Dissection of class III major histocompatibility complex haplotypes associated with RA

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Arthritis Rheum. 2004 Jul;50(7):2122-9.

Dissection of class III major histocompatibility complex haplotypes

associated with rheumatoid arthritis.

Newton JL, Harney SM, Timms AE, Sims AM, Rockett K, Darke C, Wordsworth

BP, Kwiatkowski D, Brown MA.

Wellcome Trust Centre for Human Genetics, Oxford, UK.

OBJECTIVE: We have previously identified a single-nucleotide

polymorphism (SNP) haplotype involving the lymphotoxin alpha (LTA) and

tumor necrosis factor (TNF) loci (termed haplotype LTA-TNF2) on

chromosome 6 that shows differential association with rheumatoid

arthritis (RA) on HLA-DRB1*0404 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-DRB1*0404 or for HLA-DRB1*0401.

METHODS: Fourteen SNPs lying between HLA-DRB1 and LTA were genotyped in

87 DRB1*04-positive families. High-density microsatellite typing was

performed using 24 markers spanning 2,500 kb centered around the TNF

gene in 305 DRB1*0401 or *0404 cases and 400 DRB1*0401 or *0404

controls. Single-marker, 2-marker, and 3-marker minihaplotypes were

constructed and their frequencies compared between the DRB1*0401 and

DRB1*0404 matched case and control haplotypes. RESULTS: Marked

preservation of major histocompatibility complex haplotypes was seen,

with chromosomes carrying LTA-TNF2 and either DRB1*0401 or DRB1*0404

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).

CONCLUSION: The presence of a single extended SNP haplotype between

LTA-TNF2 and both DRB1*0401 and DRB1*0404 is evidence against this

region harboring the genetic effects in linkage disequilibrium 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.

PMID: 15248209

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