The genetic and epidemiology study of the rheumatic diseases
Date Issued
2016
Date
2016
Author(s)
Yu, Hsin-Hui
Abstract
Systemic lupus erythematous (SLE) and juvenile idiopathic arthritis (JIA) are the most important autoimmune diseases in children. The multifactorial etiology with interaction of genetic factors and environmental factors is essential in the pathogenesis. SLE is characterized by grossly immune dysregulation including nuclear antigen release due to abnormal apoptosis, over-reactive antigen presenting cells with type I interferon production, polyclonal T and B cells activation, autoantibodies overproduction, impaired immune complex clearance, then inflammation and damage in multiple organ systems. JIA collectively refers to a group of chronic arthritis of at least six weeks duration in children or adolescents under the age of 16. Seven subtypes of JIA are defined as systemic JIA, oligoarticular JIA, rheumatoid factor (RF)-negative polyarticular JIA, RF-positive polyarticular JIA, enthesitis-related arthritis (ERA), psoriatic arthritis, and undifferentiated JIA. Auto-reactive T cells activation in response to synovial antigen exposure and inflammatory response involved the synovial tissues of joints (arthritis), and less frequently the eye (uveitis), are the key features in the pathogenesis of JIA. On the other hand, systemic JIA is considered to be an auto-inflammatory disease. Highly activated phagocytes and neutrophils in innate immune system cause systemic inflammatory symptoms of fever, skin rash, hepato-splenomegaly, and arthritis. We hypothesized that the single nucleotide polymorphisms (SNPs) of cytokine genes contributed to the development of SLE. We investigated 20 SNPs derived from the 8 genes encoding TH1 and TH2 cytokines: IL12, IFNG, IL18, IL4, IL5, IL10, IL13 and a transcriptional factor related to the TH2 pathway (signal transducer and activator of transcription 6, interleukin-4 induced [STAT6]) in 110 SLE patients and 138 healthy controls, using GenomeLab SNPstream platform for genotyping. Our results showed that IL4 haplotype, and gene–gene interaction between IL4 and STAT6 conferred a significantly increased risk for SLE. IL18 gene polymorphism carried increased risk for lupus nephritis. Research has shown that statins have anti-inflammatory and lipid-lowering effect. Dyslipidemia, atherosclerosis, cardiovascular diseases are common in patients with SLE. Cardiovascular diseases have emerged as a major cause of morbidity and mortality in patients with SLE. We hypothesized that statin therapy could reduce mortality and cardiovascular diseases in patients with SLE and hyperlipidemia. We identified 4095 patients with SLE and hyperlipidemia from the Taiwan National Health Insurance Research Database (NHIRD) from year 1997 to 2008. We compared the risk of all-cause mortality, coronary artery diseases, cerebrovascular disease and end-stage renal disease among SLE patients with and without using lipid-lowering medications in Cox regression hazard analysis. We observed that statins use in SLE patients with hyperlipidemia was associated with reduced mortality and morbidity. High dose statins users had more significant reduced risk of outcomes, which could be explained by the dose-dependently lipid-lowering and anti-inflammatory properties of statins. The additive effect of hydroxychloroquine and statins in reducing mortality was observed, and the mechanisms most likely involve the common effects of inflammation and lipid levels. On the other hand, the reported incidence and prevalence of JIA vary widely across the world. There has been no large-scale epidemiologic study involving long-term follow-up of JIA and JIA-associated uveitis in Asia. We identified 2636 cases of JIA from NHIRD from year 1999 to 2009. The average incidence of JIA and JIA-associated uveitis was 4.93 and 0.25 per 100,000 person-years, respectively. The average prevalence of JIA was 33.8 per 100,000 population. Higher percentage of males in patients with ERA and the strong association between ERA and uveitis are unique for children with JIA in Taiwan. Uveitis diagnosed before arthritis is an important risk factor for complications. The screening protocols of uveitis are not standardized among hospitals in Taiwan. This study may facilitate the optimization of guidelines for the screening and follow-up of JIA patients with uveitis in Taiwan. Further large-scale study with validation is required in SLE and JIA cohort to clarify whether genetic polymorphism leads to altered cytokine production and the involved inflammatory mechanism underlying the pathogenesis of autoimmune diseases. We will further explore the high-risk group beneficial for statin therapy (such as patients with elevated CRP), and the mechanism of statins and hydroxychloroquine in the process of atherosclerosis, inflammation and vascular protection. Advances in our understanding of the signaling pathway downstream endothelial dysfunction would lead to the development of novel targeted treatments for autoimmune diseases.
Subjects
systemic lupus erythematous
juvenile idiopathic arthritis
autoimmune
gene
hyperlipidemia
SDGs
Type
thesis
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