Linkage and association studies of single-nucleotide polymorphism-tagged tumor necrosis factor haplotypes in juvenile oligoarthritis.
OBJECTIVE
The presence of increased levels of tumor necrosis factor (TNF) in serum and synovial fluid of patients and the encouraging outcome of anti-TNF therapy have implicated TNFalpha in the etiopathogenesis of juvenile oligoarthritis. Although the locus is polymorphic, no study has investigated all TNF single-nucleotide polymorphisms (SNPs) with respect to disease. The aim of this study was to examine the association of multiple TNF SNPs with juvenile oligoarthritis and to construct and analyze SNP-tagged TNF haplotypes.


METHODS
A total of 144 simplex families consisting of parent and affected child, as well as 88 healthy, unrelated control subjects were available for study. In these individuals, 9 polymorphic positions of TNF were typed by a high-throughput genotyping method based on the SNaPshot assay. The chi-square and extended transmission disequilibrium tests were used to test for association and linkage, respectively. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were also calculated. Haplotype-tagging SNPs (htSNPs) for the locus were identified by ordering the haplotypes according to their frequencies.


RESULTS
The study detected association of several TNF SNPs and established linkage of the locus to juvenile oligoarthritis. The most significant association observed was between the intronic +851 TNF SNP and the persistent oligoarthritis subgroup (OR 3.86, 95% CI 1.6-9.2). Haplotype data mining showed that only 4 of the 9 SNPs need to be typed in order to capture the most frequent TNF haplotypes.


CONCLUSIONS
The TNF locus is linked and associated with juvenile oligoarthritis. Information on the htSNPs can be useful in genetic studies of diseases in which TNF may be of relevance.
Zeggini
Eleftheria
E
Arthritis Research Campaign Epidemiology Unit, University of Manchester, Manchester, UK. eleftheria@fs1.ser.man.ac.uk
Thomson
Wendy
W
Kwiatkowski
Dominic
D
Richardson
Anna
A
Ollier
William
W
Donn
Rachelle
R
D000328:Adult; D001171:Arthritis, Juvenile / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016324:Sequence Tagged Sites; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha