A biologically important single nucleotide polymorphism within the toll-like receptor-4 gene is not associated with rheumatoid arthritis.
BACKGROUND
Rheumatoid arthritis (RA) is a heterogeneous condition affecting 1-2% of the population. Genetics account for 30% of disease susceptibility, with one third arising from the Major Histocompatibility Complex. The toll-like receptor 4 (TLR-4) gene which has been mapped to chromosome 9 (9q32-q33) is involved in innate immune recognition with subsequent proinflammatory cytokine release including TNF. A single nucleotide polymorphism (+896A-->G) resulting in the amino acid substitution (Asp299Gly) has been shown to interrupt TLR-4 mediated signalling.


OBJECTIVE
We sought to determine if this TLR-4 polymorphism influences susceptibility to rheumatoid arthritis.


METHODS
DNA was extracted from 879 healthy controls and 212 rheumatoid arthritis patients recruited from the north of England. Genotyping was performed using a 5' nuclease Taqman allelic discrimination assay. Allele frequencies were compared between the two groups. We also examined whether an association existed in non-carriers of the DRB1 shared epitope alleles.


RESULTS
The frequency of the rare allele was 5.9% in the controls and 7% in the patients. Comparison of rare allele carriage between controls and patients revealed no significant difference p = 0.13. This was also the case in shared epitope negative individuals p = 0.92.


CONCLUSIONS
The TLR-4 +896 polymorphism does not appear to influence susceptibility to rheumatoid arthritis.
Kilding
R
R
Division of Genomic Medicine, Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom. r.kilding@sheffield.ac.uk
Akil
M
M
Till
S
S
Amos
R
R
Winfield
J
J
Iles
M M
MM
Wilson
A G
AG
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D011956:Receptors, Cell Surface / Q000235:genetics*; D012016:Reference Values; D012680:Sensitivity and Specificity; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D005819:Genetic Markers; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors