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

Abstract

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.     

The programmed cell death 1 gene 7209 C>T polymorphism is associated with the risk of systemic lupus erythematosus in the Polish population

Numerous investigations indicated that the programmed cell death 1 (PDCD1) gene polymorphisms contribute to the development of systemic lupus erythematosus (SLE). However, their association with SLE has been found to be controversial. Therefore, in patients with SLE (n=102) and controls (n=140) we examined the association of six polymorphisms of this gene with susceptibility to SLE in the Polish population. We found that PDCD1 7209 CT or 7209 TT genotype exhibited 3.282-fold increased risk of SLE (95% CI=1.553 - 6.935; p=0.0017). The allele and genotype frequencies of the remaining polymorphisms: 5708 C>T, 6438 G>A, 7146 G>A and 8737 G>A did not exhibit statistical differences between SLE patients and controls. Our results confirmed the association of 7209 C>T polymorphism of PDCD1 gene with SLE that was previously observed in the Taiwanese population.     

树突状细胞免疫受体基因多态性与抗环瓜氨酸肽抗体阴性类风湿关节炎相关性研究

目的 在汉族人群中研究树突状细胞免疫受体(DICR)基因多态性与类风湿关节炎(RA)及其不同亚型的易感相关性.方法 采用病例-对照研究法,选取年龄及性别相匹配的RA患者523例和健康对照510名;采用Taqman探针法检测DCIR基因rs2377422和rs10840759位点单核苷酸多态性(SNP);检测RA患者抗环瓜氨酸肽(CCP)抗体水平,分析DCIR基因多态性与不同亚型RA相关性;采用实时荧光定量聚合酶链反应(PCR)方法,定量检测DCIR在RA患者(233例)及健康者(71名)中mRNA表达水平,并进一步分析不同DCIR基因型对DCIR表达水平的影响.统计学处理采用X检验和多因素Logistic回归检验,2组间比较采用曼-惠特尼U检验.结果 ①DCIR SNP rs2377422与汉族RA发病明显相关(等位基因:OR 1.26;95％CI 1.06～1.50,P=0.005;基因型CC与TT+TC:OR 1.34;95％CI1.18～2.06,P=0.004);②DCIR SNP rs2377422主要与抗CCP抗体阴性RA发病相关(等位基因:OR 1.46;95％CI1.10～1.93,P=0.0091;基因型CC与TT+TC:OR 1.58;95％CI1.01～2.47,P=0.043);③和健康对照相比,RA患者外周血中DCIR基因mRNA水平显著增高(0.47-0.10与0.17-0.03,U=6502,P=0.000 38),且携带DCIR rs2377422 CC基因型的RA患者,其DCIR表达水平进一步明显增高(CC与TT+TC:0.429±0.069与0.238±0.023,U=1861,P=0.002).结论 汉族人群中DCIR rs2377422多态性主要与抗CCP抗体阴性RA易感相关;RA患者DCIR基因表达水平明显增高;DCIR rs2377422多态性可明显影响DCIR基因的表达.     

Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope

OBJECTIVE: To study the frequency of allele A of polymorphism PD-1.3 of the PDCD1 gene in patients with rheumatoid arthritis (RA) and its subsets, based on the presence of rheumatoid factor (RF) and the shared epitope (SE) alleles. METHODS: A total of 1,175 patients with RA and 3,404 controls were genotyped for the PD-1.3 A/G polymorphism, which previously was identified as being involved in susceptibility to systemic lupus erythematosus (SLE) in patients of European descent. RESULTS: We first detected a trend for association of allele A of the single-nucleotide polymorphism PD-1.3 with RA (P = 0.053, odds ratio [OR] 1.18, 95% confidence interval [95% CI] 0.99-1.41). To further clarify the nature of this association, patients with RA were divided into 4 groups according to the presence of RF and the SE alleles. Association was found only in the group of patients negative for both RF and the SE alleles (P = 0.0054 [corrected P = 0.015], OR 1.75, 95% CI 1.15-2.65). CONCLUSION: Patients negative for both RF and the SE alleles showed association with the same allele that we previously identified as being involved in susceptibility to SLE. These results provide the first evidence of the involvement of the human PDCD1 gene in arthritis.     

Gene–gene interaction between CD40 and CD226 gene on systemic lupus erythematosus in the Chinese Han population

The aim of the study is to investigate the impact of CD40 and CD226 gene single-nucleotide polymorphism (SNP) and additional gene–gene interaction on systemic lupus erythematosus (SLE) risk in Chinese Han populations. Three SNPs were selected for genotyping in the case–control study: rs4810485, rs763361, and rs3765456. Logistic regression was performed to investigate association between SNP within CD40 and CD226 and SLE. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the interaction among three SNPs. Logistic regression analysis showed that SLE risk was significantly higher in carriers of T allele of rs4810485 in CD40 gene than those with GG genotype (GT+ TT vs GG), adjusted OR (95 % CI) 1.84 (1.40–2.29). In addition, we also found SLE risk was also significantly higher in carriers of rs763361 T allele within CD226 gene than those with CC genotype (CT+ TT vs CC), adjusted OR (95 % CI) 1.89 (1.38–2.13). GMDR analysis suggested a potential gene–gene interaction between rs4810485 and rs763361. Overall, cross-validation consistency of the two-locus model was 10/10, and the testing accuracy was 62.17 %. We also found that subjects with GT or TT of rs4810485 and CT or TT of rs763361 genotype have the highest SLE risk, compared with subjects with GG of rs4810485 and CC of rs763361 genotype, and OR (95 % CI) was 2.14 (1.67–3.08), after covariates adjustment. Our results support an important association of rs4810485 in CD40 gene and rs763361 in CD226 gene polymorphism, combined effect of rs4810485 and rs763361 with increased risk of SLE.     

Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries

OBJECTIVE: Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin α(M) (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM. METHODS: The authors examined several markers in the ICAM1-ICAM4-ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case-control study of 17 481 unrelated participants from four ancestry populations. The single-marker association and gene-gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed. RESULTS: The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (OR(meta)=1.16, 95% CI 1.11 to 1.22; p=4.88×10(-10) and OR(meta)=1.67, 95% CI 1.55 to 1.79; p=3.32×10(-46), respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10(-5)). CONCLUSION: These findings are the first to suggest that an ICAM-integrin-mediated pathway contributes to susceptibility to SLE.     

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.     

Two single-nucleotide polymorphisms in the 5' and 3' ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus

OBJECTIVE: To test the association of osteopontin (OPN) polymorphisms with systemic lupus erythematosus (SLE). METHODS: The coding 5' and 3' flanking regions of the OPN gene were scanned for polymorphisms by denaturing high-performance liquid chromatography. A case-control association study was performed in 394 Italian SLE patients and 479 matched controls. OPN serum levels were determined by enzyme-linked immunosorbent assay in 40 patients and 124 controls, and the mean levels were compared between the different OPN genotypes. RESULTS: Among the 13 detected single-nucleotide polymorphisms (SNPs), alleles -156G (frequency 0.714 versus 0.651; P = 0.006, corrected P [P(corr)] = 0.036) and +1239C (0.377 versus 0.297; P = 0.00094, P(corr) = 0.0056) were significantly increased in the SLE patients compared with the controls. The presence of the associated allele in single or double dose conferred an odds ratio (OR) of 2.35 (95% confidence interval [95% CI] 1.38-4.02) for SNP -156 and an OR of 1.57 (95% CI 1.16-2.13) for SNP +1239. These effects were independent of each other, i.e., not a consequence of linkage disequilibrium between the 2 alleles. The risk associated with a double dose of susceptibility alleles at both SNPs was 3.8-fold higher (95% CI 2.0-7.4) relative to the complete absence of susceptibility alleles. With regard to individual clinical and immunologic features, a significant association was seen between lymphadenopathy and -156 genotypes (overall P = 0.0011, P(corr) = 0.046). A significantly increased OPN serum level was detected in healthy individuals carrying +1239C (P = 0.002), which is indicative of an association between the SLE susceptibility allele and OPN levels. CONCLUSION: These data suggest the independent effect of a promoter (-156) and a 3'-untranslated region (+1239) SNP in SLE susceptibility. We can speculate that these sequence variants (or others in perfect linkage disequilibrium) create a predisposition to high production of OPN, and that this in turn may confer susceptibility to SLE.     

