Jianyang Ma

High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry.

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10−117, odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

The association between intensive glycemic control and vascular complications in type 2 diabetes mellitus: A meta-analysis

BACKGROUND AND AIM In patients with type 2 diabetes mellitus, the relationship between lowering glycated hemoglobin (HbA(1c)) and macrovascular complications is not clear and therefore lowering the level of HbA(1c) is controversial. METHODS AND RESULTS We searched for all randomized controlled trials comparing the effects of intensive and standard glycemic control on vascular events in patients with type 2 diabetes mellitus. The primary endpoint was combined macrovascular complications, including cardiac events, stroke and peripheral vascular disease. Fixed and random effect models were used to analyze the results. Eight studies were included according to selection criteria. The results showed no benefits of intensive glycemic control on macrovascular and microvascular complications (P>0.1), but a higher rate of severe hypoglycemia (P<0.00001) in the intensive control group when the target HbA(1c) level was <7.0%. When the target HbA(1c) level was lowered to 7.0-7.9%, intensive glycemic control showed benefits on the reduction of microvascular events (P<0.05) without increasing the risk of severe hypoglycemia (P=0.74), but no influence on macrovascular complications (P>0.1). CONCLUSION The results of this analysis suggest that a target HbA(1c) level of 7.0-7.9% may be a better glycemic control target than that of <7.0% in patients with established type 2 diabetes mellitus.

Identification of the long noncoding RNA NEAT1 as a novel inflammatory regulator acting through MAPK pathway in human lupus.

Long noncoding RNAs (lncRNAs) have recently been identified to be tightly linked to diverse human diseases. However, our knowledge of Systemic Lupus Erythematosus (SLE)-related lncRNAs remains limited. In the present study we investigated the contribution of the lncRNA NEAT1 to the pathogenesis of SLE. Here, we found NEAT1 expression was abnormally increased in SLE patients and predominantly expressed in human monocytes. Additionally, NEAT1 expression was induced by LPS via p38 activation. Silencing NEAT1 significantly reduced the expression of a group of chemokines and cytokines, including IL-6, CXCL10, etc., which were induced by LPS continuously and in late stages. Furthermore, it was identified the involvement of NEAT1 in TLR4-mediated inflammatory process was through affecting the activation of the late MAPK signaling pathway. Importantly, there was a positive correlation between NEAT1 and clinical disease activity in SLE patients. In conclusion, the increased NEAT1 expression may be a potential contributor to the elevated production of a number of cytokines and chemokines in SLE patients. Our findings suggest lncRNA contributes to the pathogenesis of lupus and provides potentially novel target for therapeutic intervention.

Association of large intergenic noncoding RNA expression with disease activity and organ damage in systemic lupus erythematosus

IntroductionDespite growing evidence that large intergenic noncoding RNAs (lincRNAs) can regulate gene expression and widely take part in normal physiological and disease conditions, our knowledge of systemic lupus erythematosus (SLE)-related lincRNAs remains limited. The aim of this study was to detect the levels of four lincRNAs (ENST00000500949: linc0949, ENST00000500597: linc0597, ENST00000501992: linc1992, and ENST00000523995: linc3995) involved in innate immunity in the peripheral blood mononuclear cells (PBMCs) of patients with SLE and correlate these lincRNA levels with disease activity, organ damage, clinical features and medical therapies.MethodsPBMCs were obtained from 102 patients with SLE, 54 patients with rheumatoid arthritis (RA) and 76 healthy donors. lincRNA expression levels were measured by real-time quantitative polymerase chain reaction. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, and organ damage was evaluated with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index.Resultslinc0949 and linc0597 were significantly decreased in patients with SLE compared with patients with RA and healthy control subjects. linc0949 was correlated with SLEDAI-2K score (r = −0.329, P = 0.0007), as well as with complement component C3 level (r = 0.348, P = 0.0003). The level of linc0949 was also reduced in patients with SLE who had the presence of cumulative organ damage. In addition, decreasing expression of linc0949 was associated with lupus nephritis. linc0949 expression significantly increased after treatment, whereas neither disease activity nor organ damage correlated with linc0597 expression.ConclusionsOur results provide novel empirical evidence that linc0949 could be a potential biomarker for diagnosis, disease activity and therapeutic response in SLE.

A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type I interferon signature. Here we report a missense variant (g.74779296G>A; p.Arg90His) in NCF1, encoding the p47phox subunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by the Immunochip in the GTF2IRD1–GTF2I region at 7q11.23 with a complex genomic structure. We show that the p.Arg90His substitution, which is reported to cause reduced reactive oxygen species (ROS) production, predisposes to SLE (odds ratio (OR) = 3.47 in Asians (Pmeta = 3.1 × 10−104), OR = 2.61 in European Americans, OR = 2.02 in African Americans) and other autoimmune diseases, including primary Sjögrens syndrome (OR = 2.45 in Chinese, OR = 2.35 in European Americans) and rheumatoid arthritis (OR = 1.65 in Koreans). Additionally, decreased and increased copy numbers of NCF1 predispose to and protect against SLE, respectively. Our data highlight the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.

Brief Report: Identification of MTMR3 as a Novel Susceptibility Gene for Lupus Nephritis in Northern Han Chinese by Shared-Gene Analysis With IgA Nephropathy

Several novel susceptibility genes for systemic lupus erythematosus (SLE) and IgA nephropathy have been identified in recent genome‐wide association studies. Since both lupus nephritis and IgA nephropathy are autoimmune diseases of the kidney, they may share common disease mechanisms that overlap with genetic susceptibility. To test this hypothesis, we sought to identify genetic variants associated with IgA nephropathy in lupus nephritis.

MicroRNA-130b Ameliorates Murine Lupus Nephritis Through Targeting the Type I Interferon Pathway on Renal Mesangial Cells.

Type I interferon (IFN) is a critical pathogenic factor during the progression of lupus nephritis (LN). Although microRNAs (miRNAs) have been shown to control the IFN response in immune cells in LN, the role of miRNAs in resident renal cells remains unclear. We undertook this study to investigate the role of microRNA‐130b (miR‐130b) in the IFN pathway in renal cells as well as its therapeutic effect in LN.

Confirmation of five novel susceptibility loci for systemic lupus erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta = 1.92 × 10-13, OR = 1.14), ATG16L2 (rs11235604, Pmeta = 8.87 × 10 -12, OR = 0.78), CCL22 (rs223881, Pmeta = 5.87 × 10-16, OR = 0.87), ANKS1A (rs2762340, Pmeta = 4.93 × 10-15, OR = 0.87) and RNASEH2C (rs1308020, Pmeta = 2.96 × 10-19, OR = 0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56%) of the correlated (r2 > 0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81 × 10-198 < P < 5 × 10-3) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P < 0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.

MiR‐130b ameliorates murine lupus nephritis through targeting type I interferon pathway on resident renal cells

Type I interferon (IFN) is a critical pathogenic factor during the progression of lupus nephritis (LN). Although microRNAs (miRNAs) have been shown to control the IFN response in immune cells in LN, the role of miRNAs in resident renal cells remains unclear. We undertook this study to investigate the role of microRNA‐130b (miR‐130b) in the IFN pathway in renal cells as well as its therapeutic effect in LN.

Phenotypic and functional alterations of pDCs in lupus-prone mice.

Plasmacytoid dendritic cells (pDCs) were considered to be the major IFNα source in systemic lupus erythematosus (SLE) but their phenotype and function in different disease status have not been well studied. To study the function and phenotype of pDCs in lupus-prone mice we used 7 strains of lupus-prone mice including NZB/W F1, NZB, NZW, NZM2410, B6.NZMSle1/2/3, MRL/lpr and BXSB/Mp mice and C57BL/6 as control mice. Increased spleen pDC numbers were found in most lupus mice compared to C57BL/6 mice. The IFNα-producing ability of BM pDCs was similar between lupus and C57BL/6 mice, whereas pDCs from the spleens of NZB/W F1 and NZB mice produced more IFNα than pDCs from the spleens of C57BL/6 mice. Furthermore, spleen pDCs from MRL-lpr and NZM2410 mice showed increased responses to Tlr7 and Tlr9, respectively. As the disease progressed, IFN signature were evaluated in both BM and spleen pDC from lupus prone mice and the number of BM pDCs and their ability to produce IFNα gradually decreased in lupus-prone mice. In conclusion, pDC are activated alone with disease development and its phenotype and function differ among lupus-prone strains, and these differences may contribute to the development of lupus in these mice.