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Title: The molecular genetic basis of the association of TNFSF4 with SLE
Author: Manku, Harinder
ISNI:       0000 0005 0732 3897
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4), also known as OX40L, is an established susceptibility locus in the autoimmune disease systemic lupus erythematosus (SLE). Genetic association studies map polymorphisms that associate with disease, but linkage disequilibrium often hinders the identification of the actual casual allele(s) at a disease susceptibility locus. At TNFSF4 genetic association studies had shown that an extended 100kb haplotype upstream of the coding region of the gene was associated with SLE risk. The principle aim of the project was to conduct genetic association analyses in cohorts with different ancestry in an attempt to fine map the TNFSF4 association signal and thereby identify the causal genetic variants that underlie the genetic risk. Utilizing >17,900 subjects of European, African-American, Hispanic-American and Southeast Asian ancestry a transancestral fine mapping analysis was performed. The results demonstrate the strong association of TNFSF4 risk alleles in all populations tested. The most consistent and strongest evidence of association came from the single nucleotide polymorphism (SNP), rs2205960-T (P = 7.1 x 10-32, odds ratio = 1.63). This variant was also associated with autoantibody production in three independent cohorts. In silico analysis of the DNA sequence encompassing rs2205960-T predicts it to form part of a decameric motif, which binds the RelA (p65) component of the NF-κB transcription factor complex. A second associated SNP, rs16845607-A in TNFSF4 intron 1 was identified in Hispanic-Americans (P = 9.17 x 10-9, odds ratio = 2.06). In an attempt to further refine the association, resequencing was performed in 80 individuals who were selected on the basis of their genotype to carry risk or non-risk haplotypes upstream of TNFSF4. This sequencing study identified >200 novel variants, mostly small insertion-deletion polymorphisms indels. The data presented in this thesis largely resolves the genetic basis of the immediate upstream association signal observed at TNFSF4 with SLE and will facilitate the unraveling of the molecular basis of this genetic risk in systemic autoimmunity.
Supervisor: Vyse, Tim Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral