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


CONCLUSIONS
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.
Newton
Julia L
JL
Wellcome Trust Centre for Human Genetics, Oxford, UK.
Harney
Sinéad M J
SM
Timms
Andrew E
AE
Sims
Anne-Marie
AM
Rockett
Kirk
K
Darke
Chris
C
Wordsworth
B Paul
BP
Kwiatkowski
Dominic
D
Brown
Matthew A
MA
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006680:HLA Antigens / Q000145:classification / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008233:Lymphotoxin-alpha / Q000235:genetics; D018895:Microsatellite Repeats; D020641:Polymorphism, Single Nucleotide; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D006680:HLA Antigens; C488436:HLA DRB1*04:04 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D008233:Lymphotoxin-alpha; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha