The rs5743836 polymorphism in TLR9 confers a population-based increased risk of non-Hodgkin lymphoma

Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal.
Genes and immunity (Impact Factor: 2.91). 08/2011; 13(2):197-201. DOI: 10.1038/gene.2011.59
Source: PubMed


Non-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major subtypes in three independent case-control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls, 494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly overtransmitted in both Portuguese (odds ratio (OR), 1.85; P=7.3E-9) and Italian (OR, 1.84; P=6.0E-5) and not in the US cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.

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Available from: Lucia Pitzurra, Dec 07, 2015
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    • "Alternatively, TLR9 functions through the myeloid differentiation primary response protein 88 (MyD88)-dependent pathway leading to NF-kappa-B (NF-kB) activation, cytokine secretion and the inflammatory response [12], [13]. In the past years, numerous genetic association studies have explored the role of TLR9 gene polymorphisms in various cancers, including bladder cancer [14], prostate cancer [15], acute lymphoblastic leukemia (ALL) [16], hepatocellular carcinoma (HCC) [17], gastric cancer [18]–[20], cervical cancer [2], [13], [21], Hodgkin’s lymphoma [22], breast cancer [23], burkitt’s lymphoma [24], non-Hodgkin lymphoma [25], endometrial cancer [26], esophageal cancer [20] and lymphoma [27]. Most of the studies focused on three common single nucleotide polymorphisms (SNPs), including rs352140(C/T), rs5743836 (T/C) and rs187084(C/T) (also referred to as 2848C/T, 1237T/C, and 1486C/T, respectively). "
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    ABSTRACT: Growing studies have revealed the association between polymorphisms in the Toll-like receptor 9 (TLR9) and susceptibility to cancer, however, the results remained inconsistent. To assess the effect of three selected SNPs (rs352140, rs5743836 and rs187084) in TLR9 on cancer, we performed a meta-analysis based on 11 case-control studies, including a total of 6,585 cancer cases and 7,506 controls. Summary odds ratios (OR) and corresponding 95% confidence intervals (CIs) for polymorphisms in TLR9 and cancer risk were estimated. Our meta-analysis indicated that rs352140 was associated with an increased cancer risk, especially in Caucasian. However, no significantly increased cancer risk was detected to be associated with rs187084 and rs5743836 either the overall or subgroup estimation. These meta-analysis results indicate that polymorphisms in TLR9 may play a role in cancer development.
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    • "Over 60 publications have linked the TLR9 mutations - 1486 T/C, -1237 T/C, +1174 G/A, and/or 2848 A/G to the predisposition of a wide variety of inflammatory disorders including non-Hodgkin's lymphoma [177], cervical cancer [178], lupus nephritis [179], and cerebral malaria [180], amongst many others. Most of these studies have currently not been duplicated and consequently await verification. "
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    ABSTRACT: Toll-like receptors (TLRs), a large group of proteins which recognize various pathogen-associated molecular patterns, are critical for the normal function of the innate immune system. Following their discovery many single nucleotide polymorphisms within TLRs and components of their signaling machinery have been discovered and subsequently implicated in a wide range of human diseases including atherosclerosis, sepsis, asthma, and immunodeficiency. This review discusses the effect of genetic variation on TLR function and how they may precipitate disease.
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    ABSTRACT: In humans, allelic variants in Toll-like receptors (TLRs) associate with several pathologies. However, the underlying cellular and molecular mechanisms of this association remain largely unknown. Analysis of the human TLR9 promoter revealed that the C allele of the rs5743836 polymorphism generates several regulatory sites, including an IL-6-responding element. Here, we show that, in mononuclear cells carrying the TC genotype of rs5743836, IL-6 up-regulates TLR9 expression, leading to exacerbated cellular responses to CpG, including IL-6 production and B-cell proliferation. Our study uncovers a role for the rs5743836 polymorphism in B-cell biology with implications on TLR9-mediated diseases and on the therapeutic usage of TLR9 agonists/antagonists.
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