Genetic variation in TLR pathway and the risk of pulmonary tuberculosis in a Moldavian population

Varzari, Alexander; Deyneko, Igor V.; Vladei, Iuri; Grallert, Harald; Schieck, Maximilian; Tudor, Elena; Illig, Thomas

doi:10.1016/j.meegid.2018.12.005

Cited by 26 publications

(15 citation statements)

References 45 publications

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“…This Big Data set contains consensus human genome sequences and hundreds of millions of single-nucleotide polymorphisms (SNPs) publicly available within databases Ensembl (Zerbino et al, 2015), the UCSC Genome Browser (Haeussler et al, 2015), and dbSNP (Day, 2010). Additionally, databases ClinVar (Landrum et al, 2014) and OMIM (Amberger et al, 2015) document, systematize, and prioritize only clinically proven and experimentally studied human disease SNP markers, respectively, whose allele frequencies significantly differ between cohorts of patients and conventionally healthy volunteers as a mandatory criterion (Varzari et al, 2019). Finally, the dbWGFP database (Wu et al, 2016) does the same in whole-genome mode for all the 10 billion potential SNPs in humans.…”

Section: Introductionmentioning

confidence: 99%

Disruptive Selection of Human Immunostimulatory and Immunosuppressive Genes Both Provokes and Prevents Rheumatoid Arthritis, Respectively, as a Self-Domestication Syndrome

et al. 2021

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Using our previously published Web service SNP_TATA_Comparator, we conducted a genome-wide study of single-nucleotide polymorphisms (SNPs) within core promoters of 68 human rheumatoid arthritis (RA)-related genes. Using 603 SNPs within 25 genes clinically associated with RA-comorbid disorders, we predicted 84 and 70 candidate SNP markers for overexpression and underexpression of these genes, respectively, among which 58 and 96 candidate SNP markers, respectively, can relieve and worsen RA as if there is a neutral drift toward susceptibility to RA. Similarly, we predicted natural selection toward susceptibility to RA for 8 immunostimulatory genes (e.g., IL9R) and 10 genes most often associated with RA (e.g., NPY). On the contrary, using 25 immunosuppressive genes, we predicted 70 and 109 candidate SNP markers aggravating and relieving RA, respectively (e.g., IL1R2 and TGFB2), suggesting that natural selection can simultaneously additionally yield resistance to RA. We concluded that disruptive natural selection of human immunostimulatory and immunosuppressive genes is concurrently elevating and reducing the risk of RA, respectively. So, we hypothesize that RA in human could be a self-domestication syndrome referring to evolution patterns in domestic animals. We tested this hypothesis by means of public RNA-Seq data on 1740 differentially expressed genes (DEGs) of pets vs. wild animals (e.g., dogs vs. wolves). The number of DEGs in the domestic animals corresponding to worsened RA condition in humans was significantly larger than that in the related wild animals (10 vs. 3). Moreover, much less DEGs in the domestic animals were accordant to relieved RA condition in humans than those in the wild animals (1 vs. 8 genes). This indicates that the anthropogenic environment, in contrast to a natural one, affects gene expression across the whole genome (e.g., immunostimulatory and immunosuppressive genes) in a manner that likely contributes to RA. The difference in gene numbers is statistically significant as confirmed by binomial distribution (p < 0.01), Pearson’s χ2 (p < 0.01), and Fisher’s exact test (p < 0.05). This allows us to propose RA as a candidate symptom within a self-domestication syndrome. Such syndrome might be considered as a human’s payment with health for the benefits received during evolution.

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Section: Introductionmentioning

confidence: 99%

Disruptive Selection of Human Immunostimulatory and Immunosuppressive Genes Both Provokes and Prevents Rheumatoid Arthritis, Respectively, as a Self-Domestication Syndrome

et al. 2021

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“…We have earlier evaluated the effect of common genetic variations in TLR pathway on the risk of pulmonary TB in Moldavian population and identi ed variants in TLR2, TLR8 and TLR9 as being associated with TB [6]. In the present work, we extended the analysis to 14 additional polymorphisms from 12 TB immune response candidate genes and investigated all pairwise genetic interactions for these and the previous genetic variants (altogether 43 polymorphisms).…”

Section: Introductionmentioning

confidence: 94%

Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in Moldavian population

Varzari

Deyneko

Tudor

et al. 2020

Preprint

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BACKGROUND Host immunity is essential for efficient recognition and clearance of M. tuberculosis infection. Polymorphisms in genes that regulate immune response have been reported to influence the susceptibility/resistance to pulmonary tuberculosis (TB). Here we evaluated associations between 14 polymorphisms in 12 core genes involved in immune responses and pulmonary TB in Moldavian population, and investigated whether interactions between these and previously analyzed polymorphisms could exist and modulate the risk of pulmonary TB. METHODS Polymorphisms VDR rs7975232, VDR rs1544410, VDR rs2228570, MR1 rs1052632, TLR1 rs5743618, TLR2 rs111200466, TLR10 rs11096957, SLC11A1 rs2276631, IL1B rs1143643, IL10 rs1800896, IFNG rs2430561, TNF rs1800629, IRAK1 rs1059703, and FOXP3 rs2232365 were genotyped in 271 Moldavian pulmonary TB cases and 251 community-matched healthy controls. Associations were tested using Fisher test and logistic regression. Complemented with the data from our previous study (PMID: 30529560), investigation of gene-gene interactions was performed for a total of 43 loci. Significance level was adjusted by the Bonferroni correction. RESULTS Single polymorphism analysis revealed a nominal association between TNF rs1800629 and pulmonary TB (Fisher exact test p-value = 0.01843). Marginal differences between cases and controls were observed for haplotypes in the gene cluster TLR1-TLR6-TLR10 and gene TLR2. In the pairwise interaction analysis, the combination of genotypes TLR6 rs5743810 GA and TLR10 rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62–3.85; Fisher exact test p-value = 1.5 × 10− 5, significant after Bonferroni correction). CONCLUSION The TLR6 rs5743810 and TLR10 rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB and has potential as a novel biomarker for predicting TB susceptibility.

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“…First, we found SNP combinations associated with TB using logistic regression adjusted for sex and age under log-additive genetic model (implemented in software package SNPstats) 38 for all pairs of the 43 genetic markers from this and our previous study. 6 We used the log-additive model because it is a generalized model that is the best choice when the true inheritance pattern is unknown. Second, we found the exact genotype combination(s) that most contributed to the associations revealed in the previous step.…”

Section: Polymorphism Selection and Genotypingmentioning

confidence: 99%

“…[3][4][5] We previously evaluated the effect of common genetic variations in the TLR pathway on the risk of pulmonary TB in a Moldavian population and identified variants in TLR2, TLR8, and TLR9 as being associated with TB. 6 In the present work, we extended the analysis to 14 additional polymorphisms from 12 TB immune response candidate genes and investigated all pairwise genetic interactions for these and the previous genetic variants (43 polymorphisms altogether). The selected polymorphisms in this study have previously been shown to change the level or function of corresponding gene products and influence susceptibility/ resistance to infections (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in a Moldavian population

et al. 2021

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Polymorphisms in genes that control immune function and regulation may influence susceptibility to pulmonary tuberculosis (TB). In this study, 14 polymorphisms in 12 key genes involved in the immune response ( VDR, MR1, TLR1, TLR2, TLR10, SLC11A1, IL1B, IL10, IFNG, TNF, IRAK1, and FOXP3) were tested for their association with pulmonary TB in 271 patients with TB and 251 community-matched controls from the Republic of Moldova. In addition, gene–gene interactions involved in TB susceptibility were analyzed for a total of 43 genetic loci. Single nucleotide polymorphism (SNP) analysis revealed a nominal association between TNF rs1800629 and pulmonary TB (Fisher exact test P = 0.01843). In the pairwise interaction analysis, the combination of the genotypes TLR6 rs5743810 GA and TLR10 rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62–3.85; Fisher exact test P value = 1.5 × 10−5, significant after Bonferroni correction). In conclusion, the TLR6 rs5743810 and TLR10 rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB; due to its high frequency in the population, this SNP combination may serve as a novel biomarker for predicting TB susceptibility.

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Genetic variation in TLR pathway and the risk of pulmonary tuberculosis in a Moldavian population

Cited by 26 publications

References 45 publications

Disruptive Selection of Human Immunostimulatory and Immunosuppressive Genes Both Provokes and Prevents Rheumatoid Arthritis, Respectively, as a Self-Domestication Syndrome

Disruptive Selection of Human Immunostimulatory and Immunosuppressive Genes Both Provokes and Prevents Rheumatoid Arthritis, Respectively, as a Self-Domestication Syndrome

Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in Moldavian population

Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in a Moldavian population

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