Toll-like receptor 4 gene polymorphisms in polymyalgia rheumatica and elderly-onset rheumatoid arthritis.
OBJECTIVE
Coding variants in TLR4 gene have been reported to be associated with inflammatory diseases. The aim of this study was to determine whether two of these polymorphisms (Asp299Gly and Thr399Ile) of TLR4 contribute to the genetic background of polymyalgia rheumatica (PMR) and elderly-onset rheumatoid arthritis (EORA). Furthermore, we have attempted to correlate the functional consequences of these polymorphisms.


METHODS
164 patients with PMR, 93 with EORA and 126 unrelated age-matched controls were genotyped. The TLR4 genotypes were determined using allele-specific primers and restriction fragment length polymorphism analysis. Association of genotypes and alleles with disease susceptibility and disease phenotypes were studied. TLR4 expression was assessed on PBMCs by flow cytometry and TLR4 function was assessed by stimulating PBMCs in vitro with LPS.


RESULTS
No significant difference in allele frequency or genotype between patients with elderly-onset inflammatory conditions and controls was observed. The Thr399Ile CC genotype was associated with a higher cumulative dose of corticosteroids in patients with PMR (p=0.031). We found no association with TLR4 expression on B cells, T cells or monocytes or a distinct phenotype of TLR4 response with the Asp299Gly or Thr399Ile genotypes.


CONCLUSIONS
These results do not support the association of these TLR4 variants with two age-related inflammatory conditions. The value of determining Thr399Ile genotypes for disease prognosis in PMR should be confirmed in different populations.
Division of Rheumatology, Hospital Universitario Marques de Valdecilla-IFIMAV-Universidad de Cantabria, Spain. lorenalvar@hotmail.com
Lorena
L
Alvarez-Rodriguez
Marcos
M
López-Hoyos
Ignacio
I
Beares
Cristina
C
Mata
Maite
M
Garcia-Unzueta
Jaime
J
Calvo-Alen
Ricardo
R
Blanco
Elena
E
Aurrecoechea
Gaurav
G
Tripathi
Victor Manuel
VM
Martinez-Taboada
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011111:Polymyalgia Rheumatica / Q000235:genetics* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics*
C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4