Human genetics of mycobacterial disease

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lepromatous leprosy 1 infectiousdiseases
leprosy 93 infectiousdiseases
multibacillary leprosy 1 infectiousdiseases
paucibacillary leprosy 1 infectiousdiseases
tuberculoid leprosy 1 infectiousdiseases
tuberculosis 33 infectiousdiseases
infectious disease 2 infectiousdiseases

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infectious disease 1753 leprosy and the recent genetic findings for BU susceptibility.IntroductionA common observation in human infectious disease s is that contact with pathogens is necessary but not sufficient for infection and subsequent development
infectious disease 29900 provide further insights (Maertzdorf et al. [66]).LeprosyThe etiological agent of leprosy, a chronic infectious disease , is the slow growing Mycobacterium leprae, which primarily affects the skin and peripheral nerves. Over
lepromatous leprosy 35188 p = 0.004DOM dominant model; HLOD heterogeneity logarithm of odds; LOD logarithm of the odds; LL lepromatous leprosy ; MB multibacillary leprosy; MLB maximum likelihood binomial; PB paucibacillary leprosy; REC Recessive
leprosy 647 rare cases, by M. bovis or M. africanum. The second and third most common mycobacterial diseases are leprosy and buruli ulcer (BU), respectively. Both diseases affect the skin and can lead to permanent sequelae
leprosy 1500 of candidate genes association studies, genome-wide approaches have been widely applied for TB and leprosy . In this review, we summarize some of the findings achieved by genome-wide linkage, association and
leprosy 1649 findings achieved by genome-wide linkage, association and transcriptome analyses in TB disease and leprosy and the recent genetic findings for BU susceptibility.IntroductionA common observation in human infectious
leprosy 4107 of the human genetic background for the eventual outcome of mycobacterial infection, mainly TB and leprosy —the two most common mycobacterial diseases. Here, we provide an overview of selected findings obtained
leprosy 4324 genome-wide approaches used in the search of human genetic predisposition to clinical TB disease and leprosy . We also summarize initial genetic findings obtained for buruli ulcer (BU), the third most common mycobacterial
leprosy 29881 ethnic cohorts may provide further insights (Maertzdorf et al. [66]).LeprosyThe etiological agent of leprosy , a chronic infectious disease, is the slow growing Mycobacterium leprae, which primarily affects the
leprosy 30052 Mycobacterium leprae, which primarily affects the skin and peripheral nerves. Over the last 5 years the global leprosy incidence reported by the World Health Organization (WHO) was remarkably constant at approximately 210,000
leprosy 30456 that are being classified employing different criteria (Gaschignard et al. [48]). Based on the WHO leprosy classification system, leprosy patients are classified as paucibacillary (PB) when presenting up to
leprosy 30487 employing different criteria (Gaschignard et al. [48]). Based on the WHO leprosy classification system, leprosy patients are classified as paucibacillary (PB) when presenting up to five lesions, or multibacillary
leprosy 30664 five lesions, or multibacillary (MB) when presenting more than five lesions. An important aspect of leprosy is that during or after treatment, some patients can manifest acute episodes of dysregulated inflammation
leprosy 30787 or after treatment, some patients can manifest acute episodes of dysregulated inflammation known as leprosy reaction. As result of this condition, patients may experience pain and develop severe nerve damage
leprosy 31015 sequelae. The most common form of reactional state is type 1 reaction (T1R), which can affect 30–50% of leprosy patients depending on the epidemiologic setting (Fava et al. [42]). There is accumulating evidence that
leprosy 31169 setting (Fava et al. [42]). There is accumulating evidence that human genetics plays an important role in leprosy susceptibility, with different sets of genes modifying host predisposition to leprosy per se, its clinical
leprosy 31255 important role in leprosy susceptibility, with different sets of genes modifying host predisposition to leprosy per se, its clinical forms and reactional states (Sauer et al. [90]; Fava and Schurr [41]).Genome-wide
leprosy 31399 reactional states (Sauer et al. [90]; Fava and Schurr [41]).Genome-wide linkage studiesThe first GWLS in leprosy detected a linkage peak on chromosome region 10p13 in Indian families with PB leprosy patients (Table 3)
leprosy 31485 first GWLS in leprosy detected a linkage peak on chromosome region 10p13 in Indian families with PB leprosy patients (Table 3) (Siddiqui et al. [94]). A subsequent genomic scan in a sample of Vietnamese families
leprosy 31644 subsequent genomic scan in a sample of Vietnamese families replicated linkage to the same region with PB leprosy (Mira et al. [76]). Based on these findings, the MRC1 gene—located in the linked chromosomal interval—was
leprosy 31955 encoded by this gene is a receptor for uptake of mycobacteria. Unexpectedly, in Vietnamese and Brazilian leprosy patients, MRC1 variants were associated with leprosy per se and MB leprosy, but not PB leprosy (Alter
leprosy 32008 mycobacteria. Unexpectedly, in Vietnamese and Brazilian leprosy patients, MRC1 variants were associated with leprosy per se and MB leprosy, but not PB leprosy (Alter et al. [9]). In 2014, a gene-centered high-density
leprosy 32030 Vietnamese and Brazilian leprosy patients, MRC1 variants were associated with leprosy per se and MB leprosy , but not PB leprosy (Alter et al. [9]). In 2014, a gene-centered high-density association scan of the
leprosy 32050 Brazilian leprosy patients, MRC1 variants were associated with leprosy per se and MB leprosy, but not PB leprosy (Alter et al. [9]). In 2014, a gene-centered high-density association scan of the chromosomal 10p13
leprosy 32537 GATA3 gene, located 6.5 Mb from the linkage peak on chromosome 10p13, was tested for association with leprosy and its clinical forms in two Brazilian population samples and a single SNP was associated with leprosy
leprosy 32641 leprosy and its clinical forms in two Brazilian population samples and a single SNP was associated with leprosy per se in both samples (Medeiros et al. [73]). Combined, these association studies identified one neighboring
leprosy 32808 these association studies identified one neighboring and three 10p13 genes involved in the control of leprosy susceptibility and the MB clinical form. Why genetic studies failed to detect an association with PB
leprosy 32917 susceptibility and the MB clinical form. Why genetic studies failed to detect an association with PB leprosy is perplexing and not known. It is possible that a collection of rare variants within this region impacts
leprosy 33049 known. It is possible that a collection of rare variants within this region impacts on the risk of PB leprosy but presently there are no deep sequencing data available to test this hypothesis (Orlova et al. [83];
leprosy 33212 available to test this hypothesis (Orlova et al. [83]; Grant et al. [52]).Table 3Summary of loci linked to leprosy by genome-wide linkage studiesReferencesaPopulation sampleLocusbStudy statistical metrics/notesc,dSiddiqui
leprosy 35200 p = 0.004DOM dominant model; HLOD heterogeneity logarithm of odds; LOD logarithm of the odds; LL lepromatous leprosy ; MB multibacillary leprosy; MLB maximum likelihood binomial; PB paucibacillary leprosy; REC Recessive
leprosy 35227 heterogeneity logarithm of odds; LOD logarithm of the odds; LL lepromatous leprosy; MB multibacillary leprosy ; MLB maximum likelihood binomial; PB paucibacillary leprosy; REC Recessive model; TT tuberculoid leprosyaFollow-up
leprosy 35287 lepromatous leprosy; MB multibacillary leprosy; MLB maximum likelihood binomial; PB paucibacillary leprosy ; REC Recessive model; TT tuberculoid leprosyaFollow-up association analysis of candidate genes located
leprosy 35332 leprosy; MLB maximum likelihood binomial; PB paucibacillary leprosy; REC Recessive model; TT tuberculoid leprosy aFollow-up association analysis of candidate genes located in the regions linked to the disease are not
leprosy 35893 availableIn addition to the linkage peak in the 10p13 region, chromosome region 6q25–q27 was linked to leprosy per se susceptibility in the same Vietnamese families (Table 3) (Mira et al. [76]). A fine mapping
leprosy 36244 genes—PRKN (formerly PARK2, a well-known early onset Parkinson disease gene) and PACRG—associated with leprosy susceptibility in Vietnamese families (Mira et al. [77]). These results were validated in a Brazilian
leprosy 36922 ethnicities may explain the heterogeneity of association in previous studies between this locus and leprosy per se. Moreover, Alter et al. also demonstrated that the PRKN/PACRG association with the disease is
leprosy 37941 recent study found a new gene located at chromosome 6q25-27—the SOD2 gene—as a risk factor for leprosy susceptibility in two independent Brazilian population samples (Ramos et al. [88]). Indeed, SOD2 expression
leprosy 38271 leprae (Guerreiro et al. [54]).The GWLS conducted in the Vietnamese families detected an additional leprosy linkage signal at the HLA complex on chromosomal region 6p21 (Table 3) (Mira et al. [76]). This region
leprosy 38413 on chromosomal region 6p21 (Table 3) (Mira et al. [76]). This region had previously been linked to leprosy susceptibility in a Brazilian sample (Miller et al. [75]). In fact, several studies have reported the
leprosy 38624 involvement of HLA alleles and haplotypes as important genetic factors controlling susceptibility to leprosy (Geluk and Ottenhoff [49]; Jarduli et al. [57]). To further explore the region underlying the linkage
leprosy 39020 (Alcaïs et al. [5]). A functional SNP was identified in the LTA promoter region as a risk factor of leprosy in ethnically distinct populations. Interestingly, the LTA genetic effect on leprosy risk was age dependent,
leprosy 39105 risk factor of leprosy in ethnically distinct populations. Interestingly, the LTA genetic effect on leprosy risk was age dependent, since evidence for association became stronger with early age-at-diagnosis.
leprosy 39261 association became stronger with early age-at-diagnosis. To identify additional genetic risk factors for leprosy in the 6p21 chromosomal region, a high-density SNP association scan was conducted on a 1.9 Mb chromosomal
leprosy 39530 Employing samples from Vietnam and North India, SNPs in the HLA class I region were found associated with leprosy per se and strongly implicated the HLA-C*15:05 allele in leprosy susceptibility. In addition to the
leprosy 39595 region were found associated with leprosy per se and strongly implicated the HLA-C*15:05 allele in leprosy susceptibility. In addition to the above-mentioned genes in the HLA region, cumulative evidence indicated
leprosy 39786 cumulative evidence indicated that the class III gene TNF was also involved in the immune response against leprosy . Specifically, a promoter variant located at position − 308 of TNF has been extensively studied
leprosy 39897 Specifically, a promoter variant located at position − 308 of TNF has been extensively studied in leprosy , with inconsistent results (Cardoso et al. [25]). Interestingly, a large association study conducted
leprosy 40174 including additional genotypes from published data, reinforced the TNF − 308 protective effect in leprosy and suggested that the association is restricted to the Brazilian population (Cardoso et al. [24]).Complementary
leprosy 40394 to these findings, several GWLS have reported other chromosomal regions involved in the control of leprosy phenotypes (Table 3) (Fava and Schurr [41]). Further analysis of the first leprosy GWL data with an
leprosy 40478 the control of leprosy phenotypes (Table 3) (Fava and Schurr [41]). Further analysis of the first leprosy GWL data with an extended Indian population found an additional linkage peak on chromosomal region 20p12
leprosy 40639 additional linkage peak on chromosomal region 20p12 (Tosh et al. [108]). In Brazilian families with leprosy patients, suggestive evidence of linkage was found with the 17q22 and 20p13 chromosome regions (Miller
leprosy 40915 to the linkage peak reported in the Indian sample. Moreover, chromosomal region 21q22 was linked to leprosy polarization in families from Malawi (Wallace et al. [112]). Finally, 2p14 was significantly linked
leprosy 41026 polarization in families from Malawi (Wallace et al. [112]). Finally, 2p14 was significantly linked to leprosy per se, while regions 4q22, 8q24 and 16q24 showed suggestive evidence for linkage in Chinese families
leprosy 41283 genes underlying these linkage peaks are yet to be identified.Genome-wide association studiesThe first leprosy GWAS was conducted in 2009 in four independent Chinese case-control samples (Zhang et al. [126]). Among
leprosy 41480 [126]). Among the nearly 500,000 SNPs tested in the first population, 93 SNPs were associated with leprosy and reanalyzed in the three remaining case-control samples. In total, 15 SNPs located in five loci—HLA-DR–DQ,
leprosy 41678 five loci—HLA-DR–DQ, RIPK2, TNFSF15, NOD2 and CCDC122-LACC1—were significantly associated with leprosy (p < 1.00 × 10−10; Table 4). Moreover, a trend toward association was found for one SNP
leprosy 41956 implicated in Crohn’s disease (Schurr and Gros [91]; Zhang et al. [126]; Grant et al. [50]). After the leprosy GWAS results, several association studies attempted to replicate these genes in independent populations.
leprosy 42095 association studies attempted to replicate these genes in independent populations. The NOD2 association with leprosy was validated in a Nepalese population, where it was also found associated with leprosy reaction (Berrington
leprosy 42183 association with leprosy was validated in a Nepalese population, where it was also found associated with leprosy reaction (Berrington et al. [17]). HLA-DR–DQ and CCDC122–LACC1 loci were associated with disease
leprosy 42491 validated in an Indian population (Marcinek et al. [72]), while LRRK2 was found to be associated with leprosy and the PB clinical form in Chinese and Indian population samples (Marcinek et al. [72]; Wang et al.
leprosy 42638 Indian population samples (Marcinek et al. [72]; Wang et al. [114]).Table 4Summary of GWAS hits in leprosy phenotypesReferencesaPopulation sampleLocus, candidate gene(s)bStudy statistical metrics/notesc,dZhang
leprosy 45846 (1.17–1.45), p = 1.04 × 10−6Fava et al. ([45])Vietnamese GWAS in T1R: 221 families with 229 leprosy T1R-affected offspring and 209 families with 229 leprosy T1R-free offspring. Rep: 253 T1R cases and
leprosy 45903 ([45])Vietnamese GWAS in T1R: 221 families with 229 leprosy T1R-affected offspring and 209 families with 229 leprosy T1R-free offspring. Rep: 253 T1R cases and 563 T1R-free controls (Vietnamese). Validation: 471 T1R cases
leprosy 46889 association and SNPs tagging HLA-DR–DQ, RIPK2, NOD2 and CCDC122–LACC1 were validated as risk factors for leprosy susceptibility (Grant et al. [50]). Interestingly, when these families were stratified by the T1R status
leprosy 47005 susceptibility (Grant et al. [50]). Interestingly, when these families were stratified by the T1R status of leprosy patients, variants located in two genes that could not be replicated for leprosy per se—TNFSF15 and
leprosy 47086 the T1R status of leprosy patients, variants located in two genes that could not be replicated for leprosy per se—TNFSF15 and LRRK2—were found associated with T1R (Fava et al. [43], [44]). A total of 47
leprosy 48700 abrogated following stimulation with M. leprae (Fava et al. [44]). A stepwise association study of leprosy and the non-HLA genes that were significantly associated in the GWAS (RIPK2, TNFSF15, NOD2 and CCDC122-LACC1)
leprosy 49069 information of the five genes, in a family-based population sample from Prata Village—an isolated, leprosy hyper-endemic population located in the Brazilian Amazon. Two SNPs located in NOD2 and CCDC122-LACC1
leprosy 49199 population located in the Brazilian Amazon. Two SNPs located in NOD2 and CCDC122-LACC1 were associated with leprosy and were subsequently replicated in three independent Brazilian case-control population samples (Sales-Marques
leprosy 49541 set with additional control subjects leading to the identification of IL23R and RAB32 as additional leprosy associated genes in the Chinese sample (Table 4) (Zhang et al. [127]). Association of both genes was
leprosy 49876 expanded (Table 4) (Liu et al. [63]; Wang et al. [115]). First, six additional loci were associated with leprosy when a second independent Chinese GWAS dataset was added to the previous GWAS dataset, followed by a
leprosy 50434 the previous GWAS (Zhang et al. [126], [127]; Liu et al. [63]), four novel loci were associated with leprosy (Table 4) (Wang et al. [115]). Finally, a genome-wide association study of protein coding genes and
leprosy 50543 (Table 4) (Wang et al. [115]). Finally, a genome-wide association study of protein coding genes and leprosy susceptibility has been conducted in a Chinese sample (Liu et al. [64]). In this study, 40,491 coding
leprosy 50972 population samples which led to identification of seven nonsynonymous variants that were associated with leprosy . These findings implicated six new genes in disease susceptibility—CARD9, FLG, IL27, NCKIPSD, SLC29A3
leprosy 51205 confirmed the association of the IL23R GWAS gene (Table 4).Until now, only one GWAS for T1R risk in leprosy patients has been published. It was conducted in a family-based population sample composed of 221 Vietnamese
leprosy 51355 conducted in a family-based population sample composed of 221 Vietnamese families with 229 offspring with leprosy that were also T1R-affected and 209 families with 229 offspring with leprosy that were T1R-free (Fava
leprosy 51432 with 229 offspring with leprosy that were also T1R-affected and 209 families with 229 offspring with leprosy that were T1R-free (Fava et al. [45]). In this GWAS, 6.3 million variants—genotyped and imputed—were
leprosy 52259 studies have contributed substantially to a better understanding of the human genetic factors involved in leprosy susceptibility. Moreover, not only have these studies led to the identification of genes and pathways
leprosy 52389 Moreover, not only have these studies led to the identification of genes and pathways that play a role in leprosy pathogenesis, but they have also identified covariates that may be critical for the genetic analyses
leprosy 52674 size and phenotypic homogeneity, differences in LD pattern, and the effect of endophenotypes—for leprosy , T1R and leprosy subtypes—all can impact on the detection and interpretation of genetic findings.Genome-wide
leprosy 52691 phenotypic homogeneity, differences in LD pattern, and the effect of endophenotypes—for leprosy, T1R and leprosy subtypes—all can impact on the detection and interpretation of genetic findings.Genome-wide RNA expression
leprosy 52892 RNA expression analysisRNA expression analyses have provided valuable data to better understanding leprosy pathogenesis. Comparisons of mRNA and miRNA expression between leprotic lesions and skin biopsies of
leprosy 53142 genes differentially expressed, including DE mRNAs and miRNAs exclusively detected in samples with leprosy reactions (Belone et al. [16]; Soares et al. [99]). Moreover, contrasting nerve biopsies of leprosy
leprosy 53242 leprosy reactions (Belone et al. [16]; Soares et al. [99]). Moreover, contrasting nerve biopsies of leprosy lesions against non-leprous neuropathy ones highlighted down-regulated cytokines and genes involved
leprosy 53838 expression levels that depended on the presence of M. leprae. Specifically, stimulation of whole-blood from leprosy patients with M. leprae sonicate identified 6675 genes differentially expressed (p < 4.2 × 10−6);
leprosy 54790 by positive selection (Manry et al. [70]).In an effort to derive transcriptome biomarkers for those leprosy patients who are at increased risk of developing T1R, the transcriptome response to M. leprae sonicate
leprosy 54921 increased risk of developing T1R, the transcriptome response to M. leprae sonicate in whole blood from leprosy patient was compared between those patients who developed T1R and those who did not (Orlova et al. [84]).
leprosy 55548 T1R. The T1R signature was validated in a prospective study where blood from newly diagnosed T1R-free leprosy patients was stimulated with M. leprae antigen prior to the extraction of RNA. All patients were then
leprosy 57514 conditions after initial improvement (O’Brien et al. [79]).Candidate gene association studiesAs in TB and leprosy , following exposure of M. ulcerans there is a variability of outcome regarding both disease per se and
leprosy 58072 association studies were designed to test candidate genes based on their previous implications in TB and/or leprosy and analysis of the implicated pathways. The first association study in BU was published in 2006 employing
leprosy 58799 risk of BU. The same SNP had previously been identified as main cause of the association of PRKN with leprosy and also was shown to be a trans-eQTL for CCL2 and IL6 (de Léséleuc et al. [38]; Alter et al. [11]).Considering
leprosy 62117 additional light on pathogenic mechanisms of BU.ConclusionIn the last decade, human genetics of TB and leprosy susceptibility were extensively studied by genome-wide approaches to complement findings from candidate
leprosy 62625 new candidate susceptibility genes. Regarding GWAS data and replications of those findings, TB and leprosy studies surprised in different ways. In TB, the number of genetic risk factors and their effect size
leprosy 63026 phenotype, to host-environment interactions or to the variability of the M. tuberculosis genome. In leprosy , GWAS and replication studies provided insights into disease pathogenesis and revealed an unexpected
leprosy 63169 provided insights into disease pathogenesis and revealed an unexpected overlap in the genetic control of leprosy and its clinical presentations with common inflammatory disorders such as Crohn’s disease. In addition,
multibacillary leprosy 35212 model; HLOD heterogeneity logarithm of odds; LOD logarithm of the odds; LL lepromatous leprosy; MB multibacillary leprosy ; MLB maximum likelihood binomial; PB paucibacillary leprosy; REC Recessive model; TT tuberculoid leprosyaFollow-up
paucibacillary leprosy 35272 of the odds; LL lepromatous leprosy; MB multibacillary leprosy; MLB maximum likelihood binomial; PB paucibacillary leprosy ; REC Recessive model; TT tuberculoid leprosyaFollow-up association analysis of candidate genes located
tuberculoid leprosy 35320 multibacillary leprosy; MLB maximum likelihood binomial; PB paucibacillary leprosy; REC Recessive model; TT tuberculoid leprosy aFollow-up association analysis of candidate genes located in the regions linked to the disease are not
tuberculosis 431 the presence of mycolic acids within their cell walls. Claiming almost 2 million lives every year, tuberculosis (TB) is the most common mycobacterial disease and is caused by infection with M. tuberculosis and, in
tuberculosis 525 year, tuberculosis (TB) is the most common mycobacterial disease and is caused by infection with M. tuberculosis and, in rare cases, by M. bovis or M. africanum. The second and third most common mycobacterial diseases
tuberculosis 2410 with Bacillus Calmette–Guérin (BCG) vaccine accidentally contaminated with virulent Mycobacterium tuberculosis —the etiological agent of tuberculosis (TB) (Fox et al. [47]). As a consequence, 228 infants developed
tuberculosis 2450 vaccine accidentally contaminated with virulent Mycobacterium tuberculosis—the etiological agent of tuberculosis (TB) (Fox et al. [47]). As a consequence, 228 infants developed clinical disease and 72 died from TB
tuberculosis 2833 available data indicated that different vaccine batches were contaminated with different amounts of M. tuberculosis . It was observed that the bacterial dose had an important impact on the outcome of such exposure, since
tuberculosis 3016 the outcome of such exposure, since increased mortality could be attributed to increased levels of M. tuberculosis contamination. Of note, children who had been inoculated with similar amounts of M. tuberculosis displayed
tuberculosis 3113 M. tuberculosis contamination. Of note, children who had been inoculated with similar amounts of M. tuberculosis displayed a broad spectrum of clinical symptoms ranging from total absence of clinical disease to death.
tuberculosis 4493 buruli ulcer (BU), the third most common mycobacterial disease.TuberculosisTuberculosis is caused by M. tuberculosis and can affect any part of the body but most commonly affects the lungs leading to pulmonary TB (PTB).
tuberculosis 4830 disease, including almost 0.4 million deaths among HIV-positive individuals (WHO [118]). Exposure to M. tuberculosis leads to elimination of the pathogen and no persistent infection in 20–50% of individuals (Abel et
tuberculosis 5247 identification of a major human genetic component linked to lack of TST reactivity in subjects exposed to M. tuberculosis expands the role of genetic factors to infection resistance (Cobat et al. [32], [34]). Genetic findings
tuberculosis 5394 factors to infection resistance (Cobat et al. [32], [34]). Genetic findings of infection resistance to M. tuberculosis were recently reviewed elsewhere (Abel et al. [2]; Orlova and Schurr [82]; Simmons et al. [96]). Among
tuberculosis 5539 (Abel et al. [2]; Orlova and Schurr [82]; Simmons et al. [96]). Among individuals infected with M. tuberculosis , a person can remain in an asymptomatic state known as latent TB infection (LTBI) and never develop
tuberculosis 17694 p = 2.54 × 10−8GWAS genome-wide association study; HIV human immunodeficiency virus; Mtb Mycobacterium tuberculosis ; OR Odds ratio; PTB Pulmonary tuberculosis; Rep replication; TB tuberculosisaFollow-up association analysis
tuberculosis 17737 study; HIV human immunodeficiency virus; Mtb Mycobacterium tuberculosis; OR Odds ratio; PTB Pulmonary tuberculosis ; Rep replication; TB tuberculosisaFollow-up association analysis in independent studies are not included
tuberculosis 17771 virus; Mtb Mycobacterium tuberculosis; OR Odds ratio; PTB Pulmonary tuberculosis; Rep replication; TB tuberculosis aFollow-up association analysis in independent studies are not included in this tablebFor studies in
tuberculosis 19108 Moreover, to consider the heterogeneity of the pathogen genome, the Thai GWAS data were stratified by M. tuberculosis lineage [Beijing (39%) vs. non-Beijing lineages (61%)] (Omae et al. [80]). This approach revealed the
tuberculosis 20141 Interestingly, ASAP1 expression was reduced in dendritic cells (DCs) after stimulation with M. bovis BCG and M. tuberculosis , and the level of reduction correlated with the genotype of an associated SNP. Moreover, ASAP1-depleted
tuberculosis 21463 GWAS which employed both LTBI and clinical disease as outcomes included 3686 PTB patients, 14,724 M. tuberculosis -infected cases (made up of LTBI and clinical TB cases), and nearly 300,000 controls (Sveinbjornsson
tuberculosis 21679 al. [105]). Three SNPs in the human leukocyte antigen (HLA) class II region were associated with M. tuberculosis infection and/or PTB with modest effect on phenotype expression (Table 2). These findings were validated
tuberculosis 22572 as cases and controls, respectively. Due to immunosuppression, HIV-positive patients exposed to M. tuberculosis are at higher risk to progress to active TB. Hence, identification of HIV-positive individuals in TB
tuberculosis 23546 genetic susceptibility factors seem to vary depending on population sample, age-at-diagnosis, and M. tuberculosis lineages. Hence a first task is to define clearer TB phenotypes (e.g., TST/IGRA double positives, presence
tuberculosis 23812 create study designs with tighter age groups and when possible, take into account the causative M. tuberculosis strain. On the genetics side, replication steps should not focus only on associated SNPs since signals
tuberculosis 24320 phenotypes. In TB, transcriptomics has been used to unravel mechanisms of pathogenesis for both M. tuberculosis infection and clinical TB disease. For instance, the study of genome-wide mRNA expression levels before
tuberculosis 24465 disease. For instance, the study of genome-wide mRNA expression levels before and after infection with M. tuberculosis of monocyte-derived dendritic cells (DCs) from healthy individuals by microarray identified 3040 differentially
tuberculosis 25746 prospective study screened and followed the clinical evolution of 6363 adolescents infected with M. tuberculosis for 6 months to 2 years (Zak et al. [125]). A total of 46 subjects progressed to active PTB and their
tuberculosis 25933 progressed to active PTB and their blood transcriptomes were compared with the transcriptomes of 107 M. tuberculosis -infected subjects who remained free of TB. The samples were split in a training and test set and a 16
tuberculosis 26815 sequentially modulated over two years in TB progressors (Scriba et al. [92]).A striking effect of M. tuberculosis infection has also been described for whole blood mRNA and miRNA over a 96 h time course in samples
tuberculosis 27135 expressed (DE) genes with an absolute log fold change > 1, 75% were down-regulated in response to M. tuberculosis . By investigating maximum fold changes in relation to time points for all DE genes, the maximum suppression
tuberculosis 27655 al. [111]). Non-coding genes have previously been shown to be differentially expressed following M. tuberculosis infection (Siddle et al. [95]), and they have been suggested as putative markers of PTB (Chen et al.
tuberculosis 29151 (Wang et al. [116]). Nevertheless, recent work investigated the transcriptomic differences between M. tuberculosis infection-resistant and LTBI subjects and implicated histone deacetylase pathways as putative regulators
tuberculosis 29422 [93]). The transcriptomic assays mentioned above contributed to the knowledge of host response to M. tuberculosis in tissues or cell-types that come in contact with the pathogen/antigens in a series of events that
tuberculosis 29756 first line defense. Alveolar macrophages likely serve this function and studying their response to M. tuberculosis in diverse ethnic cohorts may provide further insights (Maertzdorf et al. [66]).LeprosyThe etiological
tuberculosis 63002 the heterogeneity of the phenotype, to host-environment interactions or to the variability of the M. tuberculosis genome. In leprosy, GWAS and replication studies provided insights into disease pathogenesis and revealed

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