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Title: Genetic susceptibility to rheumatoid arthritis
Author: MacKay, Kirsten Robyn
ISNI:       0000 0001 3615 4018
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2003
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The heritability of Rheumatoid Arthritis is approximately 60%. Although association with the HLA region is well recognised, these genes account for only 40% of the total genetic contribution. Linkage mapping and association studies need to proceed in parallel to identify which non-MHC genes are involved in the remaining 60% of the genetic contribution. The work described in this thesis represents a systematic approach to identifying these non-HLA effects, using genome-wide linkage mapping and candidate gene methods. To identify regions exhibiting genetic linkage to rheumatoid arthritis a systematic, whole genome linkage analysis was undertaken. Two hundred and fifty-one affected sibling pairs from 182 United Kingdom families were studied using 365 highly informative microsatellite markers. Highly significant linkage was identified around the HLA region on chromosome 6 (max LOD = 4.8 at 44.9cM, p=0.000001). Eighteen other sites of nominal linkage (p < 0.05) were identified on chromosomes 1, 2, 3, 4, 6, 7, 10, 12, 14, 16, 21 and the X chromosome by single point analysis (23 markers). Eight of the non-MHC regions (on chromosomes 1, 6, 7, 14, 16, 21, and X) also showed evidence of linkage by multi-point analysis. A parallel linkage study designed to replicate the 25 regions of nominal linkage (p < 0.05) reported following a genome-wide linkage study of 97 European affected sibling pair families was also undertaken. Fifty-nine microsatellites within the 25 regions of interest (including IDDM6 on chromosome 18 and IDDM9 on chromosome 3) were used to genotype 368 affected sibling pairs from 280 families. Markers on chromosomes 12, 15, and 21 (d12s95, CYP 19, d21s1252) showed evidence of nominal linkage with p values ≤ 0.05. Markers close to IDDM 6 on chromosome 18 showed p values of between 0.1 and 0.5, not lending additional support to a locus near IDDM6 in RA. Interleukin 10 (IL10), an immunoregulatory cytokine, is a potent up-regulator of B cell production and differentiation but has anti-inflammatory capabilities and can directly down-regulate TNF, IL1, IL8 and IFNy production. Data from twin and family studies suggest large inter-individual variations in secretion which are 75% heritable and as such IL10 is a plausible candidate gene for involvement in RA. It is highly polymorphic with point mutations in the promoter region and two microsatellite loci IL10.R and IL10.G, 1.1 and 4kb upstream of the transcription initiation site. Higher levels of IL10 secretion have been associated with allele 2 of IL10.R (IL10.R2) and IL10.R3 has been associated with decreased secretion. Additionally, a case-control study including two independent Caucasian populations and one African-American cohort found an over-representation of the IL10.R2 allele with a concomitant reduction of IL10.R3 in all three rheumatoid arthritis populations. Three studies investigating IL10 were undertaken. Two case-control studies including two cohorts of racially distinct RA patients (186 UK Caucasians with severe rheumatoid arthritis and 138 South Africans of Zulu or Sotho origin) were performed. An association with RA was not confirmed in either study but demonstrated significantly different frequencies of the IL10.R2 allele in the two study populations. The third study was a family-based association study and included 163 probands and their families. Single marker and haplotypic association analysis was performed by transmission disequilibrium testing (TDT analysis) using the software package TRANSMIT. The IL10.R1 allele was transmitted to affected individuals more frequently than expected (p < 0.05) and the IL10.R3 allele was transmitted less frequently than expected (p < 0.05). This effect was particularly pronounced with the IL10.R3/IL10.G10 haplotype (p < 0.005). The still stronger negative association identified with the IL10.R3/IL10.G10 haplotype suggested it was not IL10.R itself but another polymorphism on the particular haplotype that may be primarily involved with RA. The application of these methods to the examination of the genetic component of RA is discussed. Plans for future work include systematic genome-wide screening of positional candidates and evaluation of candidates from studies of other human and animal models of inflammatory disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine