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Relevance of Single-Nucleotide Polymorphisms in Human TLR Genes to Infectious and Inflammatory Diseases and Cancer

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Relevance of Single-Nucleotide Polymorphisms in Human TLR Genes to Infectious and Inflammatory Diseases and Cancer Genes and Immunity (2014) 15, 199–209 & 2014 Macmillan Publishers Limited All rights reserved 1466-4879/14 www.nature.com/gene REVIEW Relevance of single-nucleotide polymorphisms in human TLR genes to infectious and inflammatory diseases and cancer A Trejo-de la O1,3, P Herna´ndez-Sance´n2,3 and C Maldonado-Bernal1 Innate and adaptive immune responses in humans have evolved as protective mechanisms against infectious microorganisms. Toll-like receptors (TLRs) have an important role in the recognition of invading microorganisms. TLRs are the first receptors to detect potential pathogens and to initiate the immune response, and they form the crucial link between the innate and adaptive immune responses. TLRs also have an important role in the pathophysiology of infectious and inflammatory diseases. Increasing data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single-nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to infectious or inflammatory disease that might contribute to the pathogenesis of complex diseases such as cancer. The associations between diseases and SNPs are in the early stage of discovery. Important clinical insights are emerging, and these polymorphisms provide new understanding of common diseases. This review summarizes and discusses the studies that shed light on the relevance of these polymorphisms in human infectious and inflammatory diseases and cancer. Genes and Immunity (2014) 15, 199–209; doi:10.1038/gene.2014.10; published online 13 March 2014 INTRODUCTION complex1,9 and is also involved in the signaling response to other The family of Toll-like receptors (TLRs) has been identified as key exogenous stimuli. TLR5 binds flagellin, a bacterial protein 1,10 host molecules in the induction of the innate immune response to involved in motility, and TLR9 recognizes CpG, a repetitive microbial ligands.1 TLRs constitute a family of transmembrane sequence of unmethylated nucleic acids (guanine and 1,11 proteins, each of which recognizes a different spectrum of cytosine). The significance of individual TLRs in protection pathogen-associated molecular patterns that are unique to against infectious disease has been demonstrated clearly. microorganisms and are highly conserved across several species However, recent reports suggest that this family of receptors of microorganism. This ability of TLRs to recognize a broad have a substantial role in both the response to infectious diseases spectrum of microbial molecules enables the host to detect the and other types of pathology in which inflammation has a crucial 12 13 14 presence of pathogens rapidly before more widespread infection role, such as atherogenesis, diabetes and even cancer. TLRs 15 occurs.1 are also very important to homeostasis of the organism. To date, 11 related human TLRs (TLR1–11) have been identified The ability to respond properly to TLR ligands may be impaired and characterized,2–5 all of which share structural features by single-nucleotide polymorphisms (SNPs) within TLR genes, and (Figure 1). For example, the extracellular domain of TLRs is many reports have suggested that genetic variations in these characterized by leucine-rich repeats, which are associated with genes are related to susceptibility to diseases. The first report to TLR–ligand interactions, and an intracellular domain, which demonstrate a mutation in a TLR gene that had a physiological exhibits the Toll/interleukin-1 (IL-1) receptor domain. The Toll/IL-1 implication was the mutation detected in the mouse strain C3H/ 16,17 receptor binds to other Toll/IL-1 receptor domains of intracellular HeJ, which has a proline-to-histidine substitution at amino adaptor molecules and mediates a signaling cascade that includes acid (aa) 712 in the TLR4 protein. This variation causes an LPS- a complex series of intermediates that lead to deactivation of hyporesponsive phenotype, which makes this strain of mouse 16,17 nuclear factor-kB (NF-kB). The end result of TLR signaling is more susceptible to Gram-negative bacterial infections. upregulation of proinflammatory mediators, cytokines and chemo- Several SNPs have been reported recently in the human genes kines, and induction of the adaptive immune response.4,5 for TLRs (TLR1–10), and reports have also suggested that these All TLRs can initiate inflammation, and differences in the SNPs have a functional impact on and medical relevance to a inflammatory response between different TLRs have been wide variety of human diseases (Figure 2 and Table 1). It is documented. TLRs vary by their ligand specificity, which is important to mention that, to date, there are no reports regarding determined by the extracellular portion of the receptor. TLR2 polymorphisms in TLR11. recognizes a variety of microbial components, including lipopro- tein from pathogens, lipoteichoic acid and peptidoglycan.1,6 