Abstract
BackgroundIt has been suggested that polymorphisms in Toll-like Receptors (TLRs) are associated with Rheumatoid Arthritis (RA), but the implicated alleles have differed between studies. The aim of this investigation was to explore whether polymorphisms of TLR genes are associated with RA in a predominantly Caucasian population from Denmark using a case–control approach.FindingsDNA samples (3 university hospital outpatient clinics) were obtained from patients with RA (n = 704) and healthy controls (n = 639) in a Danish population. TLR single nucleotide polymorphisms (SNPs) were selected based on the previously reported associations with chronic autoimmune diseases. Genotyping for the TLR SNPs was performed using Sequenom Multiplex technology.We identified one SNP in TLR3, [(rs3775291, P = 0.02, OR (95% CI) 1.31 (1.1087-1.5493)] significantly associated with the whole RA cohort. Subgroup analysis according to IgM rheumatoid factor (RF) and anti-cyclic citrinullated peptide (CCP) status suggested a significant association of sero-negative RA with the rs3775291 A allele and disease activity in this subset.ConclusionThese observations on a RA population of Danish ancestry suggest that variations in the TLR3 locus may be implicated in the pathogenesis of sero-negative RA. Since this TLR3 SNP has previously been associated with systemic lupus erythematous (SLE), the present findings support the notion that TLR3 genetic variants may represent a common risk factor in different chronic inflammatory conditions, including RA and SLE.
Highlights
It has been suggested that polymorphisms in Toll-like Receptors (TLRs) are associated with Rheumatoid Arthritis (RA), but the implicated alleles have differed between studies
These observations on a RA population of Danish ancestry suggest that variations in the TLR3 locus may be implicated in the pathogenesis of sero-negative RA
Since this TLR3 SNP has previously been associated with systemic lupus erythematous (SLE), the present findings support the notion that TLR3 genetic variants may represent a common risk factor in different chronic inflammatory conditions, including RA and SLE
Summary
Ascertainment of patients 704 RA patients were randomly recruited from 3 university hospital outpatient clinics. All patients fulfilled the American College of Rheumatology 1987 revised criteria for RA [9]. 639 controls were healthy individuals without RA, autoimmune or systemic disorders nor a family history of RA. The study was approved by the regional ethics committees of Southern and Mid Denmark (no S20090051 and 1-10-72-388-12). Characterization of disease activity and outcomes in patients Health Assessment Questionnaire (HAQ score, 0 to 3), Visual Analogue Scale (0 to 10) (VAS pain, global and doctor) and Disease Activity Score in 28 joints (DAS28 scale, 0 to 10) were calculated. Anti-CCP (IgG antibodies) was determined by a second-generation ELISA with 25 μg/ml as the cut-off point. IgMRF was detected by ELISA; the cut-off level was >16 IU/ ml (~95th percentile of healthy subjects)
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