Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children

Abstract

Intracellular Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (dsRNA) and activates antiviral immune responses through the production of type I interferons (IFNs) and inflammatory cytokines. This receptor binds to dsRNA molecules produced during human cytomegalovirus (HCMV) replication. TLR7 senses viral single-stranded RNA (ssRNA) in endosomes, and it can interact with endogenous RNAs. We determined the genotype distribution of single-nucleotide polymorphisms (SNPs) within the TLR3 and TLR7 genes in children with HCMV infection and the relationship between TLR polymorphisms and viral infection. We genotyped 59 children with symptomatic HCMV infection and 78 healthy individuals for SNPs in the TLR3 (rs3775290, c.1377C>T, F459F; rs3775291, c.1234C>T, L412F; rs3775296, c.-7C>A) and TLR7 (rs179008, c.32A>T, Q11L; rs5741880, c.3+1716G>T) genes. SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and capillary electrophoresis. The HCMV DNA load was quantified by real-time PCR. We found an increased frequency of the heterozygous genotype TLR3 L412F in children with HCMV infection compared with uninfected cases. In individuals with a mutation present in at least one allele of the L412F SNP, an increased risk of HCMV disease was found, and this result remained highly significant after Bonferroni’s correction for multiple testing (Pc < 0.001). The heterozygous genotype of this SNP was associated with the increased risk of HCMV disease in an adjusted model that included the HCMV DNA copy number in whole blood and urine (P < 0.001 and P = 0.008, respectively). Moreover, those with a heterozygous genotype of rs3775296 showed an increased relative risk of HCMV infection (P = 0.042), but this association did not reach statistical significance after correction for multiple testing. In contrast, the rs3775290 SNP of TLR3 and TLR7 SNPs were not related to viral infection. A moderate linkage disequilibrium (LD) was observed between the SNPs rs3775291 and rs3775296 (r2 = 0.514). We suggest that the L412F polymorphism in the TLR3 gene could be a genetic risk factor for the development of HCMV disease.

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

“…TLR3 gene has 6 exons and is located on chromosome 4q35.1 in humans. L412F polymorphism in the TLR3 gene may serve as a genetic risk factor for human cytomegalovirus (HCMV) infection in children [408]. In addition, variant TLR3 genotype rs5743312 (C9948T, intron 3, C > T) is also shown to be significantly associated with increased cancer risk [409].…”

‘From immunosenescence to immune modulation’: a re-appraisal of the role of cytomegalovirus as major regulator of human immune function

“…In relation to potential variables within the host, genetic polymorphism within our genome would certainly be predicted to impact on an individual's ability to either prevent primary infection or control established persistent infection. Indeed, a wide range of genetic analyses are starting to reveal important associations between genotype and both the risk of primary infection and clinical outcome (35)(36)(37)(38)(39)(40)(41)(42)(43)(44). This important consideration is likely to become even more apparent during the interrogation of very rich epidemiological cohorts that are now available.…”

Polymorphisms in pattern recognition receptor genes of indigenous and White Leghorn breeds of chicken

“…At least 10 NS SNPs (T50C, A203T, A274C, A293G, T999G, G1197C, G1538A, C1781T, C2108T and A2299T) were shared between chicken breeds in this study and Chi- nese breeds (Huang et al, 2012). Various studies have reported the relationship between polymorphisms in the TLR3 gene and resistance or susceptibility to different viral diseases in human beings (Kindberg et al, 2011;Sironi et al, 2012;Svensson et al, 2012;Lee et al, 2013;Studzińska et al, 2017). Similar relationships between polymorphisms in the TLR3 gene and resistance or susceptibility to various diseases could exist in chickens as well.…”