RA) patients. We conducted a meta-analysis of studies on the association between the PTPRC rs10919563 A/G or the FCGR2A R131H polymorphism and responsiveness to anti-TNF therapy in RA patients. Eighteen studies (twelve on PTPRC and six on FCGR2A) from eight articles involving 3058 patients were considered in this meta-analysis. The meta-analysis showed a significant association between the PTPRC rs10919563 A allele and response to TNF-α blockers in RA. The OR of the PTPRC A allele was significantly lower in responders (OR = 0.584, 95 % CI = 0.409-0.835, P = 0.003). Meta-analysis revealed no association between the FCGR2A HH + HR genotype and responsiveness to TNF blockers in all study subjects (OR = 0.762, 95 % CI = 0.543-1.068, P = 0.115). However, stratification by TNF inhibitor type showed that the FCGR2A HH + HR genotype was associated with responsiveness to adalimumab (OR = 0.591, 95 % CI = 0.369-0.947, P = 0.029), but not infliximab and etanercept (OR = 0.929, 95 % CI = 0.354-2.440, P = 0.881; OR = 0.804, 95 % CI = 0.293-2.207, P = 0.673). The PTPRC rs10919563 A allele shows a poor response to anti-TNF therapy, and the FCGR2A HH + HR genotype shows a poor response to adalimumab for RA. Genotyping for these polymorphisms may be useful for predicting the response to TNF-α blockers with respect to personalized medicine.

The objective of the study was to determine by meta-analysis whether polymorphisms of the gene encoding peptidylarginine deiminase 4 (PADI4) are associated with susceptibility to rheumatoid arthritis (RA). A literature review was conducted to identify data sets that described analyses of genetic association between PADI4 polymorphisms and RA. Data sets were collated and a meta-analysis was performed, with a specific focus on associations within Caucasian and Asian populations. A total of 15,947 RA cases and 22,696 controls that were taken from 28 studies in 24 papers were included in this study. Meta-analysis showed a significant association between allele 2 of the PADI4&#95;94 polymorphism and RA in the overall population (odds ratio [OR] = 1.155, 95 % confidence interval [CI] = 1.069-1.249, p = 2.7 × 10(-5)). Stratification by ethnicity revealed an association between PADI4&#95;94 allele 2 and RA in Asians (OR = 1.273, 95 % CI = 1.193-1.359, p < 1.0 × 10(-9)), but not in Caucasians (OR = 1.024, 95 % CI = 0.973-1.078, p = 0.358). However, meta-analysis using homozygote contrast showed an association between PADI4&#95;94 allele 2 and RA in both Asians (OR = 2.311, 95 % CI = 1.1.858-2.875, p < 1.0 × 10(-9)) and Caucasians (OR = 1.523, 95 % CI = 1.157-2.004, p = 0.008). Meta-analysis also revealed an association between allele 2 of the PADI4&#95;104 polymorphism and RA in both Asians (OR = 1.547, 95 % CI = 1.247-1.919, p = 7.1 × 10(-6)) and Caucasians (OR = 1.096, 95 % CI = 1.025-1.172, p = 0.008). Finally, meta-analysis showed an association between allele 2 of the PADI4&#95;92 polymorphism and RA in Asians (OR = 1.263, 95 % CI = 1.153-1.384, p = 5.8 × 10(-8)), but not in Caucasians (OR = 1.123, 95 % CI = 0.980-1.287, p = 0.095). Meta-analysis indicated no association between allele 2 of either the PADI4&#95;90 or PADI4&#95;89 polymorphisms and RA in Asians. This meta-analysis revealed that the PADI4&#95;94 and PADI&#95;104 polymorphisms are associated with susceptibility to RA in Asians and Caucasians, and that the PADI4&#95;92 polymorphism is associated with susceptibility to RA in Asians, but not in Caucasians.

This study determined whether interleukin-1 (IL-1) polymorphisms are associated with susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the IL-1A, IL-1B, and IL-1 receptor antagonist (IL-1RN) polymorphisms and RA. A total of 16 studies involving 4,339 RA cases and 3,885 controls were included in the meta-analysis. Meta-analysis of the IL-1B -511 C/T polymorphism revealed an association between the IL-1B -511 T allele and RA in Caucasians (OR = 0.913, 95% CI = 0.840-0.992, p = 0.031), but not in Asians. Ethnicity-specific meta-analysis indicated an association between the TT+TC genotype of the IL-1B 3953 C/T polymorphism and RA in Caucasians (OR = 1.243, 95% CI = 1.008-1.533, p = 0.042) and in Asians (OR = 2.672, 95% CI = 1.662-4.296, p = 4.9x10-6). No association was between RA susceptibility and the IL-1A -889 C/T, IL-1A +4845 G/T, and IL-1RN +2018 C/T polymorphisms. This meta-analysis suggests the IL-1B -511 C/T polymorphism is associated with susceptibility to RA in Caucasians, and that the IL-1B +3953 C/T polymorphism is associated with susceptibility to RA in Caucasians and Asians.

Objectives: The aim of this study is to explore whether Fc gamma receptor (FCGR) polymorphisms are associated with the susceptibility to rheumatoid arthritis (RA)., Methods: We conducted a meta-analysis on the association between FCGR2A H131R (rs1801274), FCGR3A F158V (rs396991), and FCGR3B NA1/NA2 polymorphisms and RA susceptibility., Results: A total of seventeen studies reported in fourteen articles (4,418 patients with RA and 3,560 controls) were considered in our meta-analysis. In all of the study subjects, meta-analysis indicated an association between RA and FCGR2A R allele (OR=0.877, 95% CI=0.792-0.971, p=0.011). Stratification by ethnicity indicated an association between FCGR2A R allele and RA in Europeans (OR=0.816, 95% CI=0.687-0.968, p=0.020), but not in East Asians (OR=0.900, 95% CI=0.778-1.040, p=0.154). Meta-analysis revealed an association between RA and FCGR3A VV vs. FF genotype in all the study subjects (OR=1.210, 95% CI=1.067-1.479, p=0.006). Stratification by ethnicity indicated an association between FCGR3A VV genotype and RA compared toFF genotype in Europeans (OR=1.350, 95% CI=1.107-1.646, p=0.003), but not in East Asians and South Asians. No association was observed between RA and FCGR3B polymorphisms on performing the meta-analysis., Conclusions: Although no relationship was found between the FCGR3B polymorphism and RA susceptibility, FCGR2A and FCGR3A polymorphisms were found to be associated with RA in Europeans, but not in Asians.

The aim of this study was to determine whether the functional HLA-G 14 bp insertion (I)/deletion (D) and +3142 G/C polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the HLA-G 14 bp I/D, and +3142 G/C polymorphisms and SLE or RA using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) additive model. A total of 14 comparison studies from 11 articles met our inclusion criteria, comprising eight on SLE (1,284 patients and 1,885 controls) and four on RA (820 patients and 772 controls), and three studies investigated response to methotrexate (MTX) in RA according to the HLA-G 14 bp I/D polymorphisms (249 responders and 205 nonresponders). Meta-analysis revealed an association between the II + ID genotype of the HLA-G 14 bp I/D polymorphism in overall group (OR = 1.205, 95% CI = 1.036-1.403, P = 0.016). Ethnicity-specific meta-analysis showed no association between the II + ID genotype and SLE in the South American, European, and Asian population. Meta-analysis revealed a significant association between SLE and the HLA-G +3142 G allele in all study subjects (OR = 1.367, 95% CI = 1.158-1.613, P = 2.2 × 10(-5)) and in the South American group (OR = 1.531, 95% CI = 1.242-1.888, P = 6.7 × 10(-5)). However, no association between HLA-G 14 bp I/D, and +3142 G/C polymorphisms and RA was found (OR for HLA-G I allele = 1.013, 95 % CI = 0.879-1.167, P = 0.859; OR for +3142 G allele = 0.980, 95% CI = 0.742-1.294, P = 0.888). Furthermore, HLA-G 14 bp I/D polymorphism was not found to be associated with response to MTX in RA. This meta-analysis demonstrates that the HLA-G 14 bp I/D polymorphism is associated with susceptibility to SLE, and HLA-G +3142 G/C polymorphisms are associated with susceptibility to SLE in South Americans.

The aim of this study was to determine whether the prolactin -1149 G/T polymorphism confers susceptibility to systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). A meta-analysis was conducted for examining the associations between prolactin -1149 G/T polymorphism and susceptibility to SLE or RA using allele contrast, recessive and dominant models, and homozygote contrast. A total of 10 comparative studies, consisting of 4 SLE and 6 RA studies, involving 4252 patients and 4949 controls, were included in the meta-analysis. No association between the prolactin -1149 G allele and SLE was found when all study subjects were considered together (OR = 1.019, 95 % CI = 1.841-1.236, p = 0.845). Stratification by ethnicity also indicated no association between the prolactin G allele and SLE in either Caucasian or Latin American populations. In contrast, a significant association was observed between the prolactin G allele and RA in all subjects (OR = 1.123, 95 % CI = 1.052-1.198, p = 4.6 × 10(-5)). After stratification by ethnicity, the G allele was found to be significantly associated with RA in Caucasians (OR = 1.112, 95 % CI = 1.041-1.189, p = 0.002). Furthermore, the prolactin -1149 G/T polymorphism was found to be associated with RA in Caucasians under the dominant model and under homozygote contrast. This meta-analysis demonstrates that the prolactin -1149 G/T polymorphism is associated with susceptibility to RA, but not SLE, in Caucasians.

Previous studies have emphasized ethnically heterogeneous human leukocyte antigen (HLA) classical allele associations to rheumatoid arthritis (RA) risk. We fine-mapped RA risk alleles within the major histocompatibility complex (MHC) in 2782 seropositive RA cases and 4315 controls of Asian descent. We applied imputation to determine genotypes for eight class I and II HLA genes to Asian populations for the first time using a newly constructed pan-Asian reference panel. First, we empirically measured high imputation accuracy in Asian samples. Then we observed the most significant association in HLA-DRβ1 at amino acid position 13, located outside the classical shared epitope (Pomnibus = 6.9 × 10(-135)). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His > Phe > Arg > Tyr ≅ Gly > Ser)--but the observed effects in Asians are generally smaller. Applying stepwise conditional analysis, we identified additional independent associations at positions 57 (conditional Pomnibus = 2.2 × 10(-33)) and 74 (conditional Pomnibus = 1.1 × 10(-8)). Outside of HLA-DRβ1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8 × 10(-6)) and HLA-DPβ1 (Phe9, conditional P = 3.0 × 10(-5)) concordant with European populations. Our trans-ethnic HLA fine-mapping study reveals that (i) a common set of amino acid residues confer shared effects in European and Asian populations and (ii) these same effects can explain ethnically heterogeneous classical allelic associations (e.g. HLA-DRB1*09:01) due to allele frequency differences between populations. Our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of this study was to explore whether the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) play a role in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). MEDLINE and EMBASE database searches and subsequent manual searches were utilized to identify articles in which C677T and A1298C MTHFR polymorphisms were evaluated in RA patients taking MTX. A meta-analysis was conducted to identify associations between MTHFR polymorphisms and MTX toxicity. Twelve studies comprising a total of 2,288 RA patients were included in our meta-analysis. Meta-analysis revealed an association between the overall toxicity of MTX and the MTHFR 677TT genotype (odds ratio [OR] = 1.615, 95 % confidence interval [CI] = 1.185-2.200, p = 0.002). Stratification by ethnicity indicated an association between the MTHFR 677TT genotype and the overall toxicity of MTX in East Asians (OR = 1.583, 95 % CI = 1.075-2.331, p = 0.020). The toxicity of MTX also was found to be associated with the TT genotype in patients taking folate (OR = 1.893, 95 % CI = 1.283-2.793, p = 0.001). Stratification by toxicity type indicated an association between the MTHFR 677TT genotype and any adverse effects (OR = 1.716, 95 % CI = 1.127-2.612, p = 0.012). Meta-analysis stratified by toxicity type indicated an association between the MTHFR 1298CC genotype and any adverse effects (OR = 0.501, 95 % CI = 0.284-0.886, p = 0.017). The results of our meta-analysis suggest that the MTHFR C677T and A1298C polymorphisms are associated with MTX toxicity in RA patients.

Several studies have examined the effects of tumor necrosis factor receptor (TNFR) 1 +38 A/G and TNFR2 196 M/R polymorphisms on susceptibility to RA and have reported conflicting results. The purpose of this study was to examine whether the TNFR1 +38 A/G and TNFR2 196 M/R polymorphisms are associated with RA susceptibility. We performed a literature search using the Medical Literature Analysis and Retrieval System Online and Embase citation indices, and conducted a meta-analysis to examine the association between the TNFR1 +38 A/G and TNFR2 196 M/R polymorphisms and RA. Our meta-analysis included a total of 13 studies from 11 articles, consisting of 11 studies of the TNFR2 polymorphism (2,092 cases and 1,483 controls), and two studies of the TNFR1 polymorphism (672 cases and 288 controls). The meta-analysis revealed a significant association between the TNFR2 196 RR genotype and RA risk (OR 1.737, 95 % CI 1.275-2.367, P = 4.6 × 10(-5)). Stratification by ethnicity indicated an association between the TNFR2 196 RR genotype and RA in Europeans (OR 2.054, 95 % CI 1.305-3.232, P = 0.002), but not in East Asians (OR 1.596, 95 % CI 0.642-3.971, P = 0.314). Analysis using a homozygote contrast model showed the same pattern for the TNFR2 196 RR genotype in a European and East Asian population. However, no association was found between the TNFR1 +36 A/G polymorphism and RA in a European population. Our meta-analysis demonstrated that the functional TNFR2 196 M/R polymorphism is associated with susceptibility to RA in the European population.

Introduction: The purpose of this study was to examine whether a Proline (Pro)-to-Alanine (Ala) exchange at codon 12 (Pro12Ala) polymorphism of the peroxisome proliferator-activated receptor-gamma (PPARγ) is associated with susceptibility to nonalcoholic fatty liver disease (NAFLD), rheumatoid arthritis (RA), and psoriatic arthritis (PsA)., Methods: A meta-analysis was conducted on the association between the PPARγ Pro12Ala polymorphism and NAFLD, RA, and PsA., Results: Nine studies, including five on NAFLD, two on RA, and two on PsA, were available for the meta-analysis consisting of 8082 cases and 3790 controls. The meta-analysis revealed no association between the Ala allele of the PPARγ Pro12Ala polymorphism and NAFLD (odds ratios [OR]=0.936, 95% confidence interval [CI]=0.672-1.302, p=0.693). However, stratification by ethnicity indicated an association between the Ala allele and NAFLD in East Asians (OR=0.700, 95% CI=0.496-0.987, p=0.042), but not in Europeans (OR=1.128, 95% CI=0.863-1.475, p=0.378). Analysis using the dominant model showed the same Ala allele pattern in East Asians and Europeans (OR=0.688, 95% CI=0.484-0.978, p=0.037; OR=1.051, 95% CI=0.782-1.413, p=0.742), demonstrating a significant association between the Ala allele and NAFLD in East Asians. The meta-analysis revealed no association between the Ala allele and RA in East Asians (OR=0.467, 95% CI=0.188-1.161, p=0.101), and no association was found between the Ala allele and PsA in Europeans (OR=0.869, 95% CI=0.465-1.627, p=0.662)., Conclusions: Our meta-analysis demonstrates that the PPARγ Pro12Ala polymorphism is associated with susceptibility to NAFLD in East Asians, but not in European populations.

The aim of this study was to determine whether the tumor necrosis factor-α (TNF-α) promoter -308 A/G polymorphism is associated with susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. MEDLINE and EMBASE databases and manual search were used to identify articles in which TNF-α polymorphism was determined in RA patients and controls. A meta-analysis was conducted on the associations between the TNF-α -308 A/G polymorphism and RA by using (1) allelic contrast and (2) dominant models. A total of 19 studies involving 2,584 RA patients and 3,254 controls were considered. The meta-analysis showed no association between the TNF-α -308 A allele and RA when all the subjects were considered [odds ratio (OR) = 1.129, 95 % CI 0.843-1.513, P = 0.416]. After stratification by ethnicity, the meta-analysis indicated that the A allele was significantly associated with RA in Latin Americans (OR = 1.620, 95 % CI 1.234-2.111, P = 3.6 × 10(-5)), but not in the European, Arab, or Asian populations. The meta-analysis of the AA/AG genotype showed the same pattern of results as with the A allele. No association was noted between the AA/AG genotype and RA when all the subjects were considered (OR = 1.114, 95 % CI 0.812-1.529, P = 0.503), but stratification by ethnicity revealed that the AA/AG genotype was significantly associated with RA in Latin Americans (OR = 1.650, 95 % CI 1.234-2.104, P = 0.001). This meta-analysis showed that the TNF-α -308 A/G polymorphism may represent a significant risk factor for RA in Latin Americans but not in the European, Arab, or Asian populations.

The aim of this study was to determine whether toll-like receptor (TLR) polymorphisms confer susceptibility to rheumatoid arthritis (RA) and influence the clinical characteristics of RA. The authors conducted a systematic review on associations between TLR polymorphisms and RA susceptibility and clinical findings. Meta-analysis was performed if at least three comparisons of an issue were available. A total of 14 studies were included in this systematic review, which included European and Asian studies. Meta-analysis of five European studies showed no association between the TLR4 Asp299Gly (rs4986790) polymorphism and RA (OR for the minor allele = 0.907, 95% CI = 0.755-1.088, p = 0.291). Furthermore, none of these studies found any association between the polymorphism and clinical characteristics. A significant difference between TLR9 rs187084 allele frequencies in RA patients and controls was found in one Turkish study (p = 0.003), and a moderate association between RF positivity and TLR8 rs5741883 was found in an European study (p = 0.001). The numbers of guanine-thymine [(GT)n] repeats in intron II of the TLR2 gene were found a significantly higher S-allele frequency in Korean patients with RA than in controls (30.3 vs. 23.0 %, p = 0.03). This meta-analysis shows lack of an association between the TLR4 Asp299Gly polymorphism and RA. However, our finding suggests the possibility that TLR polymorphisms are associated with the development and clinical characteristics of RA. Because of a paucity of data of the TLR polymorphisms, case-control studies are required to determine whether TLR2, 4, 8, 9 polymorphisms contribute to RA susceptibility or severity in more than 2,000 patients and controls.

The aim of this study was to determine whether the Glutathione S-transferase M1 (GSTM1) and P1 (GSTP1) polymorphisms confer susceptibility to rheumatoid arthritis (RA). Meta-analysis was performed on the associations between the GSTM1 and GSTP1 null genotypes and RA, and on the association between smoking or seropositive status and the GSTM1 null genotype in RA patients. Twelve studies involving 3,990 RA patients and 2,815 controls were included in the meta-analysis. All 12 studies examined the GSTM1 polymorphism and three the GSTP1 polymorphism. Meta-analysis of GSTM1 null polymorphism in 2,291 RA and 2,713 control subjects revealed no association between RA and the GSTM1 null genotype (OR = 1.139, 95 % CI = 0.914-1.419, p = 0.246). Stratification by ethnicity indicated no association between the GSTM1 null genotype and RA in Asians or Europeans (OR = 1.245, 95 % CI = 0.729-2.124, p = 0.422; OR = 1.023, 95 % CI = 0.794-1.318, p = 0.863). Furthermore, there was no association between smoking and the GSTM1 null genotype (OR = 0.943, 95 % CI = 0.734-1.210, p = 0.642). In addition, no association was found between seropositive status including anti-CCP (anti-citrullinated antibody) and/or RF (rheumatoid factor) and the GSTM1 null genotype. Meta-analysis of 915 RA and 1,082 controls revealed no association between RA and the GSTP1 null genotype (OR = 0.965, 95 % CI = 0.802-1.161, p = 0.704). Furthermore, stratification by ethnicity indicated no association between the GSTP1 null genotype and RA in Europeans (OR = 0.794, 95 % CI = 0.594-1.061, p = 0.119). This meta-analysis suggests that the GSTM1 and GSTP1 polymorphisms are not associated with the risk of RA. However, due to the small number of studies included and our inability to perform subgroup analysis by environmental factors, further studies are required to explore the roles played by GSTM1 and GSTP1 polymorphisms in the pathogenesis of RA.

Background: The aim of this study was to determine whether the protein tyrosine phosphatase nonreceptor 22 (PTPN22) 1858 C/T (rs2476601) and macrophage migration inhibitory factor (MIF) -173 C/G polymorphisms confer susceptibility to juvenile idiopathic arthritis (JIA)., Methods: A meta-analysis was conducted on variant alleles versus common alleles of the PTPN22 1858 C/T and MIF -173 C/G polymorphisms across ten comparative studies, which containing 4,238 JIA patients and 6,012 normal control subjects., Results: Ten comparative studies, consisting of nine European, and one Turkish population, were included in his meta-analysis. Meta-analysis showed an association between the T allele of the PTPN22 1858 C/T polymorphism and JIA in Europeans [odds ratio (OR) 1.311, 95% confidence interval (CI) 1.205-1.427, P < 1 × 10(-8)]. In addition, meta-analysis revealed an association between the C allele of the MIF -173 C/G polymorphism and JIA in all subjects (OR 1.482, 95% CI 1.202-1.828, P = 2.3 × 10(-4))., Conclusions: This meta-analysis confirms that the PTPN22 1858 C/T polymorphism is associated with JIA susceptibility in Europeans and shows that the MIF -173 C/G polymorphism may be associated with susceptibility to JIA.

Objective: The aim of this study was to determine whether the p53 codon 72 polymorphism confers susceptibility to systemic lupus erythematous (SLE) and rheumatoid arthritis (RA)., Methods: A meta-analysis was conducted on the associations between the p53 codon 72 polymorphism and SLE or RA using: 1) allele contrast; 2) the recessive model; 3) the dominant model; and 4) the additive model., Results: A total of 10 studies, that is, 6 SLE and 4 RA studies, involving 1578 patients and 3138 controls were considered in the meta-analysis. Meta-analysis of the p53 codon 72 polymorphism showed no association between patients and the C allele (odds ratio (OR) = 0.834, 95% confidence interval (CI) = 0.599-1.161, p = 0.282), or between SLE and the p53 C allele (OR = 0.998, 95% CI = 0.765-1.302, p = 0.989). However, stratification by ethnicity showed an association between the p53 C allele and SLE in Asians (OR = 1.410, 95% CI = 1.044-1.906, p = 0.025), but not in Europeans (OR = 0.871, 95% CI = 0.625-1.214, p = 0.415). Furthermore, an association was found between the polymorphism and SLE in Asians using recessive and additive models. However, no association was found between RA and the p53 codon 72 polymorphism in all study subjects or in Europeans., Conclusions: This meta-analysis demonstrates that the p53 codon 72 polymorphism may confer susceptibility to SLE in Asians, but not in Europeans.

Objective: T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin-2 (IL-2). Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac., Methods: We conducted a trans-ethnic study of 8,695 SLE cases and 7,308 controls of 4 different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time polymerase chain reaction., Results: A 32-kb haplotype comprising multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans, European Americans, and Asians, but not in African Americans. Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, European American, and Hispanic American populations (odds ratio 1.3 [95% confidence interval 1.14-1.31], meta-analysis P=3.8×10(-7)). In European Americans, the largest ethnic data set studied, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-double-stranded DNA, and anti-RNP antibodies. PPP2CA expression was ∼2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying the GG genotype (P=0.007)., Conclusion: Our data provide the first evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in European Americans, Hispanic Americans, and Asians., (Copyright © 2011 by the American College of Rheumatology.)

The aim of this study was to determine whether the vitamin D receptor (VDR) polymorphisms confer susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematous (SLE). A meta-analysis was conducted on the associations between the BsmI, TaqI, FokI, and ApaI polymorphisms of VDR and RA or SLE using: (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) additive model. A total of ten studies, six RA and four SLE studies, were considered in the meta-analysis. Meta-analysis of the VDR BsmI and TaqI polymorphisms showed no association between RA in all subjects, or in European or Asian subjects. In contrast, meta-analysis of the F allele, the FF genotype, and the FF vs. the ff genotype of the FokI polymorphism showed significant associations with RA in Europeans. The overall OR of the association between the F allele and RA was 1.502 (95% CI=1.158-1.949, P=0.002). Meta-analysis of the B allele, BB+Bb genotype, and BB genotype (additive model) of the BsmI polymorphism showed significant associations with SLE and LN in Asians. The overall ORs of the associations between the B allele and SLE and LN were 3.584 (95% CI=1.407-9.130, P=0.007) and 3.652 (95% CI=1.347-9.902, P=0.011). This meta-analysis demonstrates that the VDR FokI polymorphism may confer susceptibility to RA in Europeans. Furthermore, associations were found between the VDR BsmI polymorphism and susceptibilities to SLE and LN in Asians.

Recent progress in genetics has expanded the number of the genes associated with SLE to more than 20 in the past 2 years. One might assign these candidate genetic factors into several pre-existing biological pathways: (i) innate immune response including TLR/interferon signaling pathways (IRF5, STAT4, TNFAIP3, and TREX1); (ii) adaptive immune response (HLA-DR, PTPN22, PDCD1, STAT4, LYN, BLK, and BANK1) including B, T cells, and antigen-presenting cells; and (iii) immune complex clearance mechanism (FCGRs, CRP, and ITGAM). In addition, there are also several genes and loci that could not be assigned into previous known pathways (KIAA1542, PXK, XKR6, ATG5, etc), providing possible novel mechanisms in SLE. It has also been evident that there are similarities and differences in SLE susceptibility loci across ethnic groups. Here we categorize the susceptible genes into four groups. The first group is the consistently associated genes with similar risk allele frequency between multiple ethnic populations such as STAT4, TNFAIP3, BANK1, and IRAK1/MECP2. The second group is the genes that are consistently associated but show marked difference in risk allele frequency (BLK, IRF5). The third group is the genes in which different risk variants exist within a gene or genetic loci (allelic heterogeneity) such as HLA-DR, FCGRs, and IRF5. The fourth group is the genes that show consistently discrepancy between populations such as PTPN22 and possibly ITGAM, PXK, and LYN (genetic heterogeneity). The possible explanations for differences of susceptible genetic factors between populations could be different genetic backgrounds, contribution of gene-gene or gene-environment interaction, and the relation between marker and causal variants. Therefore, efforts to identify ethnic-specific genetic factors or disease causing variants should be necessary for individualized therapy for SLE in future.

The recent discovery of interleukin 23 (IL-23), its receptor, and the underlying signal transduction pathway has improved our understanding of cellular immunity. Several studies suggest that IL-23 is an essential promoter of chronic joint inflammation. In this report, we assess the possible association of interleukin 23 receptor (IL23R) polymorphisms and haplotypes with rheumatoid arthritis (RA). The study was conducted on 1,204 RA patients and 979 healthy controls. Seven polymorphisms were selected from previous IBD reports. The seven SNPs (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032 and rs1495965) were genotyped using the TaqMan assay. Comparison of RA and control subjects revealed no statistically significant differences in the distribution of the IL23R genotypes and haplotypes. Our results clearly indicate that IL23R gene polymorphisms do not play a significant role in susceptibility to RA in the Korean population. Accordingly, we conclude that IL23R gene polymorphisms cannot be applied as an effective genetic marker for RA susceptibility.

Three-prime repair exonucleases 1 and 2 (TREX1 and TREX2) play a role in the metabolism and clearance of DNA. The objective of this study was to confirm whether polymorphisms of TREX1 and TREX2 are associated with genetic susceptibility to systemic lupus erythematosus (SLE), and examine associations with autoantibodies (auto-Abs) in SLE. We investigated the genetic variants in 24 Korean individuals by direct sequencing. The genotype distributions of single-nucleotide polymorphisms (SNPs) and haplotypes were analyzed with multiple logistic regression models while controlling for covariates. We identified 12 and 5 SNPs of TREX1 and TREX2, of which -20260G>C, -389T>C, -381C>T, and +531C>T SNPs of TREX1; -23386G>C, -14703G>A, -7279C>T, and +1747C>T SNPs of TREX2; and each of three haplotypes were selected for larger scale genotyping (n = 1,053). No statistically significant association with the risk of SLE was observed in TREX1 and TREX2. TREX1 polymorphism -20260G>C showed protective effect on the production of anti-Ro Ab, and +531C>T in exon 16 and ht2 [G-T-C-T] showed also protective effect on the production of anti-dsDNA Ab, although the effect of +531C>T disappeared after multiple correction.

Objective: Interleukin-1 (IL-1) has been implicated in the pathogenesis of several rheumatic inflammatory diseases, including adult-onset Still's disease (AOSD) and systemic-onset juvenile idiopathic arthritis (SoJIA). Several clinical trials also suggest that anakinra, a human recombinant interleukin-1 receptor antagonist (IL-1Ra), is effective in patients with AOSD and SoJIA. We have therefore investigated whether IL-1beta and IL-1Ra gene polymorphisms are associated with the development and clinical features of AOSD., Methods: Genomic DNA was isolated from 83 AOSD patients and 144 healthy controls. Genotyping of the two IL-1beta gene (IL-1B+3954 and IL-1B-511) polymorphisms was performed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Genotyping of the IL-1Ra gene (intron 2, VNTR) polymorphism was performed using PCR-based analysis. To compare genotype and allele frequencies, the chi2-test or Fisher's exact test was used. Haplotype frequencies and pairwise linkage disequilibrium were also estimated. A p-value <0.05 was considered significant., Results: There were no significant differences in the genotype and allele frequencies of the IL-1beta and IL-1Ra gene polymorphisms. No differences were also found in the IL-1 gene cluster haplotypes between both groups. IL-1 gene cluster polymorphisms had no effect on the clinical course and joint involvement pattern. Nevertheless, the IL-1B-511 and IL-1RN (VNTR) polymorphic sites were in linkage disequilibrium., Conclusion: These results suggest that IL-1beta and IL-1Ra gene polymorphisms are not associated with the development and clinical features of AOSD in Korean patients.

Objective: The MER receptor tyrosine kinase (MERTK) gene is critical for the efficient clearance of apoptotic cells and has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the genetic polymorphisms in MERTK to evaluate it as a potential candidate gene for a host genetic study of SLE and clinical manifestations in patients with SLE., Methods: By resequencing the coding and flanking regions of the MERTK gene in 24 unrelated Koreans, 37 polymorphisms were identified. Based on gene position, minor allele frequency and inter-single-nucleotide polymorphism (SNP) linkage disequilibrium, six of these polymorphisms were selected for subsequent genotyping and association analysis with the risk of SLE and haematological disorders in 350 Korean SLE patients and 330 controls., Results: Although no significant associations with the risk of SLE were found, logistic regression analyses revealed that variants +465C > G (P = 0.05) and +130215insdelT (P = 0.0005) were significantly associated with decreased risk of leucopenia in SLE patients. Further, +465C > G, +95616G > A, +123157A > G and the haplotype ht1 also showed significant associations (P = 0.006-0.05) with a decreased risk of lymphopenia in SLE patients., Conclusion: Our findings suggest that polymorphisms in MERTK might be one of the genetic risk factors for presenting leucopenia and lymphopenia in SLE patients.

Objective: To determine whether a strategy based on methylenetetrahydrofolate reductase (MTHFR) genotype screening is more cost-effective than the conventional strategy in reducing the risk of methotrexate (MTX)-related toxicity in patients with rheumatoid arthritis (RA)., Methods: We consecutively enrolled 385 patients with RA (355 female, 30 male) who had received MTX and identified toxicity associated with MTHFR C677T genotypes. We designed a hypothetical decision model to compare the genotype-based strategy with the conventional strategy. The time horizon was set as 1 year, and direct medical costs were used. The measured outcomes were the total expected cost, the effectiveness, and the incremental cost-effectiveness ratio., Results: MTHFR genotype distribution revealed 133 patients (34.6%) with 677CC, 193 (50.1%) with 677CT, and 59 (15.3%) with 677TT. A total of 154 patients (40.0%) exhibited MTX-related toxicity. Compared to RA patients with the CC genotype, the odds ratio (95% confidence interval) for risk of toxicity was 3.8 (2.29-6.33) for the CT genotype, and 4.7 (2.40-9.04) for the TT genotype. In the base-case model, the total expected cost and the probability of continuing MTX medication for the conventional and genotype-based strategies were 851,415 Korean won (710 US dollars) and 788,664 Korean won (658 US dollars), and 94.03% and 95.58%, respectively., Conclusion: The MTHFR C677T polymorphism may be an important predictor of MTX-related toxicity in patients with RA. The cost-effectiveness analysis suggests that the genotype-based strategy is both less costly and more effective than the conventional strategy for MTX therapy.

Objective: To determine the effects of genetic polymorphisms of glutathione S-transferase (GST) M1, GSTT1, and GSTP on risk and severity of rheumatoid arthritis (RA) in a Korean population., Methods: A total of 258 patients with RA and 400 disease-free controls were enrolled. GST genotypes were determined by RFLP-PCR. HLA-DRB 1 typing and further subtyping of all alleles was performed using sequence-specific oligonucleotide probe hybridization after PCR. Severity of RA among cases was assessed by Steinbrocker anatomical stage. Risk was assessed by calculating the age and sex adjusted odds ratio (OR) and 95% confidence intervals (CI)., Results: The OR for risk of RA with the GSTM1-null genotype was 1.40 (95% CI 1.02- 1.92, p = 0.04), and 1.86 (95% CI 1.12- 3.09, p = 0.005) among individuals without the shared epitope (SE). Among patients with RA, the OR for risk of severe RA for the GSTM1-null genotype was 2.45 (95% CI 1.04- 5.77, p = 0.02). No association was observed between the GSTT1 or GSTP1 genotypes and either risk or severity of RA., Conclusion: These results suggest that the deletion polymorphism of GSTM1 is associated with increased susceptibility for RA, particularly among individuals who are not carriers of the HLA-DRB 1 SE.

Polymorphisms of FcgammaR have been proposed as genetic factors that influence susceptibility to SLE. FcgammaRIIIB polymorphism in systemic lupus erythematosus (SLE) have been studied in various populations, but the results were inconsistent. The aim of this study was to determine the association of FcgammaRIIIB polymorphism in Korean lupus patients. One-hundred and eighty-three SLE patients (166 female, 17 male) meeting 1982 ACR criteria and 300 Korean disease-free controls were enrolled. Genotyping for the FcgammaRIIIB NA1/NA2 was performed by PCR of genomic DNA using allele-specific primers. There was no significant skewing in the distribution of the three FcgammaRIIIB genotypes, and alleles between SLE and the controls. The frequency of FcgammaRIIIB genotypes in SLE patients and controls was FcgammaRIIIB NA1/NA1 27.9% versus 26%, NA1/NA2 55.2% versus 51.7%, NA2/NA2 16.9% versus 22.3%, respectively. The gene frequencies of NA1 allele were 0.56 in the SLE and 0.52 in controls, respectively. Among clinical manifestations, thrombocytopenia was more common in FcgammaRIIIB NA2/NA2 genotype (P = 0.04, OR 2.4, 95% CI 1.0-5.4), and NA2 allele (P = 0.03, OR 1.7, 95% CI 1.1-2.8). Although FcgammaRIIIB polymorphism was not associated with the development of SLE in Korean, thrombocytopenia was associated with FcgammaRIIIB NA2/NA2 genotype, and NA2 allele.

DNase II is an important enzyme for DNA fragmentation and degradation during programmed cell death and, consequently, a potential candidate gene for genetic study of systemic lupus erythematosus (SLE). Genetic associations of DNase II with SLE and related phenotypes were examined in Korean patients with SLE. A total of 350 Korean SLE patients and 330 healthy subjects were enrolled. Direct DNA sequencing and TaqMan were employed. Logistic regression analyses were performed to examine the genetic association with SLE and related phenotypes. Through direct sequencing in 24 Korean individuals, six sequence variants were identified: one in the 5' flanking region, four in exons (including one nonsynonymous), and one in the 3' flanking region. Four of these polymorphisms were selected for a larger-scale genotyping (350 SLE patients and 330 normal controls). No significant associations with the risk of SLE were detected. However, further analyses of association with the risk of renal disorder among SLE patients revealed several positive associations. One promoter SNP (-1066G>C), +2630T>C (Ser145Ser), +6235G>C and one haplotype showed weak associations with the risk of nephritis among SLE patients.

We assessed the contribution of genetic polymorphisms of glutathione S-transferase M1 ( GSTM1), T1 ( GSTT1), and P1 ( GSTP1, Ile105Val) to carotid atherosclerosis in 40 postmenopausal rheumatoid arthritic (RA) women without histories of smoking. We measured mean intima-media thickness (IMT) and plaque of the common carotid arteries by ultrasonography and evaluated relationships among the known risk factors for atherosclerosis, genetic polymorphisms, RA outcomes, and markers of inflammation. Subjects with the GSTT1-0 genotype had greater IMT ( P<0.05). On univariate analysis, carotid IMT was positively associated with age, systolic BP, antihypertensive drug use, and the GSTT1-0 genotype ( P<0.05). When compared to subjects with a double-positive GSTM1/T1 genotype, IMT in those with concurrent lack of the GSTM1 and GSTT1 genes was significantly increased ( P=0.008). This study suggests that the GSTT1-0 genotype might have an interaction with carotid atherosclerosis related to RA in Korean postmenopausal RA women without histories of smoking.

Objectives: To evaluate the value of genotype-based dosing by polymerase chain reaction (PCR)-based polymorphism screening in terms of cost-effectiveness for treatment with azathioprine in Korea., Methods: Decision analysis was employed to compare a genotype-based dosing strategy with the conventional weight-based dosing strategy using a hypothetical cohort composed of rheumatoid arthritis and systemic lupus erythematosus patients. The time horizon was set up as 1 yr. Direct medical costs were used. Data used were obtained from previous reports, except for PCR and admission costs, which were from real cases. Cost-effectiveness analysis was conducted from a societal perspective. Outcomes were measured as a total expected cost and an incremental cost-effective ratio., Results: In the base case model, total expected cost and the probability of not dropping out owing to serious adverse events of the conventional weight-based dosing and the genotype-based dosing strategy were 1339 x 10(3) Korean won (1,117 US dollars) and 1109 x 10(3) Korean won (926 US dollars), and 97.06 and 99.90%, respectively., Conclusions: Our model suggests that a genotype-based dosing strategy through PCR-based thiopurine methyltransferase (TPMT) polymorphism screening is less costly and more effective than the conventional weight-based dosing strategy in Korea, as it was associated with a marked reduction in the number of serious adverse events.

The etiology of systemic lupus erythematosus (SLE) is very complex, and genetic factors appear to play a significant role in susceptibility to SLE, in determining the disease expression, and in the autoantibody profiles of individuals with SLE. DNA methyltransferase-1 (DNMT1) is a major enzyme that determines genomic methylation patterns and both maintains methyltransferase and exhibits de novo DNA methylation activity in vivo. In order to clarify the association of DNMT1 polymorphisms with SLE, we scrutinized the genetic polymorphisms in exons and their boundaries of DNMT1, including the -1,500 bp promoter region, by direct sequencing in 24 Korean individuals. Twenty-nine sequence variants were identified: two in 5'UTR, six in exons, and 21 in introns. Eight of these polymorphisms were selected for a larger-scale genotyping (n=680) by considering their allele frequencies, haplotype-tagging status, and linkage disequilibrium coefficiencies (LDs) among polymorphisms. The associations between DNMT1 polymorphisms and the clinical profiles of SLE were analyzed. No significant associations with the risk of SLE were detected. However, further analyses of association with autoantibody production among SLE patients revealed that one nonsynonymous SNP, +14463G>C (V120L) in exon 4, was weakly associated with an increased risk of anti-La antibody production (P=0.04), although the significance could not be retained after correction of multiple tests. The DNMT1 variations and haplotypes clarified in this study would provide valuable information for future genetic studies of other autoimmune diseases.

Objectives: To determine the distribution of HLA-DR type and FcgammaRIIa/IIIa polymorphisms, and to analyse the combined effects of these genes for susceptibility in Korean systemic lupus erythematosus (SLE) patients., Methods: A total of 299 SLE patients meeting 1982 ACR criteria and 144 Korean disease-free controls were enrolled. Genotyping for the FcgammaRIIa 131 R/H and FcgammaRIIIa 176 F/V was performed by polymerase chain reaction (PCR) of genomic DNA using allele-specific primers. HLA-DRB1 typing was performed by the PCR-SSOP method., Results: There was significant skewing in the distribution of the three FcgammaRIIa genotypes between the SLE patients and the controls [P = 0.002 for R/R131 vs R/H131 and H/H131, relative risk (RR) 2.6 (95% CI 1.3-5.2)], but not in FcgammaRIIIa genotypes. HLA-DRB1*15 allele was significantly more prevalent among SLE patients than the control population [P < 0.02, RR = 1.7 (1.1-2.6)]. HLA-DRB1 genotypes or allele frequencies of the SLE patients with nephritis did not differ significantly from those of the SLE patients without nephritis. We analysed the combined effects of the two candidate genes on SLE susceptibility. HLA-DRB1*15 allele was a significant predictor of SLE in individuals who were not homozygous for FcgammaRIIa-R/R131 [RR = 2.1 (1.2-3.7), P < 0.008], and the FcgammaRIIa-R/R131 genotype vice versa [RR = 5.3 (1.9-15.4), P < 0.001]. However, an additive or synergistic effect of both susceptible genes on relative risk for SLE was not evident., Conclusions: Our results suggest that FcgammaRIIa-R/R131 homozygote and HLA-DRB1*15 allele are independent risk factors in Korean SLE patients without additive or synergistic effects.

High-dose intravenous immunoglobulins alter the disease activity of adult-onset Still's disease (AOSD). Because activation status of FcgammaR is possibly dependent on their genetic polymorphisms, we investigated whether the polymorphisms of FcgammaR IIa and IIIa are risk factors, and affect the clinical features of AOSD. Genomic DNA was extracted from 36 patients and from 197 healthy controls. Polymerase chain reaction for FcgammaR IIa and IIIa using the allele-specific primers and direct sequencing of FcgammaR IIIa polymorphic site were performed. The frequencies of FcgammaR IIa/IIIa genotype between patients with AOSD and controls were not different. The allelic frequencies of FcgammaR IIa/IIIa between patients with AOSD and controls were not different, either. However, the FcgammaR IIa-R/R131 genotype was associated with a higher concentration of hemoglobin (p=0.04) and stable liver function (p=0.009) than the other genotypes. The FcgammaR IIIa-F/F176 genotype was associated with significantly lower titers of serum ferritin (p=0.025), and higher serum albumin (p=0.037) and cholesterol (p=0.014) concentrations than the other genotypes. This study suggest that the FcgammaR IIa and IIIa polymorphisms might not be genetic risk factors for AOSD in Korean, but contribute to the activity of disease. FcgammaR IIa-R/R131 and IIIa-F/F176 genotypes, low-binding genotypes for IgG2a and G1, may have more protective effects in acute stage of the disease than the other genotypes.

