Polymorphisms within Toll-like receptors are associated with systemic lupus erythematosus in a cohort of Danish females.
OBJECTIVE
Toll-like receptors (TLRs) are pattern-associated receptors in innate immunity that may be involved in the recognition of self-antigens and the production of pathogenic autoantibodies. This study was undertaken to examine whether polymorphisms of TLR genes are associated with SLE and to determine the expression of various TLRs in peripheral blood mononuclear cells (PBMCs) of patients with SLE.


METHODS
The TLR polymorphisms in a cohort of 143 Danish lupus patients and 432 healthy Danish blood donors were analysed. Groups were age matched. Genotyping for the TLR single-nucleotide polymorphisms (SNPs) was performed using Sequenom Multiplex technology. In addition, the mRNA expression of TLRs in PBMCs from 56 SLE patients and 56 healthy controls was studies by quantitative real-time PCR.


RESULTS
We found a genetic association with SLE and three SNPs located within the TLR3, TLR8 and TLR9 genes (rs3775291, P = 0.006; rs37648, P = 0.013; rs352143, P < 0.02). Furthermore, the relative TLR7, TLR8, IFN-α and LY6E mRNA expression levels were significantly higher in SLE patients than in healthy controls (P < 0.0001, P < 0.0001, P = 0.0004 and P < 0.0001, respectively).


CONCLUSIONS
These results obtained from a female lupus population of Danish ancestry suggest that variations in TLR3, TLR8 and TLR9 genes are implicated in the pathogenesis of the disease. If these polymorphisms are associated with innate immune dysfunction they may add to the growing field of theoretically well founded new therapeutic targets.
Department of Biomedicine, Aarhus University, Bartholin Building 1240, Wilhelm Meyers Alle 4, 8000 Aarhus C, Denmark. laska@hum-gen.au.dk.
Magdalena Janina
MJ
Laska
Anne
A
Troldborg
Bettina
B
Hansen
Kristian
K
Stengaard-Pedersen
Peter
P
Junker
Bjørn Andersen
BA
Nexø
Anne
A
Voss
D000293:Adolescent; D000328:Adult; D005260:Female; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
D051193:Toll-Like Receptors; D012313:RNA
SLE; SNPs; TLRs; mRNA expression