Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.

/pdf/genome-wide-association-study-in-asian-populations-25ihh5yy3j.pdf

Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease with a highly variable clinical course. Pediatric-onset SLE (pSLE) represents 10-20% of all SLE cases, and is associated with higher disease severity, including more-rapid damage accrual, than adult-onset SLE. As in adults, pSLE disease expression varies according to ethnicity, with a milder disease course in white patients. The majority of pSLE patients will have developed damage within 5-10 years of disease onset, most frequently involving the musculoskeletal, ocular, renal and neuropsychiatric systems. Owing to improvements in disease management and recognition over the past 20-30 years, patients now live longer, but as a result have increased disease damage. Premature atherosclerosis and osteoporosis have become increasingly prevalent morbidities in pSLE patients. Early atherosclerosis leads to a considerable rise in cardiovascular and cerebrovascular events, and failure to develop adequate peak bone mass during adolescence-a crucial period of bone accrual-is likely to lead to early osteoporosis and fractures. Patients with pSLE have an incurable, potentially devastating disease that occurs during a vulnerable period of psychosocial development, leading to specific and unique psychosocial stressors. Additional large, long-term follow-up studies in pSLE are needed to better understand the disease prognosis and to facilitate development of tailored treatments.

Prevalence and burden of pediatric-onset systemic lupus erythematosus.

The genetics and molecular pathogenesis of systemic lupus erythematosus (SLE) in populations of different ancestry.

Systemic lupus erythematosus is a rare lifelong multi-systemic autoimmune condition. Juvenile-onset SLE (JSLE) is recognized to have a more active disease course when compared with adult-onset disease and patients have a worse long-term survival. Kidney involvement occurs in over 50% of children and treatment decisions are guided by the histological classification. Several international groups have produced treatment protocols that rely on an intense period of immunosuppression to halt the acute kidney inflammatory process, followed by maintenance therapy with close observation for disease improvement and prompt evaluation of disease flares. A reduced glomerular filtration rate at presentation is predictive of later stage chronic kidney disease (CKD) in multivariate analysis. Kidney remission remains suboptimal with only 40–60% of patients achieving complete remission. Kidney flares are seen in over a third of patients. The rate of CKD 5 is reported to be up to 15% and the presence of lupus nephritis (LN) has an established link with an associated increase in mortality. In established kidney failure, transplantation seems to be the optimal kidney replacement modality for this group of patients, ideally after a period of disease quiescence. Modified outcome measures in clinical trials have demonstrated that biologic agents can be effective in this disease. Current biologic agents under investigation include obinutuzimab, belimumab, atacicept, anifrolumab, tocilizumab, eculizumab, dapirolizumab, and abatacept. Future research should focus on discovering early disease biomarkers, including surrogates for later cardiovascular disease, and evaluating biological agents as adjuncts to improve the rates of complete remission and subsequently influence the kidney outcome. The aim of this review article is to summarize the current kidney outcomes for this disease with a view to identifying key areas that may help to reduce the risk of long-term CKD.

/pdf/kidney-outcomes-for-children-with-lupus-nephritis-3eserelih5.pdf

Kidney outcomes for children with lupus nephritis.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic involvement. The susceptibility genes identified so far can only explain a small proportion of disease heritability. Through a genome-wide association in a Hong Kong Chinese cohort and subsequent replication in two other Asian populations, with a total of 3164 patients and 4482 matched controls, we identified association of ELF1 (E74-like factor 1) with SLE (rs7329174, OR = 1.26, joint P= 1.47 × 10(-8)). ELF1 belongs to the ETS family of transcription factors and is known to be involved in T cell development and function. Database analysis revealed transcripts making use of three alternative exon1s for this gene. Near equivalent expression levels of distinct transcripts initiated from alternative exon1s were detected in peripheral blood mononuclear cells from both SLE patients and healthy controls. Although a direct association of rs7329174 with the three forms of transcripts for this gene was not detected, these findings support an important role of ELF1 in SLE susceptibility and suggest a potentially tight regulation for the expression of this gene.

/pdf/elf1-is-associated-with-systemic-lupus-erythematosus-in-1eps56sn56.pdf

ELF1 is associated with systemic lupus erythematosus in Asian populations

We report a multicenter study of Chinese children in Hong Kong with systemic lupus erythematosus (SLE) nephritis Children were included if: they fulfilled the ACR criteria, had significant proteinuria or casturia, were Chinese and younger than 19 years and had been diagnosed with SLE between January 1990 and December 2003 Investigators in each center retrieved data on clinical features, biopsy reports, treatment and outcome of these patients There were 128 patients (eight boys, 120 girls; mean age: 119+/-28 years) About 50% presented with multisystem illness and 40% with nephritic/nephrotic symptoms Negative anti-dsDNA antibodies were found in 6% of the patients Renal biopsy revealed WHO Class II, III, IV and V nephritis in 13 (10%), 22 (17%), 69 (54%) and 13 (10%) patients, respectively The clinical severity of the nephritis did not accurately predict renal biopsy findings The follow-up period ranged from 1 to 165 years (mean+/-SD: 576+/-361 years) During the study five patients died (two from lupus flare, one from cardiomyopathy, two from infections) Four patients had endstage renal failure (ESRF) (one died during a lupus flare) All deaths and end-stage renal failure occurred in the Class IV nephritis group Chronic organ damage was infrequent in the survivors The actuarial patient survival rates at 5, 10 and 15 years of age were 953, 918, and 918%, respectively For Class IV nephritis patients, the survival rates without ESRF at 5, 10, and 15 years were 915, 823 and 76%, respectively The survival and chronic morbidity rates of the Chinese SLE children in the present study are comparable to those of other published studies

pdf/lupus-nephritis-in-chinese-children-a-territory-wide-cohort-177kuwonlg.pdf

Lupus nephritis in Chinese children--a territory-wide cohort study in Hong Kong

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Lupus nephritis in Chinese children--a territory-wide cohort study in Hong Kong