TLR3 is the receptor for double-stranded RNA,1,7 and TLR7 and TLR1 POLYMORPHISMS TLR8 are receptors for single-stranded RNA.1,8 TLR4 is the signal- TLR1 is mapped to chromosome 4p14 and is encoded by one transducing element of the lipopolysaccharide (LPS) receptor exon. The protein recognizes triacyl lipopeptides and soluble 1Laboratorio de Investigacio´n en Inmunologı´a y Proteo´ mica, Hospital Infantil de Me´xico Federico Go´mez, Me´xico City, Me´xico and 2Departamento de Asesorı´a Molecular, Roche Diagnostics Me´xico, Me´xico City, Me´xico. Correspondence: Dr C Maldonado-Bernal, Laboratorio de Investigacio´n en Inmunologı´a, Hospital Infantil de Me´xico Federico Go´mez, Dr Ma´rquez No. 162 Col. Doctores, C.P, Me´xico City 06720, Me´xico. E-mail: [email protected] 3These authors contributed equally to this work. Received 9 September 2013; revised 30 January 2014; accepted 3 February 2014; published online 13 March 2014 TLR polymorphisms and human diseases A Trejo-de la O et al 200 Triacyl Diacyl LPS lipopetides lipopeptides Mannans Flagellin Profillin TLR1 TLR5 TLR2 TLR6 TLR2 TLR4 TLR11 NF-B p38 MAPK JNK IRFs Transcription factors TLR8 TLR7 TLR9 TLR3 dsRNA ssRNA DNA Inflammatory cytokines Immune regulation Endosome Proliferation Survival Figure 1. TLRs and their main ligands. dsRNA, double-stranded RNA; LPS, lipopolysaccharide; ssRNA, single-stranded RNA. factors of Neisseria meningitides, and is functionally associated with mycobacteria; TLR1 has an important role in discriminating TLR2.18 In 2006, Sun et al.19 reported the presence of 11 SNPs in between different microbial components. Previous reports have this gene in the Swedish population. Three of these SNPs were shown that SNPs in this gene modify the activation of its protein, more frequent in patients with prostate cancer than in controls; implying that the genetic variation in the TLR1 gene might affect two of the SNPs were located in the promoter region, À 7202A/G the innate immune response and clinical susceptibility to a wide to À 6399C/T; and the third was located in the intron of the gene spectrum of pathogens. These SNPs may also confer a higher risk ( À 833C/T) (Table 1). The À 6399T allele had a synergistic for prostate cancer, but may confer protection against GC and effect when interacted with 7987G/C and 652T/C variants in leprosy.19,21,22 However, because the biological relevance of these IRAK4 (IL-1 receptor-associated kinase 4) and increased the risk of SNPs has yet to be proven, their clinical relevance requires developing prostate cancer. We know that the chronic or confirmation. recurrent inflammation is a causal factor in several human malignancies, including prostate cancer. Genetic predisposition is also a strong risk factor in the development of prostate TLR2 POLYMORPHISMS cancer. In particular, the TLR6-1-10 gene cluster is involved in TLR2 recognizes a variety of microbial components and was the prostate cancer development, and IRAK1 and 4 are critical first human TLR involved in host defense to be described. The components in the TLR signaling pathway. On the other TLR2 gene has two exons located in 4q32. hand, SNP À 7202A/G alters the putative core binding site of In 2000, Lorenz et al.24 described the substitution of a guanine the proto-oncogene PU.1. for an adenine at 2258 bp, a change that results in an arginine-to- Another SNP in the codifying region, T1805G, which changes an glutamine substitution at residue 753. When this SNP is isoleucine to a serine at aa 602 (I602S) in the extracellular region transfected into human embryonic kidney 293 (HEK293) cells, (Figure 3), diminishes the activation of NF-kB, and the synthesis of the minor allele affects the ability of the cells to respond to IL-6 diminished the inflammatory response.20 This SNP (I602S) bacterial peptides in vitro, and the cells are not activated in affects the function and cell surface expression of TLR1 and its response to these peptides. Mononuclear cells of individuals ability to transport TLR1 to the cell surface; this SNP seems to be a heterozygous for the SNP Arg753Gln exhibit less induction of protective factor against leprosy.21 About homozygous 602S allele, tumor necrosis factor-a (TNF-a) and interferon-g upon stimulation recently Yang et al.22 found that it is associated with a reduced risk with Borrelia lysate compared with individuals not exhibiting this of Helicobacter pylori-induced gastric diseases, such as gastric variation,25 although this seems to protect from the development cancer (GC) and peptic ulcer, probably via diminished T helper of late-stage Lyme disease rather than being a risk factor for the type 1 responses. disease. This 753Q allele is associated with a higher risk of Omueti et al.23 studied three SNPs found in the extracellular developing tuberculosis.26 In children, the SNP is a predisposing region of the protein: S248N, H305L and P315L. All three exhibited factor for urinary tract infection by Gram-positive pathogens27 and attenuated responses to synthetic lipopeptides and microbial increases the risk of recurrent febrile infections28 and rheumatic agonists.
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