Evidence of epistasis between interleukin 1 and selenoprotein-S with susceptibility to rheumatoid arthritis.
OBJECTIVE
Selenoprotein-S (SELS) is involved in the stress response within the endoplasmic reticulum (ER) and inflammation. Recently, promoter variants in the SELS gene were shown to be associated with plasma levels of interleukin (IL)6, IL1beta and tumour necrosis factor (TNF). It was hypothesised that these variants could influence rheumatoid arthritis (RA) susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL1, IL6 and TNF.


METHODS
Genotyping was performed in 988 unrelated healthy controls and 965 patients with RA. Stratified analysis was used to test for interactions. Single gene effects and evidence of epistasis were investigated using the Mantel-Haenszel (M-H) test and the linkage disequilibrium (LD)-based statistic.


RESULTS
No association of SELS -105 genotype and RA susceptibility was detected. Stratification of SELS -105 genotypes by IL1 -511 genotypes showed that the disease risk (comparing AA/GA to GG at the SELS -105 locus) in individuals with the GG/AG genotype at the IL1beta -511 locus was significantly lower than that in individuals having the AA genotype at the IL1beta -511 locus (odds ratio (OR): 0.9 and 2.3, respectively; p = 0.004 by M-H test). Significant epistasis was also detected using the LD-based statistic (p = <0.001). No interaction was observed between SELS -105 and IL6 or TNF variants.


CONCLUSIONS
Our results reveal evidence of strong epistasis in two genes in the IL1 production pathway and highlight the potential importance of gene-gene interactions in the pathogenesis of RA.
Marinou
I
I
School of Medicine & Biomedical Sciences, The University of Sheffield, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK.
Walters
K
K
Dickson
M C
MC
Binks
M H
MH
Bax
D E
DE
Wilson
A G
AG
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051140:Selenoproteins / Q000235:genetics*
D007375:Interleukin-1; D008565:Membrane Proteins; C487710:SELENOS protein, human; D051140:Selenoproteins