Susceptibility to tuberculosis is associated with TLR1 polymorphisms resulting in a lack of TLR1 cell surface expression

Uciechowski, Peter; Imhoff, Heidi; Lange, Christoph; Meyer, Christian G.; Browne, Edmund; Kirsten, D; Schröder, AC; Schaaf, Bernhard; Al‐Lahham, Adnan; Reinert, Ralf René; Reiling, Norbert; Haase, Hajo; Hatzmann, Adelheid; Fleischer, Daniela; Heussen, Nicole; Kleines, Michael; Rink, Lothar

doi:10.1189/jlb.0409233

Cited by 73 publications

(67 citation statements)

References 52 publications

(87 reference statements)

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“…52 The simplifying explanation is that all of these polymorphisms are in strong LD with an uncharacterized regulatory variant. However, reduced TLR1 function decreases the risk of sepsis, 19,20 leprosy, 21,22,25,26,28 tuberculosis, 13,27 and other diseases. 18,31,50 Thus, variants that disrupt the function of TLR1 may be beneficial to the survival of the organism.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12] TLR1, when in a heterodimer with TLR2, recognizes a variety of triacylated lipoproteins, 11 as well as other lipoproteins, and specific recognition targets include M. leprae, M. tuberculosis, Borrelia species, and a variety of fungal pathogens. 10,[12][13][14][15][16][17][18] Activation of the TLR1-TLR2 heterodimer is not always beneficial to the organism, as multiple studies have found that derived alleles at some SNPs inhibit TLR1 activity and reduce the risk of sepsis, leprosy, prostate cancer, pelvic inflammatory disease, and tuberculosis. [19][20][21][22][23][24][25][26][27] The foremost of these is rs5743618, whose derived allele c.2079T4G (p.(Ile602Ser)) reduces surface trafficking of the TLR1-TLR2 heterodimer, 28 resulting in a reduced response to heterodimer antagonists and, in turn, reduced activation of the NFkB pathway.…”

Section: Introductionmentioning

confidence: 99%

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Haplotype structure and positive selection at TLR1

et al. 2013

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Toll-like receptor 1, when dimerized with Toll-like receptor 2, is a cell surface receptor that, upon recognition of bacterial lipoproteins, activates the innate immune system. Variants in TLR1 associate with the risk of a variety of medical conditions and diseases, including sepsis, leprosy, tuberculosis, and others. The foremost of these is rs5743618 c.2079T4G(p. (Ile602Ser)), the derived allele of which is associated with reduced risk of sepsis, leprosy, and other diseases. Interestingly, 602Ser, which shows signatures of selection, inhibits TLR1 surface trafficking and subsequent activation of NFjB upon recognition of a ligand. This suggests that reduced TLR1 activity may be beneficial for human health. To better understand TLR1 variation and its link to human health, we have typed all 7 high-frequency missense variants (45% in at least one population) along with 17 other variants in and around TLR1 in 2548 individuals from 56 populations from around the globe. We have also found additional signatures of selection on missense variants not associated with rs5743618, suggesting that there may be multiple functional alleles under positive selection in this gene.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Haplotype structure and positive selection at TLR1

et al. 2013

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“…The other strong signals identified were either directly or indirectly related to diet, corresponding to genes encoding proteins involved in fatty acid metabolism, vitamin D levels, and celiac disease, or corresponded to genes involved in skin pigmentation [132]. Interestingly, the authors also detected strong selection signals in immunity-related genes, such as the TLR1–TLR6–TLR10 gene cluster, which is essential for the induction of inflammatory responses and is associated with susceptibility to infectious diseases [159, 160]. Thus, ancient DNA studies can help us to understand the mode of selection following changes in human lifestyle, and the extent to which such selective events increased the frequency of functional alleles associated with specific traits or disease conditions [131, 132, 161, 162].…”

Section: Favoring Advantageous Variants To Increase Adaptationmentioning

confidence: 99%

Understanding rare and common diseases in the context of human evolution

Quintana-Murci

2016

Genome Biol

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The wealth of available genetic information is allowing the reconstruction of human demographic and adaptive history. Demography and purifying selection affect the purge of rare, deleterious mutations from the human population, whereas positive and balancing selection can increase the frequency of advantageous variants, improving survival and reproduction in specific environmental conditions. In this review, I discuss how theoretical and empirical population genetics studies, using both modern and ancient DNA data, are a powerful tool for obtaining new insight into the genetic basis of severe disorders and complex disease phenotypes, rare and common, focusing particularly on infectious disease risk.

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“…Present literature indicates that the outcome of Mtb infection is affected not only by virulence of the infecting strain of M. tuberculosis [17], but also by host environment, disease co-morbidities, and the genetic composition of the host, specifically the presence or absence of genes that regulate the immune system [14, 16, 18–20]. Following Mtb infection, approximately 10 % of individuals will develop active TB (ATB) during their lifetime, while the majority of individuals will exhibit latent TB infection (LTBI) [21, 22].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of host genetics on outcome of tuberculosis infection due to differences in killer immunoglobulin-like receptor gene frequencies and haplotypes

et al. 2015

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BackgroundOutcome of Mycobacterium tuberculosis (Mtb) infection is affected by virulence of the infecting strain of Mtb, host environment, co-morbidities, and the genetic composition of the host, specifically the presence or absence of genes involved in immune responses/regulation. It is hypothesized that specific killer immunoglobulin-like receptor (KIR) genes may be associated with Mtb infection and clinical outcome. This cross-sectional study examined the KIR gene frequencies, profiles, and haplotypes of individuals with active tuberculosis, latent tuberculosis infection, compared to TB and HIV negative healthy controls.ResultsAnalysis of KIR gene frequencies revealed differences among disease status groups, suggesting that enrichment or depletion of specific KIR genes may direct the disease outcome. Mtb infected individuals were more likely to have a centromeric-AA haplotype compared to controls.ConclusionThe differences in KIR gene frequencies and haplotypes may result in differential cytokine expression, contributing to different disease outcomes, and suggest a genetic influence on Mtb susceptibility and pathogenesis.

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Susceptibility to tuberculosis is associated with TLR1 polymorphisms resulting in a lack of TLR1 cell surface expression

Cited by 73 publications

References 52 publications

Haplotype structure and positive selection at TLR1

Haplotype structure and positive selection at TLR1

Understanding rare and common diseases in the context of human evolution

Evaluation of host genetics on outcome of tuberculosis infection due to differences in killer immunoglobulin-like receptor gene frequencies and haplotypes

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