Common variants at 11p13 are associated with susceptibility to tuberculosis

Thye, Thorsten; Owusu‐Dabo, Ellis; Vannberg, Fredrik; Crevel, Reinout van; Curtis, James; Sahiratmadja, Edhyana; Balabanova, Yanina; Ehmen, Christa; Muntau, Birgit; Ruge, Gerd; Sievertsen, Jürgen; Gyapong, John; Nikolayevskyy, Vladyslav; Hill, Philip C.; Sirugo, Giorgio; Drobniewski, Francis; Vosse, Esther van de; Newport, Melanie J.; Alisjahbana, Bachti; Nejentsev, Sergey; Ottenhoff, Tom H. M.; Hill, Adrian V. S.; Horstmann, Rolf D.; Meyer, Christian G.

doi:10.1038/ng.1080

Cited by 198 publications

(189 citation statements)

References 11 publications

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“…We also know much more about the genetic diversity of the M. tuberculosis complex. Further research in this field of study, including exploring resistance and susceptibility genes 30 , and establishing ancient phylogeographic patterning around the world, will be a useful addition to understanding why people succumbed to this infection in past times. There is also much more research needed in palaeopathology to link the most common epidemiological factors for TB to the evidence of TB in human remains.…”

Section: Discussionmentioning

confidence: 99%

Old World tuberculosis: Evidence from human remains with a review of current research and future prospects

Roberts

2015

Tuberculosis

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. (2015) 'Old World tuberculosis : evidence from human remains with a review of current research and future prospects.', Tuberculosis., 95 (Supplement 1). S117-S121.Further information on publisher's website: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. aDNA analysis has provided data on species and strains of the M. tuberculosis complex organisms affecting people in the past. The extant data suggest the first epidemiological transition (Neolithic agriculture and permanent settlements) led to an increase in TB, with later increases in urban environments of the late Medieval period. A number of causative factors were at play. Future research, particularly using biomolecular analysis, has the potential to further contribute to our understanding of the origin and evolution of TB, thus merging the disciplines of palaeopathology and evolutionary medicine.

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Section: Discussionmentioning

confidence: 99%

Old World tuberculosis: Evidence from human remains with a review of current research and future prospects

Roberts

2015

Tuberculosis

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“…Studies of the host genetic susceptibility to TB encompass twin (3,4), linkage, candidate gene association, and genomewide association studies (5)(6)(7)(8)(9)(10)(11)(12). We and others have identified associations between common polymorphisms in innate immunity genes and susceptibility to TB and clinical phenotypes (6,8,11,13).…”

Section: Clinical Relevancementioning

confidence: 99%

Common Polymorphisms in the CD43 Gene Region Are Associated with Tuberculosis Disease and Mortality

Campo

Randhawa

Dunstan

et al. 2015

Am J Respir Cell Mol Biol

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CD43, a surface glycoprotein, regulates Mycobacterium tuberculosis macrophage binding, replication, and proinflammatory cytokine induction in a murine model. We hypothesized that single-nucleotide polymorphisms (SNPs) in the CD43 gene region are associated with human tuberculosis (TB) susceptibility. We performed a casepopulation study in discovery (352 TB cases and 382 control subjects) and validation cohorts (339 TB cases and 376 control subjects). We examined whether 11 haplotype-tagging SNPs in the CD43 gene region were associated with tuberculous meningitis (TBM) and pulmonary TB (PTB) in Vietnam. Three SNPs from the CD43 gene region were associated with TB susceptibility with a genotypic model. The association fit a recessive genetic model and was greater for TBM than for PTB (for TBM: rs4788172, odds ratio [OR], 1.64; 95% confidence interval [CI], 1.04-2.59, rs17842268 [OR, 2.20; 95% CI, 1.29-3.76, and rs12596308 [OR, 2.38; 95% CI, 1.47-3.89]). Among TBM cases, rs17842268 was associated with decreased survival (hazard ratio, 2.7; 95% CI, 1.1-6.5; P = 0.011). In addition, rs12596308 and rs17842268 were associated with focal neurologic deficit at TBM presentation. Our data suggest that CD43 polymorphisms are associated with TB susceptibility, disease manifestations, and worse outcomes. To our knowledge, this is the first report that links CD43 genetic variants with susceptibility and outcome from a disease.

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“…The detection of trans-eQTLs suffers, however, from a high burden of multiple testing while effects may be only of modest size (Gilad et al 2008;Majewski and Pastinen 2011;Montgomery and Dermitzakis 2011). Given that regulatory variants have been observed to overlap with SNPs associated with complex phenotypes (Nica et al 2010;Nicolae et al 2010), we restricted our analysis to SNPs that have been suggestively associated (P < 1 3 10 À5 ) with TB susceptibility by genome-wide association studies (GWAs) (Hindorff et al 2009;Thye et al 2010;Thye et al 2012). In doing so, we identified a putative trans-eQTL for let-7i, a strongly induced, pro-inflammatory miRNA, the expression of which was associated with rs9373523 upon MTB infection (Bonferronicorrected P = 7.78 3 10…”

Section: à4mentioning

confidence: 99%

A genomic portrait of the genetic architecture and regulatory impact of microRNA expression in response to infection

et al. 2014

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MicroRNAs (miRNAs) are critical regulators of gene expression, and their role in a wide variety of biological processes, including host antimicrobial defense, is increasingly well described. Consistent with their diverse functional effects, miRNA expression is highly context dependent and shows marked changes upon cellular activation. However, the genetic control of miRNA expression in response to external stimuli and the impact of such perturbations on miRNA-mediated regulatory networks at the population level remain to be determined. Here we assessed changes in miRNA expression upon Mycobacterium tuberculosis infection and mapped expression quantitative trait loci (eQTL) in dendritic cells from a panel of healthy individuals. Genome-wide expression profiling revealed that ∼40% of miRNAs are differentially expressed upon infection. We find that the expression of 3% of miRNAs is controlled by proximate genetic factors, which are enriched in a promoter-specific histone modification associated with active transcription. Notably, we identify two infection-specific response eQTLs, for miR-326 and miR-1260, providing an initial assessment of the impact of genotype-environment interactions on miRNA molecular phenotypes. Furthermore, we show that infection coincides with a marked remodeling of the genome-wide relationships between miRNA and mRNA expression levels. This observation, supplemented by experimental data using the model of miR-29a, sheds light on the role of a set of miRNAs in cellular responses to infection. Collectively, this study increases our understanding of the genetic architecture of miRNA expression in response to infection, and highlights the wide-reaching impact of altering miRNA expression on the transcriptional landscape of a cell.

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Common variants at 11p13 are associated with susceptibility to tuberculosis

Cited by 198 publications

References 11 publications

Old World tuberculosis: Evidence from human remains with a review of current research and future prospects

Old World tuberculosis: Evidence from human remains with a review of current research and future prospects

Common Polymorphisms in the CD43 Gene Region Are Associated with Tuberculosis Disease and Mortality

A genomic portrait of the genetic architecture and regulatory impact of microRNA expression in response to infection

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