Study On The Genetic Susceptibility Of Behcet’s Disease And The Causal Association Between Various Components Of Metabolic Syndrome And Glaucoma-Related Traits

PART ONE THE ASSOCIATION OF GENETIC POLYMORPHISMS IN IL1RL1-IL18R1 REGION AND THE SUSCEPTIBILITY TO BEHCET’S DISEASE AND ITS FUNCTIONAL EXPLORATIONPurpose: Single nucleotide polymorphisms(SNPs)in the IL1RL1–IL18R1 region are associated with various immune-mediated diseases.This study was carried out to investigate the associations of functional variants in the IL1RL1–IL18R1 region with Behcet’s disease(BD)and elucidate the biological mechanisms underlying the associations.Methods: Nine candidate functional SNPs were prioritized with bioinformatics analysis,followed by a two-stage association study in 694 ocular BD patients and 1458 unaffected controls of Chinese Han population.Functional studies were performed in the peripheral blood mononuclear cells(PBMCs)of 45 healthy men and 16 active male BD patients.Genotyping was performed using the Mass ARRAY System.The m RNA expressions of IL1RL1,IL18R1,IL18 RAP,and SLC9A4 were assayed by real-time PCR and secretion of cytokines was examined by ELISA.Results: Significantly lower frequencies of the rs12987977 GG genotype/G allele,rs12999364 TT genotype/T allele,and rs4851569 AA genotype/A allele were observed in BD patients compared with the controls.Functional experiments revealed a downregulation of IL1RL1,IL18R1,and SLC9A4 and a decreased secretion of IFN-γ in the anti-CD3/CD28antibody-treated PBMCs as well as a decreased production of TNF-α in the lipopolysaccharide(LPS)-stimulated PBMCs in carriers of the protective homozygous rs12987977/GG genotype compared with the TT genotype.Conclusions: Our findings show that functional SNPs—rs12987977,rs12999364,and rs4851569—in the IL1RL1–IL18R1 region are associated with BD in a Chinese Han population.Certain genotype of rs12987977 may confer susceptibility to BD by influencing the expression of IL1RL1,IL18R1,and SLC9A4 and the secretion of IFN-γ and TNF-α.PART TWO ESTIMATING THE CAUSAL INFLUENCE OF VARIOUS COMPONENTS OF METABOLIC SYNDROME ON GLAUCOMA-RELATED TRAITS: A TWO-SAMPLE MENDELIAN RANDOMIZATION STUDYAims: This study aimed to examine possible causal associations between various components of metabolic syndrome and glaucoma-related traits.Methods: A two-sample Mendelian randomization study was conducted with the models of inverse-variance weighted,weighted median,and MR-Egger regression.We accessed data from publicly available genome-wide association studies for individual parameters of metabolic syndrome as the exposures and the data for glaucoma and its endophenotypes as the outcomes.Results: Among eleven exposures and six outcomes examined in this Mendelian randomization study,only fasting blood glucose level showed evidence of a causal influence on intraocular pressure.Results analyzed by the inverse-variance weighted model suggested that each one-SD increase in genetically predicted fasting blood glucose level was significantly associated with 0.80 SD elevation in intraocular pressure(β: 0.80,95%CI:0.38-1.22,P: 2.12e-4).The weighted median model(β: 0.78,95%CI:0.17-1.39,P: 0.012)showed a nominally significant effect and the MR-Egger model(β: 0.63,95%CI:-0.32-1.59,P: 0.212)showed a consistent direction of effect but was not statistically significant.Several sensitivity analyses including the intercept of MR-Egger regression,the leave-one-out plot,and the funnel plot indicated no evidence of directional horizontal pleiotropy that would bias the result.Conclusion: This Mendelian randomization study provides evidence for a causal role for genetically determined higher fasting blood glucose level in the development of increased intraocular pressure.This finding could be considered in the monitoring and control of intraocular pressure and prevention strategies for high-tension glaucoma.