Dissection of class III major histocompatibility complex haplotypes associated with rheumatoid arthritis

Newton, J. L., Harney, S. M. J., Timms, A. E., Sims, A. M., Rockett, K., Darke, C., Wordsworth, B. P., Kwiatkowski, D., & Brown, Matthew A. (2004) Dissection of class III major histocompatibility complex haplotypes associated with rheumatoid arthritis. Arthritis and Rheumatism, 50(7), pp. 2122-2129.

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We have previously identified a single-nucleotide polymorphism (SNP) haplotype involving the lymphotoxin α (LTA) and tumor necrosis factor (TNF) loci (termed haplotype LTA-TNF2) on chromosome 6 that shows differential association with rheumatoid arthritis (RA) on HLA-DRB10404 and *0401 haplotypes, suggesting the presence of additional non-HLA-DRB1 RA susceptibility genes on these haplotypes. To refine this association, we performed a case-control association study using both SNPs and microsatellite markers in haplotypes matched either for HLA-DRB10404 or for HLA-DRB1*0401.


Fourteen SNPs lying between HLA-DRB1 and LTA were genotyped in 87 DRB104-positive families. High-density microsatellite typing was performed using 24 markers spanning 2,500 kb centered around the TNF gene in 305 DRB10401 or 0404 cases and 400 DRB10401 or 0404 controls. Single-marker, 2-marker, and 3-marker minihaplotypes were constructed and their frequencies compared between the DRB10401 and DRB1*0404 matched case and control haplotypes.


Marked preservation of major histocompatibility complex haplotypes was seen, with chromosomes carrying LTA-TNF2 and either DRB10401 or DRB10404 both carrying an identical SNP haplotype across the 1-Mb region between TNF and HLA-DRB1. Using microsatellite markers, we observed two 3-marker minihaplotypes that were significantly overrepresented in the DRB1*0404 case haplotypes (P = 0.00024 and P = 0.00097).


The presence of a single extended SNP haplotype between LTA-TNF2 and both DRB10401 and DRB10404 is evidence against this region harboring the genetic effects in linkage disequillbrium with LTA-TNF2. Two RA-associated haplotypes on the background of DRB1*0404 were identified in a 126-kb region surrounding and centromeric to the TNF locus.

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ID Code: 87781
Item Type: Journal Article
Refereed: Yes
Additional Information: No file attached.
Keywords: lymphotoxin, tumor necrosis factor, article, case control study, chromosome 6, controlled study, gene frequency, gene linkage disequilibrium, gene locus, genetic analysis, genetic association, genetic recombination, genotype, haplotype, human, major clinical study, major histocompatibility complex, microsatellite marker, polymerase chain reaction, priority journal, rheumatoid arthritis, single nucleotide polymorphism, Arthritis, Rheumatoid, Case-Control Studies, Chromosomes, Human, Pair 6, Genetic Predisposition to Disease, Haplotypes, HLA Antigens, HLA-DR Antigens, Humans, Linkage Disequilibrium, Lymphotoxin-alpha, Microsatellite Repeats, Polymorphism, Single Nucleotide, Tumor Necrosis Factor-alpha
DOI: 10.1002/art.20358
ISSN: 0004-3591
Divisions: Current > Schools > School of Biomedical Sciences
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 28 Sep 2015 05:29
Last Modified: 28 Sep 2015 05:29

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