Association of Fcgamma receptor IIb and IIIb polymorphisms with susceptibility to systemic lupus erythematosus in Thais

We recently reported association of a newly identified polymorphism of Fcgamma receptor (FcgammaR) IIb, I232T, with systemic lupus erythematosus (SLE) in Japanese. To date, information on FcgammaR genotypes and their association with SLE is limited in South-east Asian populations. To gain further insight into the role of FcgammaR polymorphisms in the genetic predisposition of SLE, association of FcgammaRIIa-H131R, IIb-I232T, IIIa-F176V and IIIb-NA1/NA2 (HNA-1a/1b) polymorphisms with SLE was analyzed in the Thai population, using case-control association analysis. FcgammaRIIb-232T/T and IIIb-NA2/NA2 genotypes were associated with SLE with the odds ratio of 2.55. Genotype relative risk analysis revealed significant association of IIb-232T/T and IIIb-NA2/NA2, and a tendency of association of the IIIa-176F/F genotype. Moreover, carriers of FcgammaRIIa-131R were significantly increased in patients with lupus nephritis. Significant linkage disequilibrium was present among FcgammaRIIb, IIIa and IIIb, and two-locus analyses suggested that the tendency of association of FcgammaRIIIa could derive from linkage disequilibrium with IIb and IIIb. These results provided evidence that FcgammaR polymorphisms may be an important predisposing factor also in Thais in a complex manner.     

Studies on the association of Fc gamma receptor IIA,IIB, IIIA and IIIB polymorphisms with rheumatoid arthritis in the Japanese: evidence for a genetic interaction between HLA-DRB1 and FCGR3A

We recently detected a new single nucleotide polymorphism of FcgammaRIIB gene, which alters an amino acid within the transmembrane domain from Ile to Thr (I232T), and its association with SLE in the Japanese. This study was performed to examine whether FCGR2B-I232T was associated with susceptibility to rheumatoid arthritis in the Japanese. At the same time, FCGR2A, 3A and 3B polymorphisms were also examined. Genotyping of FCGR2B-I232T, FCGR2A-H131R, FCGR3A-F176V and FCGR3B-NA1/2 polymorphisms were performed using genomic DNA. Association with RA was analyzed in 382 Japanese patients with RA and 303 healthy individuals using a case-control approach. In addition, the same groups of patients and controls were genotyped for HLA-DRB1 to examine possible interaction with FCGR genes. Significantly different distribution of genotype, allele carrier and allele frequencies was not observed between patients with RA and healthy individuals in any of the four polymorphisms. When the subjects were stratified according to the carriage of HLA-DRB1 shared epitope (SE), significant increase of FCGR3A-176F/F genotype was observed in SE positive patients compared with SE positive healthy individuals (P=0.009, P(corr)=0.07). In conclusion, FCGR3A-176F/F genotype was considered to confer risk through genetic interaction with HLA-DRB1 SE.     

FcγRIIa and FcγRIIIb polymorphisms and associations with clinical manifestations in systemic lupus erythematosus patients

Abstract

In this study, we aimed to investigate whether the distribution of the FcγRIIa and FcγRIIIb polymorphisms determines susceptibility to systemic lupus erythematosus (SLE) and acts as predictors of SLE clinical manifestations in the Brazilian patients. A total of 157 patients that fulfilled the American College of Rheumatology classification criteria for SLE and 160 healthy volunteers were included in this study. FCGR2A and FCGR3B genotypes were determined by polymerase chain reaction-based allotyping methods with allele-specific primers; the clinical features were obtained from the patients' official medical records. In the case of FcγRIIa polymorphism, it was observed association of the allele FCGR2A-R-131 (p?=?0.02, odds ratio (OR)=1.44) and genotype RR-131 (p?=?0.03, OR?=?2.09) with SLE. These associations were higher with allele (p?<?0.01, OR?=?1.67) as well genotype (p?=?0.01, OR?=?2.85) when lupus nephritis was considered. In contrast, the allele FCGR2A-H-131 was associated with susceptibility to arthritis and anti-DNA antibodies (p?=?0.05 for both). As for FcγRIIIb polymorphism, skewing did not differ significantly between patients and controls, however the genotype FCGR3B*02*02 was associated with susceptibility to arthritis (p?=?0.02) and malar rash (p?=?0.03), but no association with nephritis was found. The results demonstrate that FcγRIIa polymorphism is associated with susceptibility to SLE in Brazilian patients, whereas for FcγRIIIb polymorphism no association was found. However, notably, both polymorphisms present allelic variants that influence the clinical manifestations and may contribute to the pathogenesis of the disease. In addition, to our knowledge, this is the first study considering the frequency of FcγRIIIb polymorphism in Brazilian SLE patients.     

Role of B cell inhibitory receptor polymorphisms in systemic lupus erythematosus: a negative times a negative makes a positive

B lymphocytes play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). Here, we will review our studies on the role of polymorphisms of two genes coding for B cell inhibitory receptors, FCGR2B and CD72. In FCGR2B, a single nucleotide polymorphism leading to a nonsynonymous substitution, Ile232Thr, within the transmembrane domain was identified, and a significant association of the 232Thr/Thr genotype with SLE was observed in Japanese, Thai and Chinese populations, while this allele was found to be rare in Caucasians. On the other hand, the association of FCGR2B promoter polymorphism with SLE in Caucasians has been reported by two independent groups, but this allele was not found to be present in Japanese. These observations demonstrate that the association of FCGR2B polymorphisms with SLE is common to multiple populations, but the alleles associated with SLE depend upon the genetic background of each population. Functional analyses using a human B cell line lacking endogenous FcγRIIb revealed that SLE-associated 232Thr allele product was partially excluded from membrane lipid rafts under resting conditions and after coligation with B cell receptor, and was significantly less potent at inhibiting B cell activation. Two haplotypes were identified in CD72, one of which was associated with increased production of an alternative splicing isoform that substantially alters the extracellular region of CD72. Interestingly, the presence of the haplotype significantly decreased the risk of SLE conferred by FCGR2B-232Thr in an epistatic manner. These observations emphasize the need to understand human immune system diversity if we are to improve our understanding of the pathogenesis of autoimmune diseases.     

免疫球蛋白受体3A基因-72R/S单核苷酸多态性与系统性红斑狼疮的遗传易感性

目的探讨位于人类1号染色体长臂2区3带(1q23-24)免疫球蛋白受体3A(Fc gamma recep-tor3A,FCGR3A)基因-72R/S单核苷酸多态性与系统性红斑狼疮(systemic lupus erythematosus,SLE)的遗传易感性关联情况。方法采用聚合酶链反应和限制性酶切片段长度多态性方法检测人类1q23FCGR3A基因多态性,采用家系内关联性分析(family-based association test,FBAT),对119个中国汉族SLE患者家系(核心家系95个)119例SLE患者和316个家系成员中FCGR3A-72R/S多态性位点进行等位基因和基因型别分析,SLE的诊断采用1997年美国风湿学修定的标准。结果在119例SLE患者中,R、S等位基因频率分别是39.4%和60.6%;基因型RR、RS和SS的频率分别是9.1%、60.6%、30.3%。FBAT软件分析结果显示-72R/S(rs403016)与SLE显著相关;在附加模型(Z=2.544,P=0.01097)、隐性模型(Z=2.198,P=0.02795)均显示-72R等位基因与SLE遗传易感性有关。传递不平衡检验显示其中R等位基因优势传递给患病子女(χ2=9.30,P=0.0032)。结论在中国汉族SLE家系中发现FCGR3A-72R/S多态性与SLE存在关联或者与疾病基因座存在连锁;说明携带-72R等位基因可能与提高SLE遗传易感性有关。     

Role of Fc gamma receptor IIb polymorphism in the genetic background of systemic lupus erythematosus: insights from Asia

FCGR2B codes for an inhibitory receptor expressed in B cells and monocytes. Polymorphisms of Fcgr2b in mice have been shown to be associated with autoimmune diseases including systemic lupus erythematosus (SLE) and targeted disruption of Fcgr2b renders mice susceptible to induced or spontaneous autoimmunity, depending on the genetic background. Polymorphism screening of FCGR2B has been hampered by the complexity and extreme homology among FCGR family members. We established a specific genotyping system, detected a SNP that changes position 232 amino acid in the transmembrane region from Ile to Thr and found a significant association of 232Thr with SLE in the Japanese, Thai and Chinese populations. In contrast, promoter polymorphism of FCGR2B, but not Ile232Thr, was shown to be associated with SLE in Caucasians. Linkage disequilibrium was observed among FCGR2A, 2B, 3A and 3B genes with varying degrees, but in the Asian populations, each of FCGR2B, 3A and 3B genes was suggested to contribute to the susceptibility to SLE. These results indicate that FCGR2B is a susceptibility gene to SLE in the context of a genetic background, both in humans and mice.     

Study of common functional genetic polymorphisms of FCGR2A, 3A and 3B genes and the risk for cryptococcosis in HIV-uninfected patients.

A pilot candidate gene association study was conducted to investigate the role of three common functional genetic polymorphisms of the low-affinity Fc gamma receptors, FCGR2A (131H/R), FCGR3A (158F/V) and FCGR3B (NA1/NA2) in Cryptococcus neoformans infections in individuals not infected with HIV. The FCGR2A 131RR and FCGR3A 158VV genotypes were over-represented [OR: 1.67 (1.05-2.63) and 2.04 (1.06-4.00), respectively] whereas the FCGR3B NA2NA2 was under-represented in patients with cryptococcosis (28% vs. 40% in controls). An analysis of haplotypes showed a significant difference in distribution between cases and controls overall and in Caucasians.     

Genetic variations in low-to-medium-affinity Fcγ receptors and autoimmune neutropenia in early childhood in a Danish cohort

Autoimmune neutropenia (AIN) in early childhood is caused by autoantibodies directed against antigens on the neutrophil membrane and is a frequent cause of neutropenia in children. Association of AIN with Fcγ receptor (FCGR) 3B variants is well described. In this study, we investigate genetic variations in the FCGR locus and copy number variation of FCGR3B. A total of 130 antibody-positive AIN patients, 64 with specific anti-HNA-1a antibodies and 66 with broad-reacting anti-FcγRIIIb antibodies, were genotyped with a multiplex ligation probe assay and compared with healthy controls. Positive findings were confirmed with real-time q-PCR. We determined copy numbers of the FCGR2 and FCGR3 genes and the following SNPs: FCGR2A Q62W (rs201218628), FCGR2A H166R (rs1801274), FCGR2B I232T (rs1050501), FCGR3A V176F (rs396991), haplotypes for FCGR2B/C promoters (rs3219018/rs780467580), FCGR2C STOP/ORF and HNA-1 genotypes in FCGR3B (rs447536, rs448740, rs52820103, rs428888 and rs2290834). Generally, associations were antibody specific, with all associations being representative of the anti-HNA-1a-positive group, while the only association found in the anti-FcγRIIIb group was with the HNA-1 genotype. An increased risk of AIN was observed for patients with one copy of FCGR3B; the HNA genotypes HNA-1a, HNA-1aa or HNA-1aac; the FCGR2A 166H and FCGR2B 232I variations; and no copies of FCGR2B 2B.4. A decreased risk was observed for HNA genotype HNA-1bb; FCGR2A 166R; FCGR2B 232T; and one copy of FCGR2B promoter 2B.4. We conclude that in our Danish cohort, there was a strong association between variation in the FCGR locus and AIN. The findings of different genetic associations between autoantibody groups could indicate the presence of two different disease entities and disease heterogeneity.     

Tumor necrosis factor gene polymorphisms are associated with systemic lupus erythematosus susceptibility or lupus nephritis in Mexican patients

The TNF -238G/A (rs361525) and -308G/A (rs1800629) polymorphisms have consistently been associated with systemic lupus erythematosus (SLE) in several populations; however, these findings have not been verified in all populations. Here, we aimed to examine whether the TNF -238G/A, -308G/A, -376G/A (rs1800750), and -1031T/C (rs1799964) polymorphisms confer SLE or lupus nephritis (LN) susceptibility in a Mexican population. Our study included 442 patients with SLE and 495 controls. For genotyping, we used the TaqMan 5′ allele discrimination assay. The TNF -238G/A and -1031T/C polymorphisms were associated with SLE susceptibility (odds ratio (OR) 2.1, p?=?0.0005 and OR 1.4, p?=?0.003, respectively). Gender stratification showed a strong association between TNF -238G/A and SLE in women (OR 2.2, p?=?0.00006), while TNF -1031T/C had an OR of 1.5 (p?=?0.007). With regard to the TNF -376G/A polymorphism, this also showed association with SLE susceptibility (OR 1.95, p?=?0.036) and LN (OR 3.5, p?=?0.01). In conclusion, our study provides the first demonstration of association between the TNF -376G/A polymorphism and SLE and LN susceptibility. In addition, our study is the second documenting an association of TNF -1031T/C with SLE susceptibility. We also observed a strong association between TNF -238G/A and SLE susceptibility. The TNF 308G/A polymorphism was not associated with SLE or LN.     

转录因子FOXP3基因多态性与广西壮族系统性红斑狼疮的遗传易感性

目的 探讨转录因子FOXP3基因单核苷酸多态性与广西壮族系统性红斑狼疮(systematic lupus erythematosus,SLE)易感性之间的关系.方法 以120例SLE患者和160名健康对照者为研究对象,应用聚合酶链反应-限制性片段长度多态性和DNA测序的方法对FOXP3基因-2383 C/T、-3281 C/A单核苷酸多态性进行基因分型.结果 FOXP3基因-3281 C/A多态性在SLE组和正常人群中的分布差异无统计学意义(P＞0.05),而FOXP3基因-2383 C/T多态性在两组人群中的分布差异有统计学意义(P＜0.05),等位基因频率的相对风险分析发现,-2383 T等位基因携带者患系统性红斑狼疮的风险是-2383 C等位基因的1.715倍(OR=1.715,95%CI:1.165～2.525).联合基因型分析发现,FOXP3的-2383 T/-3281 A等位基因频率在SLE组中显著高于对照组(P＜0.05),-2383 T/-3281 A等位基因携带者显著增加了SLE的发病风险(OR=2.196,95%CI:1.165～4.142).结论 FOXP3基因-2383 C/T多态性与SLE的发病具有相关性,其中-2383 T等位基因可能是SLE的遗传易感基因.     

Role of Fcγ receptor IIb polymorphism in the genetic background of systemic lupus erythematosus: Insights from Asia

FCGR2B codes for an inhibitory receptor expressed in B cells and monocytes. Polymorphisms of Fcgr2b in mice have been shown to be associated with autoimmune diseases including systemic lupus erythematosus (SLE) and targeted disruption of Fcgr2b renders mice susceptible to induced or spontaneous autoimmunity, depending on the genetic background. Polymorphism screening of FCGR2B has been hampered by the complexity and extreme homology among FCGR family members. We established a specific genotyping system, detected a SNP that changes position 232 amino acid in the transmembrane region from Ile to Thr and found a significant association of 232Thr with SLE in the Japanese, Thai and Chinese populations. In contrast, promoter polymorphism of FCGR2B, but not Ile232Thr, was shown to be associated with SLE in Caucasians. Linkage disequilibrium was observed among FCGR2A, 2B, 3A and 3B genes with varying degrees, but in the Asian populations, each of FCGR2B, 3A and 3B genes was suggested to contribute to the susceptibility to SLE. These results indicate that FCGR2B is a susceptibility gene to SLE in the context of a genetic background, both in humans and mice.     

Fcγ受体Ⅱa多态性与系统性红斑狼疮关联性及连锁证据研究

目的：探讨中国南方汉族人群中Ｆｃγ受体Ⅱａ（ＦｃγＲⅡａ）多态性与系统性红斑狼疮的关联及连锁关系。方法：应用聚合酶链反应－特异性寡核苷酸杂交的方法,对７１例系统性红斑狼疮（ｓｙｓｔｅｍ ｌｕｐｕｓ ｅｒｙｔｈｅｍａｔｏｓｕｓ,ＳＬＥ）患者、６４名健康对照和１５例ＳＬＥ患者及其父母进行了基因分析。对ＦｃγＲⅡａ１３１基因多态性进行了研究。结果：⑴携带ＦｃγＲⅡＡ－Ｒ１３１等位基因和ＦｃγＲⅡａ－Ｒ／Ｒ１３１基因型者发生ＳＬＥ的危险性大（ＯＲ＝２．０６,Ｐ＜０．０１;ＯＲ＝４．１７,Ｐ＝０．０１３５）;⑵种族间ＦｃγＲⅡａ－１３１多态性存在差异,中国汉族人与日本人等位基因频率相似;⑶家系关联分析和传递不平衡分析结果无统计学意义,可能与样本量小有关。结论：ＦｃγＲⅡａ－１３１多态位点是中国南方汉族人群中ＳＬＥ患者的易     

Impact of the IL-17F,IL-23 and IL-23R on susceptibility and phenotype of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a disease characterized by excessive proinflammatory cytokine production and damage to multiple organ systems. To investigate the potential association between cytokine gene polymorphisms and SLE, we performed a case-control study based on Polish population. SLE patients and controls, were examined for IL-23A rs11171806?G/A and IL-23R (rs1884444?G/T, rs10489629?G/A) by TaqMan SNP genotyping assay, for IL-17F rs763780 A/G and rs2397084A/G using the PCR– RFLP method. An increased frequency of AG genotype as well as G allele of the IL-17F rs763780 was found in patients with SLE, as compared with healthy subjects (OR?=?3.947; p?=?0.001 and OR?=?3.538; p?=?0.002, respectively). Frequencies of the rs1884444 TT genotype (OR?=?138.1) and the rs1884444 T allele (OR?=?2.176) were also higher in SLE patients (both p?0.0001). Overall, weak LD was observed between the IL-17F rs763780 A/G and rs2397084 A/G polymorphisms (D'-0.003, r² – 0.000). From four possible haplotypes, frequencies of AG showed differences between both examined groups (p?0.0001). We also observed a weak LD between the IL-23R rs10489629G/A and rs1884444?G/T (D'-0.199, r² –0.026). The genotype–phenotype analysis showed significant association between the IL-17F rs2397084 and mean value of the hemoglobin (p?=?0.01), the IL-17F rs763780 and age (p?=?0.008) and lupus anticoagulant (p?=?0.09), the IL-23 rs11171806 and urea (p?=?0.08) and C3 complement (p?=?0.03), and the IL-23R rs1884444?G/T and activated partial thromboplastin time (p?=?0.06). Present findings indicated that IL-17F rs763780 A/G and IL-23R rs1884444?G/T polymorphisms may be involved in susceptibility to SLE in the Polish population.     

