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Title: Identification of rheumatoid arthritis susceptibility genes mapping to regions of linkage homologous to those identified in animal models of inflammatory arthritis
Author: Spreckley, Kristian B. S.
ISNI:       0000 0001 3475 6082
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2007
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Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease in which both environmental and genetic components interact to determine disease susceptibility. Animal models of disease potentially provide a mechanism to dissect out genetic and environmental susceptibility factors. Animal models of RA, in which arthritis is induced in susceptible rats or mice, have identified several regions of linkage. The aim of the current study was to investigate three candidate RA susceptibility regions, homologous to those identified in animal models of inflammatory arthritis, to identify RA susceptibility genes. Complementary approaches were used to investigate regions of interest. Firstly, gel1e expression studies were used to investigate the oil-induced arthritis (Oia) 3 susceptibility region, homologous to human chromosome 17q23. Gene expression was investigated using cDNA from lymph node and spleen tissue of three rat variants. Gene expression was investigated in 34 genes common to both homologous regions. Two genes, ICAM2 and PSMC5, were found to be differentially expressed in spleen tissue of susceptible and resistant rat strains. The ICAM2 gene was resequenced to identify novel variants and these were tested for association with RA. However, no evidence for association was detected. The PSMC5 gene and a further 20 genes that were found-to be expressed in the rat tissues were prioritised for association studies. Secondly, human chromosome 12p13, homologous to the rat Oia2 susceptibility locus, was investigated initially using linkage analysis in RA families but no evidence for linkage to the region was detected. Twelve candidate genes mapping within the refined O.ScM Oia2 region of linkage in rat models were tested for association with RA. Nine single nucleotide polymorphisms (SNPs) were found to be associated in the initial screening cohort. Five of these 9 SNPs were successfully genotyped in a larger cohort but the association was not replicated. In a combined analysis only 1 SNP, rs7963015 mapping to the CIS gene, remained associated (P=0.03) by carriage of 2 copies of the minor allele. Following further genotyping in additional control samples (n = 2024), 1 SNP, rs4322490 mapping to the CLEC4A gene, was found to be significantly associated with RA (P=2.4xl0-6). However, due to differences between control allele frequencies compared to previously reported findings, this SNP will require further testing to validate the result. The third approach was to perform association testing directly of a candidate RA susceptibility gene selected from literature searches. The complement 5 (C5) gene was selected as it maps under peaks of linkage identified in animal models of inflammatory arthritis and in studies ofRA families. Nineteen SNPs were selected to span the C5 gene but none of these SNPs showed evidence for association with RA. The use of animal models to inform studies investigating genetic susceptibility underlying common human diseases is particularly attractive because environmental factors can be kept constant between resistant and susceptible animal strains, eliminating this as a confounding factor in studies of complex disease. However, despite investigating 3 candidate regions in the human genome, selected because the homologous regions showed evidence for linkage with experimental arthritis in rats, using a variety of approaches, none of the regions shows convincing evidence for association with RA. As results of whole genome association studies of complex diseases emerge, it is clear that hypothesis-free study designs are achieving success in identifying susceptibility genes and this type of approach is likely to be used more in the future.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available