title: 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.
authors.affiliation: Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland.
authors.forename: Mirosława
authors.initials: M
authors.lastname: Studzińska
authors.affiliation: Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jabłońska
authors.affiliation: Department of Pediatrics, Immunology, and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Wiśniewska-Ligier
authors.affiliation: Department of Perinatology and Gynecology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Nowakowska
authors.affiliation: Department of Perinatology and Gynecology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Gaj
authors.affiliation: Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland.
authors.forename: Zbigniew J
authors.initials: ZJ
authors.lastname: Leśnikowski
authors.affiliation: 3rd Department of Pediatrics, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
authors.forename: Teresa
authors.initials: T
authors.lastname: Woźniakowska-Gęsicka
authors.affiliation: 2nd Department of Obstetrics and Gynecology, Warsaw Medical University, Warsaw, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Wilczyński
authors.affiliation: Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland.
authors.forename: Edyta
authors.initials: E
authors.lastname: Paradowska
mesh_terms: D000483:Alleles; D000998:Antiviral Agents; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000235:genetics*; D004279:DNA, Viral / Q000097:blood / Q000652:urine; D011992:Endosomes / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007223:Infant; D015810:Linkage Disequilibrium; D008297:Male; D015233:Models, Statistical; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D051196:Toll-Like Receptor 3 / Q000235:genetics*; D051199:Toll-Like Receptor 7 / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; C495344:TLR3 protein, human; C495348:TLR7 protein, human; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7