A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese

OBJECTIVE: The programmed death 1 (PD-1) molecule is a negative regulator of T cells, and a genetic association between PD-1 and systemic lupus erythematosus and rheumatoid arthritis (RA) in Caucasians has been reported. The aim of this study was to investigate the association of PDCD1 polymorphisms and haplotypes with RA in the Chinese population. METHODS: Three single-nucleotide polymorphisms (SNPs), PD-1.1 G/A, PD-1.3 G/A, and PD-1.5 C/T, were genotyped in 180 patients with RA and 647 healthy controls in a case-control association study. Analyses of the association of genotypes and alleles with disease, haplotype construction, and linkage disequilibrium (LD) were performed. RESULTS: We constructed haplotypes with the alleles of markers PD-1.1 G/A and PD-1.5 C/T and found that the GT haplotype was overrepresented in patients with RA (31%) compared with controls (23%) (P = 0.001, odds ratio [OR] 1.54, 95% confidence interval [95% CI] 1.18-1.99). Among GT double homozygotes the risk of RA was increased even further (OR 2.31, 95% CI 1.31-4.08, P = 0.006). We also observed that the AA genotype of SNP PD-1.1 was associated with a decreased risk for developing RA (OR 0.38, 95% CI 0.15-0.99, P = 0.034). No association for SNP PD-1.5 in RA was found, and SNP PD-1.3 was nonpolymorphic in the Chinese population. CONCLUSION: Our results support the involvement of PDCD1 as a susceptibility gene for RA in the Chinese population.     

ATG16L1 and IL23R are associated with inflammatory bowel diseases but not with celiac disease in the Netherlands

BACKGROUND: Inflammatory bowel disease (IBD)--Crohn's disease (CD) and ulcerative colitis (UC)--and celiac disease are intestinal inflammatory disorders with a complex genetic background. Recently, two novel genes were found to be associated with IBD susceptibility. One, an uncommon coding variant (rs11209026) in the gene encoding for the interleukin-23 receptor (IL23R), conferred strong protection against CD. The other, rs2241880 in the autophagy-related 16-like 1 gene (ATG16L1), was associated with CD. We performed a case-control study for the association of IBD with IL23R and ATG16L1 in a Dutch cohort. We also looked at the association of IL23R and ATG16L1 with celiac disease. METHODS: Five hundred eighteen Dutch white IBD patients (311 CD and 207 UC, including 176 trios of patients with both parents), 508 celiac disease patients, and 893 healthy controls were studied for association with the rs11209026 (IL23R) and rs2241880 (ATG16L1) single nucleotide polymorphisms (SNP). RESULTS: The rs11209026 SNP in IL23R had a protective effect for IBD in the case-control analysis (odds ratio [OR] 0.19, 95% confidence interval [CI] 0.10-0.37, P= 6.6E-09). Both CD (OR 0.14, CI 0.06-0.37, P= 3.9E-07) and UC (OR 0.33, CI 0.15-0.73, P= 1.4E-03) were associated with IL23R. For ATG16L1, the rs2241880 SNP was associated with CD susceptibility (OR 1.36, CI 1.12-1.66, P= 0.0017). The population-attributable risk of carrying allele G is 0.24 and is 0.19 for homozygosity for allele G in CD. No association was found between IL23R or ATG16L1 and celiac disease. CONCLUSIONS: We confirmed the association of IL23R and ATG16L1 with CD susceptibility and also the association of IL23R with UC. We found IL23R and ATG16L1 were not associated with celiac disease susceptibility.     

Epistatic interactions between HLA-DRB1 and interleukin 4, but not interferon-gamma, increase susceptibility to giant cell arteritis

OBJECTIVE: To assess the roles of the interleukin 4 (IL-4) and interferon-g (IFN-g) gene polymorphisms in a series of patients with biopsy-proven giant cell arteritis (GCA). METHODS: Eighty-two patients with biopsy-proven GCA and 102 ethnically matched controls from the Lugo region (Northwest Spain) were studied. The following single nucleotide polymorphisms (SNP) were assessed: IL-4 (SNP1: rs2070874, SNP2: rs2227284, SNP3: rs2227282, SNP4: rs2243266, and SNP5: rs2243267) and IFN-g (SNP1: rs1861494, SNP2: rs1861493, and SNP3: rs2069718). RESULTS: Significant differences in allele and genotype frequencies were observed for the IL-4 SNP between HLA-DRB1*04 negative patients and controls. Epistatic interaction between SNP2 (rs2227284) with HLA-DRB1 showed a significant interaction (p = 0.001) and carriage of the SNP2*T allele in the absence of HLA-DRB1*04 resulted in a 4-fold risk of developing GCA (OR 4.2, 95% CI 1.1-15.6). Also, a significant increase in the frequency of the T-T-C-A-C IL-4 haplotype was observed in HLA-DRB1*04 negative GCA patients compared to the controls (p = 0.02; OR 2.0, 95% CI 1.0-3.9). Similar distributions of allele and genotype frequencies were observed for the IFN-g polymorphisms in both GCA patients and controls. CONCLUSION: Our results suggest an association with IL-4 gene polymorphism that is dependent on HLA-DRB1 genotype in GCA susceptible individuals. These data indicate an interaction between HLA-DRB1 and IL-4 that contributes to pronounced disease susceptibility.     

Association of TNFSF4 polymorphisms with systemic lupus erythematosus: a meta-analysis

Abstract

Introduction To more precisely estimate the association between the tumor necrosis factor ligand superfamily member 4 (TNFSF4) gene polymorphisms and systemic lupus erythematosus (SLE) risk, we surveyed studies on the association of the TNFSF4 rs2205960, rs1234315, rs844644, and rs844648 polymorphisms with SLE.

Methods A literature-based search was conducted to identify all relevant studies. A total of eight independent studies were identified and subsequently reviewed in the meta-analysis.

Results The meta-analysis showed an association between the TNFSF4 rs2205960 polymorphism and SLE in all subjects [ odds ratio (OR) 1.327, 95 % confidence interval (CI) 1.227–1.436, P < 0.001]. In a subgroup analysis by ethnicity, a significantly increased risk for SLE was associated with TNFSF4 rs2205960 T allele among patients of European (OR 1.254, 95 % CI 1.185–1.328, P < 0.001) and Asian ethnicity (OR 1.425, 95 % CI 1.352–1.501, P < 0.001). The meta-analysis of the rs1234315 polymorphism revealed no association between SLE and the rs1234315 T allele in all subjects (OR 1.167, 95 % CI 0.874–1.558, P = 0.296), but the results of the subgroup analysis revealed significant association in subjects of Asian ethnicity (OR 1.386, 95 % CI 1.318–1.458, P < 0.001). No association was found between the rs844644 and rs844648 polymorphisms and SLE.

Conclusion The results of our meta-analysis suggest that the TNFSF4 rs2205960 polymorphism may confer susceptibility to SLE in different populations and that the TNFSF4 rs1234315 polymorphism is associated with susceptibility to SLE in Asians.     

Endothelial nitric oxide synthase gene polymorphism is associated with systemic lupus erythematosus

OBJECTIVE: In systemic lupus erythematosus (SLE), endothelial nitric oxide synthase (eNOS) gene locus has been found to be suggestive of linkage with disease, nitric oxide (NO) is produced in significant amounts, and endothelial cell dysfunction is observed. eNOS gene polymorphism may affect both the synthesis of eNOS protein and its enzymatic activity. We examined the influence of eNOS gene polymorphisms on susceptibility to SLE. METHODS: Genomic DNA from 88 Northwestern Colombian women with SLE, as well as 199 controls matched for sex, age, and ethnicity, was genotyped for the -786T -- > C polymorphism in the promoter region, the intron 4 variable number of tandem repeats, and the Glu298Asp polymorphism in exon 7 of the eNOS gene by polymerase chain reaction and restriction fragment length polymorphism techniques. Haplotype and allele frequency comparisons, a Hardy-Weinberg equilibrium test, and linkage disequilibrium (LD) analysis were performed. RESULTS: The intron 4b allele was associated with SLE (OR 2.2, 95% CI 1.29-3.60, pc = 0.005) as was the 4bb genotype (OR 2.9, 95% CI 1.61-5.33, pc = 0.0009), while the 4a allele was protective (OR 0.4, 95% CI 0.26-0.76, pc = 0.005), as was the 4ab genotype (OR 0.29, 95% CI 0.15-0.56, pc < 0.0001). In controls, all loci were in linkage disequilibrium (p < 0.02). In patients, intron 4 was in Hardy-Weinberg disequilibrium, due to an excess of homozygotes (p = 0.01). CONCLUSION: eNOS polymorphism influences SLE predisposition. Since intron 4bb genotype is responsible for higher levels of eNOS synthesis and intron 4 ab genotype is associated with lower synthesis, our results might provide insight into the elevated levels of NO observed in SLE patients.     

白细胞介素-7受体α基因多态性对亚洲人多发性硬化易感性的影响

目的 探讨亚洲人群白细胞介素-7受体α(IL-7RA)基因rs6897932多态性位点与多发性硬化(MS)遗传易感性的关系。 方法 采用反转录聚合酶链反应(RT-PCR)技术,对78例MS和视神经脊髓炎( neuromyelitis optica,NMO)患者(NMO组),187非MS的视神经脊髓炎(non-NMO MS)患者（non-NMO MS组）及158例健康对照组筛查IL-7RA基因分布频率,并进行统计学分析。结果 non-NMO MS组C等位基因频率89.3％（167例）明显高于对照组79.8％（126例）,差异有统计学意义(OR=2.12,95％CI:1.38～3.25,P＜0.01);CC等位基因型频率分别为78.6％( 147例)与63.3％（100例）,差异有统计学意义(OR=2.13,95％CI;1.32～3.43,P＜0.01);而NMO组与对照组C、CC等位基因频率比较,差异无统计学意义。 结论 IL-7RA基因rs6897932多态性位点影响亚洲人群MS遗传易感性。C等位基因为MS的易感因子,T等位基因则可能为MS的保护因子。     

The association between the PTPN22 C1858T polymorphism and systemic lupus erythematosus: a meta-analysis update

The aim of this study was to determine whether the functional protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism (rs2476601) confers susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. A meta-analysis was conducted on the PTPN22 C1858T polymorphism across 11 comparative studies. Meta-analysis showed an association between the PTPN22 1858T allele and SLE in all study subjects (odds ratio (OR) 1.560, 95% confidence interval (CI) 1.336, 1.822, p = 2.0 × 10(-8)). Analysis after stratification by ethnicity indicated that the PTPN22 1858T allele was significantly associated with SLE in Europeans and Hispanics (OR 1.490, 95% CI 1.280, 1.735, p = 2.0 ×10(-8); OR 2.355, 95% CI 1.644, 3.373, p = 2.9 × 10(-6)). The meta-analysis showed that the C/T + T/T genotype was associated with susceptibility to SLE in all study subjects, Europeans, and Hispanics populations, and an association between the T/T genotype with SLE in Europeans. African Americans had a much lower prevalence of the T allele (2.2%) than any other population studied, and Europeans had the highest frequency (9.5%). In conclusion, this meta-analysis confirms that the PTPN22 C1858T polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.     

The association between single-nucleotide polymorphisms of NCF2 and systemic lupus erythematosus in Chinese mainland population

Systemic lupus erythematosus (SLE) is a complex immune disease. The genetic variation in the NCF2 gene was found to associate with SLE in US and European populations. However, the association of rs10911363 with SLE was not extensively studied in Chinese mainland population. A total of 488 SLE patients and 380 controls were recruited. Unlabeled probe-based high-resolution melting analysis (HRMA) was used in genotyping. HRMA with unlabeled probe successfully distinguished all genotypes. Neither genotype nor allele frequencies of single-nucleotide polymorphism (SNP) rs10911363 showed statistically significant differences between SLE patients and controls. The association of SNP rs10911363 with the diagnostic criteria of SLE was also examined. Minor allele (G) of rs10911363 was found to significantly associate with the incidence of arthritis (p?=?0.024, odds ratio (OR)?=?1.35, and 95% confidence interval (CI)?=?1.04?C1.75) and increased abnormalities of antinuclear antibody (p?=?0.002, OR?=?1.51, and 95%CI?=?1.17?C1.95) and anti-DNA (p?=?0.013, OR?=?1.40, and 95%CI?=?1.07?C1.82). Polymorphisms of rs13277113 in NCF2 gene were associated with arthritis and autoantibody production, but not disease risk, of SLE in Chinese population.     

Angiotensin-converting enzyme insertion/deletion polymorphism and systemic lupus erythematosus: a metaanalysis

OBJECTIVE: To explore whether insertion (I) and deletion (D) polymorphisms within intron 16 of the angiotensin-converting enzyme (ACE) gene confer susceptibility to systemic lupus erythematosus (SLE) and lupus nephritis (LN). METHODS: We surveyed studies of ACE I/D polymorphism and SLE using Medline and manual searches. We conducted a metaanalysis of the DD genotype (recessive effect), DD and DI genotype (dominant effect), and D allele of the ACE overall and in each ethnic population. We performed a metaanalysis of ACE I/D polymorphism in SLE and LN. RESULTS: Thirteen comparison studies were included in our metaanalysis consisting of 1411 patients with SLE and 1551 controls. We found no association of ACE I/D polymorphism with SLE in the total sample and by ethnic groups. There was a trend for association of the DD genotype (OR 1.212, 95% CI 0.966-1.520, p = 0.097) and the D allele with SLE in Caucasian patients (OR 1.157, 95% CI 0.991-1.349, p = 0.064); however, this was not statistically significant. The metaanalysis also showed no association of the ACE I/D polymorphisms with LN. CONCLUSION: This metaanalysis of 2962 subjects showed there is a lack of association of the ACE I/D polymorphism with SLE and LN.     

Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: support for a crucial role of intron 1 polymorphisms

OBJECTIVE: To determine whether the IRF5 gene, which encodes interferon regulatory factor 5, is associated with systemic lupus erythematosus (SLE) in a Japanese population. METHODS: A case-control study was performed in 277 SLE patients and 201 healthy controls. Associations between the IRF5 genotype and levels of messenger RNA (mRNA) for interferon (IFN) pathway genes were examined using an mRNA expression database of HapMap samples. RESULTS: Carriers of the rs2004640T single-nucleotide polymorphism (SNP) were slightly increased among SLE patients (58.8%) as compared with controls (50.2%). When data from our Japanese population were combined with previously published data from a Korean population, the T allele frequency was found to be significantly increased in SLE patients (P = 8.3 x 10(-5)). While no association was observed for the rs10954213 SNP or the exon 6 insertion/deletion, significant associations with 3 intron 1 SNPs (-4001, rs6953165, and rs41298401) were found. The allele frequency of rs41298401G was significantly decreased in SLE patients (13.0% versus 18.7% in controls; P = 0.017), and the allele frequency of rs6953165G, which was in absolute linkage disequilibrium with -4001A, was increased in SLE patients (8.8% versus 5.2% in controls; P = 0.034). The Caucasian risk haplotype was not present; instead, a protective haplotype carrying rs2004640G, rs41298401G, the deletion in exon 6, and rs10954213A was identified. SNP rs10954213, but not intron 1 SNPs, was associated with IRF5 at the mRNA level; nevertheless, intron 1 SNPs were also associated with levels of mRNA for several IFN pathway genes, suggesting a functional role. CONCLUSION: IRF5 was found to be associated with SLE in Asian populations. Intron 1 SNPs, rather than exon 6 and 3'-untranslated region polymorphisms, appeared to play a crucial role.