A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex genetic basis that includes susceptibility gene(s) within the chromosome 1q41-1q42 region. Toll-like receptor 5 (TLR5), the innate immune receptor for bacterial flagellin, maps to chromosome 1q41 and contains a common stop codon polymorphism that abrogates signaling (allele C1174T) and is associated with an increased risk of infection. By using transmission disequilibrium testing in a cohort containing 199 affected patients and their 75 unaffected siblings and 326 parents, we found that allele 1174C, but not 1174T (with the stop codon), was preferentially transmitted to SLE-affected offspring (a 19:6 transmitted/not transmitted ratio, P = 0.009). In contrast, the alleles of the other three TLR5 SNPs did not exhibit preferential transmission. In addition, we found that allele 1174C was not preferentially transmitted to unaffected offspring (3:6 transmitted/not transmitted ratio, P value not significant). The allele frequency of 1174T in the probands was 3.2% compared with 5.8% in unaffected individuals, which was consistent with a protective association (odds ratio, 0.51; 95% confidence interval, 0.26-0.98; P = 0.041). Subjects with the TLR5 stop codon produced significantly lower levels of proinflammatory cytokines in comparison with individuals with the wild-type genotype. Together, these results indicate that the TLR5 stop codon polymorphism is associated with protection from the development of SLE. These data support a role for flagellated bacteria and the innate immune response in the development of SLE with implications for novel immunomodulatory treatment strategies.
Hawn
Thomas R
TR
Department of Medicine, University of Washington School of Medicine, 1959 Northeast Pacific Street, Seattle, WA 98105, USA. thawn@u.washington.edu
Wu
Hui
H
Grossman
Jennifer M
JM
Hahn
Bevra H
BH
Tsao
Betty P
BP
Aderem
Alan
A
D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D018388:Codon, Terminator / Q000235:genetics*; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D051198:Toll-Like Receptor 5 / Q000235:genetics*
D018388:Codon, Terminator; D016207:Cytokines; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5