Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.784178
Title: Identification of single nucleotide polymorphisms predicting susceptibility of ankylosing spondylitis and the response to anti-TNFα therapy
Author: Tong, Qiang
ISNI:       0000 0004 7969 7428
Awarding Body: University of Huddersfield
Current Institution: University of Huddersfield
Date of Award: 2018
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Abstract:
INTRODUCTION: Different genetic features may result in different incidences of diseases, treatment response and adverse events following medical therapy. The studies included in this thesis collectively aim to identify polymorphisms associated with ankylosing spondylitis (AS) and those can predict therapeutic efficacy and adverse events of anti-tumor necrosis factor-α (TNFα) treatment in Chinese Han patients. METHODS: We performed a case-control study including 149 Chinese Han ankylosing spondylitis patients ethnicity- and gender-matched to 106 healthy controls, and genotyped 14genes encompassing 28 short nucleotide polymorphisms (SNPs) by using the Matrix-assisted Laser Desorption/ionization-time of Flight Mass Spectrometry technique in order to evaluate which genes and SNPs are associated with AS. Furthermore, we performed genotyping on 106 Chinese Han patients with AS, who received infliximab or a recombinant human TNFα receptor II-IgG Fc fusion protein (rhTNFR-Fc) therapy, for evaluating associations between drug response and polymorphisms of TNFα gene -238, -308, -857, and -1031. We also conducted a meta-analysis on the same set of SNPs in 211 spondyloarthritis (SpA) patients and 392 inflammatory bowel disease (IBD) to validate their capability in predicting response toward anti-TNFα therapy. Finally, 402 Chinese AS patients with anti-TNFα monotherapy were monitored for short-term adverse events within two hours. Additionally, long-term adverse effects of anti-TNF therapy were profiled for 172 patients at 8, 12, 52, and 104 weeks, and their incidences were analyzed for the frequency of the aforementioned SNPs of TNFα gene. RESULTS: We demonstrated that SNPs in TNFα-857 (rs1799724, p=0.0002), TNFα-308 (rs1800629, p=0.0484), tumor necrosis factor receptor super-family 1A (TNFRSF1A) (rs4149577, p=0.0087), human leukocyte antigen B27tagged (HLA-B27tagged) (rs4349859, p=0.0004), and interleukin 23 receptor (IL-23R) (rs1004819, p=0.0131), have close associations with AS. Regarding the pharmacogenomics of infliximab and rhTNFR-Fc therapy, we revealed that TNFα -857 C/C and -1031 T/T genotypes were significant predictors of treatment response. The results from meta-analysis showed that TNFα genotypes -308 G/G (p = 0.0020) and -857 C/C (p = 0.0100) responded better to anti-TNFα therapy. By analyzing the side effects of TNF inhibitors (TNFi), we found elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as well as the duration of disease are highly associated with increased risk for short-term and long-term adverse events (p < 0.05). Additionally, rhTNFR-Fc therapy was associated with less adverse events than Infliximab during long-term treatment (p < 0.01). However, when we correlated the SNP frequencies in TNFα genes to the occurrence of adverse events, none of them was found to be an effective predictor of side effects in AS patients treated with TNF blockers. CONCLUSION: Collectively, these studies outline AS-related SNPs in Chinese Han patients. In particular, SNPs at promoter regions of TNFαare closely associated with the predisposition of SpA and IBD, and responsiveness to anti-TNFα therapy. The prevalence of short- and long-term adverse events of TNFi monotherapy were profiled and were not associated with SNPs at TNFα promoter. Future studies are expected to confirm these findings in larger cohorts and perhaps establish these SNPs as reliable biomarkers at clinics.
Supervisor: McHugh, Patrick Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.784178  DOI: Not available
Keywords: R Medicine (General)
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