Serum cytokine profiles of SLE patients and their correlations to susceptibility genes

Professor Lau, Yu Lung   (Principal Investigator (PI))

Professor Yang Wanling   (Co-Investigator)

12

2010-11-01

50811

Serum cytokine profiles of SLE patients and their correlations to susceptibility genes

cytokines, Systemic Lupus Erythematosus

Genetic Disease,Rheumatology

201007176147

Small Project Funding

2010

Completed

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease characterized by various aberrations in the immune system, leading to formation of autoantibodies against nucleic acid and associated proteins and finally, multiple end-organ damage. Due to the tissue damage caused by immune complex deposition and inflammatory processes, SLE usually presents a diverse spectrum of clinical symptoms, including skin manifestation, oral ulcers, arthritis, renal involvement, and central nervous system damage. Both genetic and environmental factors contribute to the etiology of this disease. Large-scale genome-wide association studies (GWAS) have seen many successes in identifying the major risk alleles involved in several complex diseases, including SLE[1, 2]. A GWAS in our group has made discoveries on several novel SLE susceptibility genes[2-5]. An on-going effort in our group is to look for potential correlations between genetic variations and clinical manifestations. For the reasons described in the following, we believe that adding serum cytokine levels into this endeavor as intermediate phenotypes will greatly help our chances to better understand the disease mechanisms and the roles that genetics play in this deadly disease. Despite initial great successes, recently, GWAS seems having encountered a bottleneck because of the exhaustion of the ""low hanging fruits"". Indeed, gene-hunting expeditions by GWAS have shown some weakness in identifying common alleles with mild genetic effects. True but weaker association signals usually are buried in the ocean of false positive and false negative signals. For that reason, well-controlled stratification based on clinical phenotypes seems to be a way out for solving such problems, considering that certain association might only exist in patients with particular types of clinical manifestations. However, since patients are enrolled from different hospitals, their clinical records are far from complete, uniform, and updated. Thus, other biomarkers might be explored to enhance the approach of subphenotype stratification and help with the search of more susceptibility genes involved in the disease. Numerous pieces of evidence have demonstrated that almost all the immune lineages are involved in the pathogenesis of SLE. Cytokines trafficking through immune system mediate signals for different cellular events, and diverse cytokines secreted by various immune cells constitute a complicated cytokine network. Literatures suggest a burgeoning number of cytokines are also involved in the pathogenesis of SLE. Some of the cytokines that are associated with SLE undoubtedly contribute to disease pathogenesis, while others might reflect compensatory mechanisms that are failing to inhibit the development of autoimmunity. Therefore, it is considered that cytokine profiles might represent a missing piece for bridging genetic variants and clinical abnormalities. Serum levels of some cytokines, such as IL-6, IL-10[6], IL-17[7], IL-18[8], and IFN-α[9] etc were reported to alter in SLE, and correlate with disease activity. Thus, cytokine profiles may give us a valuable piece of information in inferring disease activity, and may provide great help to link genetic variants with cellular abnormalities, and ultimately clinical manifestations. Recently, our GWAS work identified rs1128334, a single nucleotide polymorphisms (SNP) located in the 3’-UTR of ETS1, to be associated with SLE in Asian population[3]. Our preliminary result also demonstrated lower gene expression level as well as increased serum level of IL-17 in the risk allele carriers, which is consistent with the negative role of ETS1 in regulating Th17 cells. Such observations support the feasibility of using cytokine information in genetic studies. In this proposal, using the technique of multiplex assay, we aim to establish a platform that examines 20 cytokines profiles in a multiplex format on Hong Kong SLE patients. By so doing, we could add valuable information and to improve the accuracy of our association studies. Besides, we also aim to investigate the intrinsic correlation between genetic variants and cytokine alterations, which should be important for a better understanding of the disease mechanisms both in genetic and in functional aspects. Reference 1. Han, J.W., et al., Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet, 2009. 41(11): p. 1234-7. 2. Chang, Y.K., et al., Association of BANK1 and TNFSF4 with systemic lupus erythematosus in Hong Kong Chinese. Genes Immun, 2009. 10(5): p. 414-20. 3. Yang, W., et al., Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet, 2010. 6(2): p. e1000841. 4. Yang, W., et al., ITGAM is associated with disease susceptibility and renal nephritis of systemic lupus erythematosus in Hong Kong Chinese and Thai. Hum Mol Genet, 2009. 18(11): p. 2063-70. 5. Yang, W., et al., Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese. Genes Immun, 2009. 10(3): p. 219-26. 6. Chun, H.Y., et al., Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin Immunol, 2007. 27(5): p. 461-6. 7. Shah, K., et al., Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther, 2010. 12(2): p. R53. 8. Wong, C.K., et al., Elevation of plasma interleukin-18 concentration is correlated with disease activity in systemic lupus erythematosus. Rheumatology (Oxford), 2000. 39(10): p. 1078-81. 9. Dall'era, M.C., et al., Type I interferon correlates with serological and clinical manifestations of SLE. Ann Rheum Dis, 2005. 64(12): p. 1692-7.