Xiang Pei Li

Meta-analysis Followed by Replication Identifies Loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as Associated with Systemic Lupus Erythematosus in Asians

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases.

Type 17 T-helper cells might be a promising therapeutic target for systemic lupus erythematosus.

Emerging data implicate a novel subset of CD4+ T cells, termed TH17 cells, in the pathogenesis of several autoimmune diseases. In this Viewpoint article, the authors discuss the role of TH17 cells in systemic lupus erythematosus and discuss their potential as a therapeutic target.

The correlation between monocyte chemoattractant protein-1 and the arthritis of systemic lupus erythematosus among Chinese

Monocyte chemoattractant protein-1 (MCP1) polymorphism has been reported to be associated with systemic lupus erythematosus (SLE). However, the correlation between the polymorphism and SLE is poorly understood. In this study we investigated the role of this polymorphism together with that of chemokine SDF1-3′A and chemokine receptor CCR2-V64I. The association between gene polymorphism and SLE was explored by way of a case-control study. In 143 patients with SLE and 157 healthy controls, the polymorphisms of SDF1-3′A, −2518MCP-1 and CCR2-V64I were determined using PCR-RFLP and an amplification-refractory mutation system, respectively. No significant difference was found in allelic and genotype frequency of SDF1-3′A, CCR2-V64I and −2518MCP-1 between SLE patients and controls. However, a significant increase in the frequency of the AG genotype of MCP-1 was found among patients with arthritis (Pc=0.003, OR 3.08, 95%CI 1.27–7.57). The frequency of individuals having G at position −2518 of the MCP-1 gene was also increased among patients with arthritis (Pc=0.028, OR 2.99, 95%CI 1.13–8.08). It is noteworthy that the frequency of −2518MCP-1G in the Chinese Han population was 64%. The results indicate an association between the presence of G at position −2518 in the MCP-1 promoter region and the presence of arthritis in patients with SLE.

Polymorphisms in the promoter region of RANTES in Han Chinese and their relationship with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease afflicting more than 600,000 individuals in China. RANTES (regulated on activation, normal T cell expressed and secreted, 17q11.2-q12) is a member of the proinflammatory cytokine family known as “chemokines”. It plays an important role in the attraction and recruitment of lymphocytes, monocytes and eosinophils to sites of inflammation. A total of 146 SLE patients and 159 random healthy volunteer individuals in Han Chinese patients were enrolled in this study. Genotypes of RANTES −403 locus and −28 locus were observed to be different in all racial groups. The frequency of individuals who possessed G allele at −28 locus among SLE patients was not significantly different from that among normal controls. A total of seven compound genotypes at −403 locus and −28 locus were observed in this study. The frequency of this compound genotype (−403 G/G, −28 C/C) was different between the two groups. The distribution of genotypes and alleles at RANTES-403 locus was observed to be significantly different between renal damaged group and no renal damaged group (P<0.05), while there was no significant difference in distribution of genotypes and alleles at RANTES-28 locus between the two groups. These results suggest that (a) two genetic polymorphisms in the RANTES promoter do not correlate with SLE as individual polymorphisms. (b) interaction of the polymorphisms at two loci probably exerts a risk effect against SLE and (c) polymorphism at RANTES-403 locus is probably related with renal damage.

Role of the Fcγ receptor IIIA-V/F158 polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis.

Objective: To perform a meta-analysis to assess the risk of the Fc-gamma receptor type IIIA (FcγRIIIA)-V/F158 polymorphism for lupus nephritis and systemic lupus erythematosus (SLE). Methods: We surveyed studies on V/F158 and SLE and/or lupus nephritis using Medline, Blackwell, and EMBASE databases up to January 2009. Sufficient original data were available to calculate odds ratios (ORs) for SLE and/or lupus nephritis based on the American College of Rheumatology (ACR) criteria. Two investigators independently assessed the data quality and extracted the data. Results: The F158 allele presented overall consistent association evidence for SLE, SLE without nephritis, and lupus nephritis [OR 1.27, 95% confidence interval (CI) 1.13–1.43; OR 1.20, 95% CI 1.05–1.37; OR 1.15, 95% CI 1.04–1.28, respectively]. FF homozygosity had a dose–response relationship for SLE with maximal OR 1.68 (95% CI 1.26–2.23). It also strongly influenced the risk of lupus nephritis and of SLE without nephritis, with maximal OR 1.30 (95% CI 1.04–1.64) and 1.43 (95% CI 1.07–1.92), respectively. Ethnic subgroup analyses revealed that the F158 allele was significantly higher in SLE patients of European and Asian descent [OR 1.30 (95% CI 1.07–1.58) and OR 1.24 (95% CI 1.04–1.48), respectively] but not in SLE patients of African descent and was only highly associated with lupus nephritis in those of Asian descent [OR 1.26 (95% CI 1.06–1.50)]. The FF genotype was significantly associated with SLE in those of European and Asian descent, with maximal OR 1.61 (95% CI 1.03–2.53) and 1.70 (95% CI 1.12–2.58), respectively, but not for lupus nephritis and SLE without nephritis of any subgroup. Conclusions: The FcγRIIIA-V/F158 polymorphism might be a common susceptibility factor for SLE and lupus nephritis and play an important role in the overall development of SLE, showing different risks within ethnic populations, which should provide novel insights into the pathogenesis of the disease.

Three SNPs in chromosome 11q23.3 are independently associated with systemic lupus erythematosus in Asians

Systemic lupus erythematosus (SLE) has a complex etiology and is affected by both genetic and environmental factors. Although more than 40 loci have shown robust association with SLE, the details of these loci, such as the independent contributors and the genes involved, are still unclear. In this study, we performed meta-analysis of two existing genome-wide association studies (GWASs) on Chinese Han populations from Hong Kong and Anhui, China, and followed the findings by further replication on three additional Chinese and Thailand cohorts with a total of 4254 cases and 6262 controls matched geographically and ethnically. We discovered multiple susceptibility variants for SLE in the 11q23.3 region, including variants in/near PHLDB1 (rs11603023, P(_combined) = 1.25E-08, OR = 1.20), DDX6 (rs638893, P(_combined) = 5.19E-07, OR = 1.22) and CXCR5 (rs10892301, P(_combined) = 2.51E-08, OR = 0.85). Genetic contributions from the newly identified variants were all independent of SNP rs4639966, whose association was reported from the previous GWAS. In addition, the three newly identified variants all showed independent association with the disease through modeling by both stepwise and conditional logistic regression. The presence of multiple independent variants in this region emphasizes its role in SLE susceptibility, and also hints the possibility that distinct biological mechanisms might be involved in the disease involving this genomic region.

Genetic susceptibility and haplotype analysis between Fcγ receptor IIB and IIIA gene with systemic lupus erythematosus in Chinese population

The objective of this study is to understand the role of FcγRIIB and FcγRIIIA gene in susceptibility to systemic lupus erythematosus (SLE), and to examine possible susceptible haplotypes between two genes. A total of 119 patients with SLE from 95 nuclear families, aged from 14 to 78 years, were selected according to 1997 criteria of American College of Rheumatology. In addition, 316 family members of these patients were also genotyped. A family-based association study was used to explore the relationship between gene polymorphism and SLE. We studied 13 single-nucleotide polymorphisms (SNPs) encoding non-synonymous substitution in the FcγRIIB and FcγRIIIA gene (four SNPs in the FcγRIIB gene and nine SNPs in the FcγRIIIA gene) with respect to genetic susceptibility to SLE. All SNPs were genotyped by restriction fragment length polymorphism method. Among 13 SNPs, univariate (single-marker) family-based association tests showed that variant alleles at only four SNPs (rs10917661 and rs1050501, in exon 2 and exon 5 of FcγRIIB gene, rs403016 and rs428888, in exon3 of FcγRIIIA gene respectively) were significantly associated with genetic susceptibility to SLE. Furthermore, the haplotype-specific FBATs showed 50Ter-225Thr (34.1%, in FcγRIIB gene) and 72Arg-118Asn (40%, in the FcγRIIIA gene) haplotype were more frequently transmitted in SLE than other haplotypes (Z = 3.539, P = 0.00042; Z = 2.678, P = 0.007412 respectively). But haplotypes were not found between FcγRIIB and FcγRIIIA gene Our results suggest that there were meaningful haplotype in FcγRIIIA and FcγRIIB gene respectively. FcγRIIIA and FcγRIIB genes in the pathogenesis of SLE may play an independent role in Chinese population.

Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease.

Ets-1: a new player in the pathogenesis of systemic lupus erythematosus?

v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) (Ets-1) is a member of the Ets family of transcription factors that share a unique Ets DNA binding domain. They control a wide variety of cellular processes including cell proliferation and differentiation. Recently, two genome-wide association studies in systemic lupus erythematosus (SLE) independently identified genetic variants in Ets-1 associated with SLE. Interestingly, previous studies have found that Ets-1-deficient mice develop lupus-like disease characterized by high titers of IgM and IgG autoantibodies, immune complex-mediated glomerulonephritis, and local activation of complement. In addition, Ets-1 is also involved in many cellular abnormalities that are known to participate in SLE pathogenesis, such as its role in negative regulation of Th17 cell and B cell differentiation. All these findings suggest that Ets-1 may play an important role in the pathogenesis of SLE. This article will focus on current understanding of the role of Ets-1 in the physiological and pathological functions associated with SLE. It is the intention of the article to provide insights which may assist in the development of Ets-1 based approaches for the treatment of SLE.

Study on clinical features and complications with systemic lupus erythematosus (SLE) activity in Chinese Han population

Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting multiple organs/systems with variable activities. We performed a retrospective study to investigate the relationship of clinical characteristics and complications with SLE activity in Chinese Han population. A cohort of 1,490 SLE inpatients was evaluated for disease activity using the systemic lupus erythematosus disease activity index (SLEDAI). Chi-square test or Fisher’s exact test was used to compare differences of clinical and laboratory features between active and inactive SLE patients. Logistic regression was chosen to explore the pattern of risk factors for disease activity. We found that neuropsychiatric involvement, nephritis, arthralgia, anti-dsDNA, serositis, hypocomplementemia, oral ulcerations, erythrocyte sedimentation rate, low C3, hematological abnormalities, and systolic pressure (1.010 < odds ratio < 10.568, 1.002 < 95% confidence interval < 31.599, 0.000 < P < 0.026) were major factors associated with disease activity, but not headaches, anti-ribonucleoprotein or anti-Sm, C-reactive protein, and anemia (P > 0.05, respectively). The involvements of urinary system, respiratory system, and central nervous system were significantly more frequent in active SLE than inactive SLE (0.000 < P < 0.014), except for alimentary system (P = 0.399). Our study has comprehensively evaluated the relationship of clinical characteristics and organs/systems involvement of SLE with SLEDAI in Chinese Han population and presented a compendium of factors affecting SLE, which should be useful for better evaluating disease activity and predicting organs/systems damage in SLE for clinical assessments and managements.