Systemic lupus erythematosus (SLE) is an inflammatory multisystem disease of unknown etiology with immunologic aberrations. Many studies have shown that genetic and environmental factors are implicated in the development of SLE. Angiotensin-converting enzyme (ACE) affects various immune phenomena through the renin-angiotensin and kallikrein-kininogen systems by creating angiotensin II and inactivating bradykinin. We investigated the correlation between insertion/ deletion polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement and lupus nephritis. Two-hundred and eleven Korean patients fulfilling the ACR criteria and 114 healthy subjects were enrolled. The ACE genotype was determined by polymerase chain reaction using genomic DNA from peripheral blood. The nephritis patients were classified by the WHO classification. In addition, the activity and chronicity index were used to assess the severity of renal involvement. We evaluated vascular involvement by the presence or absence of hypertension, Raynaud's phenomenon, livedo reticularis, antineutrophil cytoplasmic antibody and the SLICC/ACR Damage Index. The gene frequency of ACE gene polymorphism was as follows: II 39 vs 34%, ID 41 vs 50%, DD 20 vs 16% in SLE patients and controls, respectively. There was no difference in genotype frequency between both groups. There were no significant differences between the distribution of ACE gene genotypes and lupus nephritis and its related parameters, including WHO classification, activity index, chronicity index, renal dysfunction and amount of 24 h urinary protein. The ACE genotypes and alleles did not affect the presence of vascular manifestations evaluated, but the frequency of DD genotype was significantly low in SLE patients with Raynaud's phenomenon compared to those without Raynaud's phenomenon (P = 0.002 for ACE ID vs DD and II, OR 2.7, 95% CI 1.43-5.09; P=0.023 for ACE DD vs ID and II, OR 0.33, 95% CI 0.12-0.89). Also skewing from DD to II genotype was noted in patients with anti-Sm antibody compared to those without anti-Sm antibody (P = 0.025 for ACE DD vs ID and II, OR 0.21, 95% CI 0.05-0.93). The onset age of serositis was older in patients with the ID genotype than the others (ID= 34.5+/-10.8, II + DD = 25.6+/-10.2, P= 0.002). Also the onset age of malar rash was older in patients with II genotype than the others (II=26.7+/-8.4, ID+DD=21.3+/-9.0; P=0.021). The patients with I allele showed a significantly higher frequency of serositis (P = 0.022). Taken together, the I/D polymorphisms of ACE gene did not affect susceptibility of SLE, lupus nephritis and the vascular manifestations, including Raynaud's phenomenon, in Korean SLE patients, although the DD genotype was negatively associated with Raynaud's phenomenon among SLE patients. However, it would be valuable to evaluate the role of other genes potentially related to vascular events, such as endothelin, nitric oxide or angiotensin II receptor as well as ACE gene.

The aim of this study was to determine the distribution of the FcgammaRlla and FcgammaRIIIa polymorphisms and their association with clinical manifestations in Korean lupus patients. Three hundred SLE (systemic lupus erythematosus) patients (48 male, 252 female) meeting 1982 ACR criteria and 197 Korean disease-free controls were enrolled. Genotyping for FcgammaRlla 131 R/H and FcgammaRIIIa 176 F/V was performed by PCR of genomic DNA using allele-specific primers and the FcgammaRIIIa genotype was confirmed by direct sequencing of PCR product in some cases. There was significant skewing in the distribution of the three FcgammaRIIa genotypes between the SLE and the controls (P=0.002 for R/R131 vs R/H131 and H/H131, OR 2.5 (95% Cl 1.4-4.5), but not in FcgammaRIIIa genotypes. FcgammaRIIa-R allele was a significant predictor of lupus nephritis, as compared with SLE patients without nephritis (P=0.034 for R131 vs H131, OR 1.4 (95% Cl 1.03-1.9)), but proliferative nephritis (WHO class III and IV) was less common in patients with FcgammaRlla-R/R131 and in FcgammaRIIa-R allele. In 300 SLE patients, high binding allele combination H131/V176 was less common in SLE with nephritis than in SLE without nephritis. Hemolytic anemia was less common in R131/F176 allele combination among four FcgammaRIIa/FcgammaRIIIa allelic combinations. Male SLE patients showed a higher frequency of renal involvement, serositis, thrombocytopenia, malar rash and discoid rash than female SLE, and male SLE had a higher frequency of FcgammaRIIa-R/R131 or R131-allele than male controls, but FcgammaRIIa or FcgammaRIIIa genotypes had no association with renal involvement in male SLE patients. FcgammaRIIa-H/H131 showed a higher frequency of hemolytic anemia and less pulmonary complications in male SLE. Female SLE patients showed higher frequency of any hematologic abnormality, lymphopenia, anticardiolipin antibody (+) and anti-Ro antibody (+) than male SLE, and had earlier onset of first symptoms. There was no skewing in FcgammaRIIa or FcgammaRIIIa genotypes between female SLE and female controls, but FcgammaRIIa-R131 allele showed skewing between female SLE with nephritis and female SLE without nephritis. The age at onset of thrombocytopenia was earlier in FcgammaRIIa R/R131 among three FcgammaRIIa genotypes, and serositis in FcgammaRIIIa-F/F176 among three FcgammaRIIIa genotypes. FcgammaRIIa-R131 homozygote was a major predisposing factor to the development of SLE and FcgammaRIIa-RI31 homozygote and R131 allele were a predisposing factor, and H131/V176 was a protective allele combination in lupus nephritis. In contrast to other ethnic patients, in our study cohort, clinical manifestation was different between male and female, and FcgammaRIIa and FcgammaRIIIa showed somewhat different clinical associations between the genders.