Biology subjects

Lecca, L.

Publications and source records attributed to Lecca, L..

15 recordsLinked to original sources

bioRxiv2026

CD1b-specific T cells are transcriptionally closer to conventional CD4 T cells than to innate-like NKT and MAIT cells

Unconventional T cells recognize non-peptide antigens presented by molecules other than the major histocompatibility complex (MHC) proteins. Among unconventional T cells, natural killer T (NKT) cells, which recognize CD1d-lipid complexes, mucosal-associated invariant T (MAIT) cells, which recognize MR1-metabolite complexes, and {gamma}{delta} T cells, are thoroughly studied. CD1b presents self- and mycobacterial lipids to relatively understudied T cell subsets. Like MAIT cells and type I NKT cells, CD1b-specific cells include subpopulations with conserved TCRs. Consequent to their recognition of a nearly monomorphic antigen-presenting molecule, CD1b-specific T cells might share innate-like features with MAIT, type I NKT, and {gamma}{delta} T cells. Due to their low frequency in the peripheral blood, CD1a-, CD1b-, and CD1c-specific T cells have been studied predominantly as in vitro-expanded clones, so even basic information about their native ex vivo immunophenotypes is lacking. Here, we sort and transcriptionally profile ex vivo two T cell populations that recognize CD1b presenting mycobacterial mycolipids and compare them with conventional CD4 and CD8 T cells, {gamma}{delta} T cells, NK cells, MAIT cells, and NKT cells. We show that both the invariant TCR-expressing CD4+, CD1b-GMM-specific germline encoded mycolyl-reactive (GEM) T cells, as well as the diverse TCR-expressing CD1b-GMM-specific T cells, are transcriptionally closer to conventional T cells than to the innate-like T cell populations {gamma}{delta}, MAIT and type I NKT cells. Thus, despite their recognition of non-polymorphic antigen presenting molecules, CD1b-specific T cells show adaptive rather than innate-like transcriptional features.

immunology↗

bioRxiv2025

Evolution of Mycobacterium tuberculosis transcription regulation is associated with increased transmission and drug resistance

Mycobacterium tuberculosis (Mtb) has co-evolved with humans for thousands of years causing variation in virulence, transmissibility, and disease phenotypes. To identify bacterial contributors to phenotypic diversity, we developed new RNA-seq and phylogenomic tools to capture hundreds of Mtb isolate transcriptomes, link transcriptional and genetic variation, and find associations between variants and epidemiologic traits. Across 274 Mtb clinical isolates, we uncovered unexpected diversity in expression of virulence genes which we linked to known and previously unrecognized regulators. Surprisingly, we found that many isolates harbor variants associated with decreased expression of EsxA (Esat6) and EsxB (Cfp10), which are virulence effectors, dominant T cell antigens, and immunodiagnostic targets. Across >55,000 isolates, these variants associate with increased transmissibility, especially in drug resistant Mtb strains. Our data suggest expression of key Mtb virulence genes is evolving across isolates in part to optimize fitness under drug pressure, with sobering implications for immunodiagnostics and next-generation vaccines.

microbiology↗

bioRxiv2021

Modeling memory T cell states at single-cell resolution identifies in vivo state-dependence of eQTLs influencing disease

Many non-coding genetic variants cause disease by modulating gene expression. However, identifying these expression quantitative trait loci (eQTLs) is complicated by gene-regulation differences between cell states. T cells, for example, have fluid, multifaceted functional states in vivo that cannot be modeled in eQTL studies that aggregate cells. Here, we modeled T cell states and eQTLs at single-cell resolution. Using >500,000 resting memory T cells from 259 Peruvians, we found over one-third of the 6,511 cis-eQTLs had state-dependent effects. By integrating single-cell RNA and surface protein measurements, we defined continuous cell states that explained more eQTL variation than discrete states like CD4+ or CD8+ T cells and could have opposing effects on independent eQTL variants in a locus. Autoimmune variants were enriched in cell-state-dependent eQTLs, such as a rheumatoid-arthritis variant near ORMDL3 strongest in cytotoxic CD8+ T cells. These results argue that fine-grained cell state context is crucial to understanding disease-associated eQTLs.

genetics↗

bioRxiv2021

A sex-specific evolutionary interaction between ADCY9 and CETP

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3,400 Peruvians. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues, which also differs between males and females. We also detected interaction effects of the two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. We propose that ADCY9 and CETP coevolved during recent human evolution due to sex-specific selection, which points towards a biological link between dalcetrapibs pharmacogene ADCY9 and its therapeutic target CETP.

genetics↗

bioRxiv2021

Dual TCR-alpha expression on MAIT cells as a potential confounder of TCR interpretation

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are highly abundant in human blood and tissues. Most MAIT cells have an invariant T cell receptor (TCR) chain that uses TRAV1-2 joined to TRAJ33/20/12 and recognize metabolites from bacterial riboflavin synthesis bound to the antigen-presenting molecule, MR1. Recently, our attempts to identify alternative MR1-presented antigens led to the discovery of rare MR1-restricted T cells with non-TRAV1-2 TCRs. Because altered antigen specificity is likely to lead to altered affinity for the most potent known antigen, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), we performed bulk TCR and {beta} chain sequencing, and single cell-based paired TCR sequencing, on T cells that bound the MR1-5-OP-RU tetramer, but with differing intensities. Bulk sequencing showed that use of V genes other than TRAV1-2 was enriched among MR1-5-OP-RU tetramerlow cells. Whereas we initially interpreted these as diverse MR1-restricted TCRs, single cell TCR sequencing revealed that cells expressing atypical TCR chains also co-expressed an invariant MAIT TCR chain. Transfection of each non-TRAV1-2 TCR chain with the TCR{beta} chain from the same cell demonstrated that the non-TRAV1-2 TCR did not bind the MR1-5-OP-RU tetramer. Thus, dual TCR chain expression in human T cells and competition for the endogenous {beta} chain explains the existence of some MR1-5-OP-RU tetramerlow T cells. The discovery of simultaneous expression of canonical and non-canonical TCRs on the same T cell means that claims of roles for non-TRAV1-2 TCR in MR1 response must be validated by TCR transfer-based confirmation of antigen specificity.

immunology↗

bioRxiv2020

Dysglycemia is associated with Mycobacterium tuberculosis lineages in tuberculosis patients of North Lima - Peru.

This study was performed to investigate the role of dysglycemia on the genetic diversity of Mycobacterium tuberculosis (MTB) among pulmonary tuberculosis (TB) patients to build scientific evidence about the possible mechanisms of TB transmission. MTB isolates obtained of patients affected by pulmonary tuberculosis from health care facilities of North Lima - Peru, were analyzed using whole genome sequencing and 24-locus mycobacterial interspersed repetitive-unit-variable-number tandem repeats (MIRU-VNTR). Subsequently, clinical and epidemiological characteristics were associated with clustering, lineages and comorbid conditions. The analysis carried out 112 pulmonary TB patients from various health centers in North Lima, 17 (15%) had diabetes mellitus (DM) and 33 (29%) had pre-diabetes (PDM). Latin American-Mediterranean, Haarlem and Beijing were the most frequent MTB lineages found in those patients. Previous TB (adjusted odds ratio [aOR]=3.65; 95%CI: 1.32-17.81), age (aOR=1.12; 95%CI: 1.03-1.45) and Beijing lineage (aOR=3.53; 95%CI: 1.08-13.2) were associated with TB-DM comorbidity. Alcoholism (aOR=2.92; 95%CI: 1.10-8.28), age (aOR=1.05; 95%CI: 1.03-1.12) and Haarlem lineage (aOR=2.54; 95%CI: 1.04-6.51) were associated with TB-PDM comorbidity. Beijing and Haarlem lineages were independently associated with TB-DM and TB-PDM comorbidities, respectively. Although these findings may be surprising, we must be cautious to suggest that dysglycemia could be associated with a highly clustering and predisposition of MTB lineages related to a serious impact on the severity of TB disease, which requires further research.

molecular biology↗

bioRxiv2020

Multimodal memory T cell profiling identifies a reduction in a polyfunctional Th17 state associated with tuberculosis progression

Mycobacterium tuberculosis (M.tb) results in 10 million active tuberculosis (TB) cases and 1.5 million deaths each year1, making it the worlds leading infectious cause of death2. Infection leads to either an asymptomatic latent state or TB disease. Memory T cells have been implicated in TB disease progression, but the specific cell states involved have not yet been delineated because of the limited scope of traditional profiling strategies. Furthermore, immune activation during infection confounds underlying differences in T cell state distributions that influence risk of progression. Here, we used a multimodal single-cell approach to integrate measurements of transcripts and 30 functionally relevant surface proteins to comprehensively define the memory T cell landscape at steady state (i.e., outside of active infection). We profiled 500,000 memory T cells from 259 Peruvians > 4.7 years after they had either latent M.tb infection or active disease and defined 31 distinct memory T cell states, including a CD4+CD26+CD161+CCR6+ effector memory state that was significantly reduced in patients who had developed active TB (OR = 0.80, 95% CI: 0.73-0.87, p = 1.21 x 10-6). This state was also polyfunctional; in ex vivo stimulation, it was enriched for IL-17 and IL-22 production, consistent with a Th17-skewed phenotype, but also had more capacity to produce IFN{gamma} than other CD161+CCR6+ Th17 cells. Additionally, in progressors, IL-17 and IL-22 production in this cell state was significantly lower than in non-progressors. Reduced abundance and function of this state may be an important factor in failure to control M.tb infection.

immunology↗

bioRxiv2019

Detection of Mycobacterium tuberculosis in pediatric stool samples using TruTip technology

BackgroundRapid and accurate diagnosis of childhood tuberculosis (TB) is challenging because children are often unable to produce the sputum sample required for conventional tests. Stool is an alternative sample type that is easy to collect from children, and studies investigating the use of stool for molecular detection of Mycobacterium tuberculosis (Mtb) have led to promising results. However, tests performed thus far are not able to examine multi-drug resistance. The TruTip workstation (Akonni Biosystems) is an automated lysis and extraction platform that can be integrated with a closed amplification system to detect both Mtb and resistance-associated mutations. Our objective here was to evaluate the use of TruTip extraction technology for Mtb detection in stool. MethodsWe tested stool samples of 259 children with TB symptoms, ages 0-14 years old, in Lima, Peru. We used the TruTip workstation for sample processing and extraction, followed by IS6110 real-time PCR to detect the presence of Mtb DNA. We calculated assay sensitivity in two groups: (1) children with culture confirmed TB (N=22); and (2) children with unconfirmed, clinically diagnosed TB (N=84). We calculated specificity among children in whom TB was ruled out (N=153). Among children with TB, we examined factors associated with a positive stool test. ResultsOverall assay sensitivity was 59% (95% confidence interval 39%-80%) and 1.2% (0.0%-6.5%) in children with culture-confirmed and clinically-diagnosed TB, respectively, and specificity was 97% (93%-99%). The assay detected Mtb in stool of 7/7 children with smear-positive TB [100% sensitivity; (59%-100%)], and in 6/15 [40% (16%-68%)] of children with smear-negative, culture-confirmed TB. Older age, smear positivity, culture positivity and cavitary disease were associated with a positive stool result. ConclusionFor molecular Mtb detection from stool, the TruTip workstation, in combination with IS6110 amplification, led to sensitivity and specificity estimates comparable to other tests such as Xpert. Future optimization is required to also diagnose TB disease in children who now received an unconfirmed diagnosis.

microbiology↗

bioRxiv2019

A positively selected, common, missense variant in FBN1 confers a 2.2 centimeter reduction of height in the Peruvian population

Peruvians are among the shortest people in the world. To understand the genetic basis of short stature in Peru, we examined an ethnically diverse group of Peruvians and identified a novel, population-specific, missense variant in FBN1 (E1297G) that is significantly associated with lower height in the Peruvian population. Each copy of the minor allele (frequency = 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). This is the largest effect size known for a common height-associated variant. This variant shows strong evidence of positive selection within the Peruvian population and is significantly more frequent in Native American populations from coastal regions of Peru compared to populations from the Andes or the Amazon, suggesting that short stature in Peruvians is the result of adaptation to the coastal environment. One Sentence SummaryA mutation found in Peruvians has the largest known effect on height for a common variant. This variant is specific to Native American ancestry.

genomics↗

bioRxiv2018

Isoniazid preventive therapy protects against tuberculosis among household contacts of isoniazid-resistant patients.

