Association of TLR4 gene non-missense single nucleotide polymorphisms with rheumatoid arthritis in Chinese Han population

Abstract

Toll-like receptor4 (TLR4) plays an important role in the induction and regulation of the innate or adaptive immune responses. Thus, the genetic variation in TLR4 gene may influence the development of autoimmune diseases such as rheumatoid arthritis (RA). Several studies have investigated the roles of genetic polymorphisms of TLR4 gene in RA, but most of these studies were restricted to two cosegregating functional missense polymorphisms Asp299Gly and Thr399Ile. To determine whether non-missense genetic polymorphisms located in regulatory region of TLR4 are related to RA in a Chinese Han population, four single nucleotide polymorphisms (SNPs) situated on 3' untranslating region (UTR) and 5' UTR were genotyped in 213 RA patients and 247 unrelated ethnically matched controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing techniques. Significant genetic associations were observed with the 3' UTR SNP rs41426344 and rs7873784. The minor allele C and homozygotic variant genotype CC of rs41426344 and minor allele C of rs7873784 were identified to be risk factors for the development of RA in Chinese Han people. Furthermore, by comparing the variation allele frequencies to other populations, prevalent genetic ethnic specificity was observed in all the four SNPs. Our study suggested that the effect of non-missense polymorphisms located in regulatory region would not be neglected in disease association analysis.

Association of Toll-like receptor polymorphisms with HIV status in North Americans

“… 50 , 64 – 66 The −1607C allele may be a risk factor for prostate cancer 47 and traffic-related air pollution-associated childhood asthma, 51 and the +12186C allele may be a risk factor for rheumatoid arthritis. 56 However, none of these studies looked into the possible mechanisms of these allelic associations. In female genital epithelial cells, TLR4 binds to HIV-1 gp120 and triggers pro-inflammatory cytokine production via activation of NF-kB.…”

“…A total of 45 SNPs in 8 TLR genes ( TLR1 , 2 , 3 , 4 , 6 , 7 , 8 , and 9 ), which have been evaluated in HIV/AIDS 28 – 35 and other infectious 36 – 45 as well as inflammatory and immune-mediated non-infectious 46 – 56 diseases, were included in the present study. These SNPs were located in promoter regions, 5′-UTRs, exons, introns, and 3′-UTRs ( Supplementary Table A ).…”

“…Many of the SNPs included in the study were from aforementioned HIV/AIDS studies. 28 – 35 Other SNPs, including those in TLR1 and TLR6 , have been evaluated in other infectious 36 – 45 as well as inflammatory and immune-mediated non-infectious 46 – 56 diseases. In addition to the SNP-based association analyses, we performed gene as well as heterodimer haplotype-based analyses.…”

Analysis of the genetic diversity in TLR4 3'-untranslated region among Asian populations and the biological effects of altofrequent SNPs

“…In addition, limited population-based genetic studies have demonstrated that the polymorphism loci of rs41426344, rs7873784, and rs11536891 are associated with the risk of rheumatoid arthritis and juvenile idiopathic arthritis [9,10], IgA nephropathy [6], and bipolar disorder [7]. In contrast, the luciferase activities of constructs corresponding to these variations produced almost constant levels of luciferase activity.…”

“…Analysis of the dbSNP database revealed 669 SNPs in the TLR4 3'-UTR (http://www.ncbi.nlm.nih.gov/SNP/). Only six of these SNPs (rs41426344, rs7869402, rs11536889, rs7873784, rs11536891, and rs11536896) had been analyzed in specific populations using case-control studies [6][7][8][9][10][11][12]. Of these SNPs, rs11536889 is the most extensively studied.…”