Both risk alleles for FcgammaRIIA and FcgammaRIIIA are susceptibility factors for SLE: a unifying hypothesis

The aim of this study was to analyze in families with SLE for the presence of linkage and the structure and transmission of haplotypes containing alleles for the low-affinity Fcgamma receptors. The Fcgamma receptor polymorphisms FcgammaRIIA-131R/H, FcgammaRIIIA-176F/V and FcgammaRIIIB-NA1/2 and a polymorphism in the FcgammaRIIB gene were genotyped with RFLP, allele-specific PCR or pyrosequencing. Individual SNPs and haplotypes were tested for linkage in multicase families and for association using contingency tables, transmission disequilibrium test and affected family-based control groups in Swedish and Mexican single-case families. No linkage or association could be detected using the FcgammaR polymorphisms in the multicase families. However, an association was found for both FcgammaRIIA-131R and IIIA-176F alleles in the single-case families, but not for IIIB or IIB. Allelic association to SLE was found for a haplotype that included both risk alleles, but not in haplotypes where only one or the other was present. We propose that FcgammaRIIA-131R and FcgammaRIIIA-176F are both risk alleles for SLE transmitted primarily, but not exclusively on a single major haplotype that behaves functionally in a situation similar to that of compound heterozygozity.     

Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus

A regulatory single nucleotide polymorphism (SNP) PD1.3G/A located on programmed cell death 1 (PDCD1) gene, was shown to be involved in susceptibility to systemic lupus erythematosus (SLE) in Swedish, European American, and Mexican cases. However, association to childhood-onset SLE has not been analyzed. The aim of this study was to investigate the association of PDCD1 polymorphisms and haplotypes with susceptibility to childhood-onset SLE in Mexican population. Three PDCD1 SNPs, PD1.3G/A, PD1.5C/T, PD1.6G/A, were analyzed in 250 childhood-onset SLE Mexican patients and 355 healthy controls in a case-control association study. Polymorphisms were genotyped by TaqMan technology. Stratification analysis was performed on the SLE cohort to investigate the SNP association with renal disorder. In addition, haplotypes were constructed with these three SNPs. The PD1.3A allele was significantly associated to childhood-onset SLE (P=0.0019, odds ratio (OR) 2.73, 95% confidence interval (95% CI) 1.35-5.56). The other PDCD1 SNPs did not show association. A total of 155 patients (62%) had nephritis, and no association was observed with PDCD1 SNPs. The ACG haplotype (PD1.3A, PD1.5C, PD1.6G) included almost all PD1.3A alleles, and it was more frequent in SLE patients (5.5%) than in controls (2.1%) (P=0.003; OR 2.73, 95% CI 1.37-5.46). The haplotype structure in Mexican controls was significantly different from those reported in Spanish and Swedish. Our results support association of the PD1.3A SNP to susceptibility of childhood-onset SLE in Mexican population and does not show association to lupus nephritis in this age group.     

Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis

There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of 1 was a significant risk factor for SSc (OR=1.55 (1.13-2.14), P=0.007) relative to CN2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity.     

FcgammaRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling

The B cell inhibitory receptor FcgammaRIIB plays crucial roles in the maintenance of self-tolerance. We have identified a polymorphism FCGR2B c.695T>C that results in the non-conservative replacement of 232Ile at the transmembrane helix to Thr and demonstrated the association of the polymorphism with susceptibility to systemic lupus erythematosus (SLE) in Asians. In this study, we examined the impact of FCGR2B c.695T>C on the functional properties of FcgammaRIIB by expressing each allele product in a human B cell line ST486 lacking endogenous FcgammaRIIB. FcgammaRIIB 232Thr was found to be significantly less potent than wild-type 232Ile in inhibiting B cell receptor (BCR)-mediated phosphatidylinositol-3,4,5-trisphosphate accumulation, Akt and PLCgamma2 activation and calcium mobilization, and to display decreased levels of tyrosine phosphorylation and SH2-containing 5'-inositolphosphate phosphatase recruitment compared with 232Ile after IgG Fc-mediated coligation with BCR. Notably, a quantitative analysis of the subcellular distribution of FcgammaRIIB using 125I-labeled anti-FcgammaRIIB revealed that FcgammaRIIB 232Thr is less effectively distributed to detergent-insoluble lipid rafts than 232Ile, findings in accordance with the importance of the transmembrane amino acid residues, in particular large hydrophobic amino acids including Ile, in the association of membrane proteins with lipid rafts. Given the crucial roles of lipid rafts in integrating BCR signaling, decreased association of FcgammaRIIB 232Thr could contribute to its impaired inhibitory potential. Collectively, the present findings indicate that the Ile232Thr substitution affects the localization and function of FcgammaRIIB and that the molecular mechanism may link the polymorphism and susceptibility to SLE.     

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

Although large-scale studies established many susceptibility genes to systemic lupus erythematosus (SLE), effect of each gene is not sufficiently large to be used alone to identify individuals with strong genetic predisposition. In this study, we analyzed the cumulative number of risk alleles at eight established susceptibility loci, HLA-DRB1, IRF5, STAT4, BLK, TNFAIP3, TNIP1, FCGR2B and TNFSF13, in 282 Japanese female SLE and 222 healthy female controls. The average number of risk alleles was significantly increased in SLE (8.07±1.60) than healthy controls (7.02±1.64) (P=1.63 × 10(-12)). Significant gene-gene interaction was not detected. When the subjects carrying seven risk alleles were used as a reference, the odds ratio (OR) for individuals carrying 10 and 11-13 risk alleles were 4.17 (95% confidence interval (CI) 1.89-9.19, P=0.0002) and 8.77 (95% CI 1.92-40.0, P=0.0016), respectively. In contrast, subjects with ≤4 risk alleles were significantly decreased in SLE (OR 0.15, CI 0.03-0.67, P=0.007). The proportion of the patients with neurologic disorder was significantly increased in those carrying ≥10 risk alleles than those with <10 (OR 2.30, CI 1.09-4.83, P=0.025). This study suggested that the cumulative number of risk alleles may efficiently distinguish groups with high and low genetic predisposition to SLE and its severe manifestation.     

Genetic polymorphisms in tumor necrosis factor (TNF)-alpha and TNF-beta in a population-based study of systemic lupus erythematosus: associations and interaction with the interleukin-1alpha-889 C/T polymorphism

Tumor necrosis factor (TNF) is involved in the pathogenesis of systemic lupus erythematosus (SLE), but the role of TNF polymorphisms in SLE susceptibility remains unclear. Previous studies in different populations report an inconsistent association of the TNF-alpha -308A allele with SLE, sometimes depending on the presence of HLA-DR3. We examined the association of polymorphisms in TNF-alpha (-308G/A, -238G/A) and TNFbeta (+252A/G) in a population-based study of SLE in the southeastern United States and considered TNF-SLE associations with respect to HLA-DR3 and DR2 and the interleukin (IL)-1alpha -889C/T polymorphism, previously linked to SLE in this population. Genotypes were analyzed for 230 recently diagnosed SLE patients who met American College of Rheumatology classification criteria and 276 age- and sex-matched controls, randomly selected from driver's license registries. Carriage of the TNF-alpha -308A allele was significantly associated with SLE in Caucasians (OR = 2.3; 95% CI 1.4, 3.9), but not African Americans. Analyses stratified by IL-1alpha -889 genotypes (C/C vs C/T or T/T) revealed independent associations of SLE with TNF-alpha -308A or HLA-DR2 and DR3. This reflected a significant interaction of TNF and IL-1 genotypes in Caucasians, and yielded a strong association (OR = 8.0, p < 0.00001) for the combined "HLA-DR3, TNF-alpha -308A, IL-1alpha -889C/C" genotype. These findings provide evidence of cytokine gene epistasis in SLE susceptibility.