BackgroundThe World Health Organization recommends the use of isoniazid (INH) alone or combination INH and rifapentine therapy to treat latent tuberculosis infection (LTBI) in groups at high risk of tuberculosis (TB) progression. The recent rise of INH- and multi-drug resistant (MDR) TB has complicated the choice of LTBI treatment regimen. We examine the risk of TB disease among household contacts (HHCs) who received INH after being exposed to patients with drug-sensitive, INH-resistant, or MDR tuberculosis. MethodsIn this prospective cohort study conducted Between September 2009 and August 2012 in Lima, Peru, we identified 4,500 index TB patients and measured incident TB disease in their 14,044 HHCs over a one-year follow-up period. HHCs under 19 years of age were offered INH preventive therapy (IPT). We used a Cox frailty proportional hazards model to evaluate whether the effect of IPT on incident TB disease varied by the resistance profile of the index case. We repeated the analyses in a second independent dataset. FindingsAmong 4,216 HHCs under 19 years of age, 2,106 (50%) initiated IPT at enrolment. The protective effect of INH was more extreme in HHCs exposed to drug-sensitive (Hazard Ratio [95% confidence interval]=0{middle dot}2[0{middle dot}20-0{middle dot}50]) and to MDR-TB (0{middle dot}26[0{middle dot}08-0{middle dot}77]) compared to those exposed to mono-INH-resistant (0{middle dot}80[0{middle dot}23 to 2{middle dot}79]). Among those who received at least three months of INH, effectiveness increased across all three groups (INH-sensitive:0{middle dot}20 [0{middle dot}10 to 040]; MDR:0{middle dot}16 [0 02-127]; mono-INH-resistant:0{middle dot}72 [0{middle dot}16-3{middle dot}16]). In the second independent study, TB occurred in none of the 76 HHCs who received IPT compared to 3% (8/273) of those who did not. InterpretationWe found that IPT use is associated with reduced incidence of TB disease among contacts of MDR-TB patients. This finding suggests that INH may have role in the management of MDR-LTBI. FundingNational Institutes of Health and the National Institute of Allergy and Infectious Diseases CETR (U19AI109755) and TBRU (U19AI111224)

epidemiology↗

bioRxiv2018

Vitamin D status and risk of incident tuberculosis disease: a systematic review and individual participant data meta-analysis

BackgroundFew studies have evaluated the association between pre-existing vitamin D deficiency (VDD) and incident TB. We assessed the impact of baseline vitamin D on TB risk. MethodsWe assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6751 household contacts of TB patients in Peru. We also conducted a one-stage individual participant data meta-analysis searching PubMed and Embase for studies of vitamin D and TB until December 31, 2017. We included studies that assessed vitamin D before TB diagnosis. We defined VDD as 25-(OH)D <50 nmol/L, insufficiency as 50-75 nmol/L and sufficiency as >75nmol/L. We estimated the association between vitamin D and incident TB using conditional logistic regression in the Peru cohort and generalized linear mixed models in the meta-analysis. FindingsIn Peru, baseline VDD was associated with a statistically insignificant increase in incident TB (aOR 1{middle dot}70, 95% CI 0{middle dot}84-3{middle dot}46; p=0{middle dot}14). We identified seven studies for the meta-analysis and analyzed 3544 participants. Individuals with VDD and very low vitamin D (<25nmol/L) had increased TB risk (aOR 1{middle dot}48, 95% CI 1{middle dot}04-210;p=0{middle dot} 03 and aOR 2 08, 95% CI 0{middle dot}88-4{middle dot}92; p trend=002 respectively). Among HIV-positive patients, VDD and very low vitamin D conferred a 2-fold (aOR 2.18, 95% CI 1{middle dot} 22-3{middle dot}90; p=0{middle dot} 01) and 4-fold (aOR 4{middle dot}28, 95% CI 0{middle dot}85-21{middle dot}44; p trend=0{middle dot}01) increased risk of TB respectively. InterpretationOur findings suggest vitamin D predicts TB risk in a dose-dependent manner and vitamin D supplementation may play a role in TB prevention. FundingNational Institute of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Dental and Craniofacial Research (NIDCR), Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Foundation, Ujala Foundation, Wyncote Foundation, NIH - Fogarty International Center Program of International Training Grants in Epidemiology Related to AIDS, NIAID Byramjee Jeejeebhoy Medical College HIV Clinical Trials Unit, NIAIDs Baltimore-Washington-India Clinical Trials Unit, National Commission on Biotechnology, the Higher Education Commission, International Research Support Initiative Program of the Higher Education Commission Government of Pakistan, the Bill and Melinda Gates Foundation, and the NIH Fogarty International Center. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSNumerous studies have found lower serum vitamin D levels among patients with active TB disease compared to healthy controls. However, research has not clarified whether low vitamin D increases TB risk or whether TB disease leads to decreased vitamin D levels. We conducted PubMed and Medline searches for all studies available through December 31, 2017 on the association between vitamin D status and TB disease. We included the following keywords: "vitamin D," "vitamin D deficiency," "hypovitaminosis D," "25-hydroxyvitamin D," "1,25-dihydroxyvitamin D," "vitamin D2," "vitamin D3," "ergocalciferol," "cholecalciferol," and "tuberculosis." We found only seven studies had prospectively evaluated the impact of baseline vitamin D levels on risk of progression to TB disease. We report here the results of a case control study nested within a large prospective longitudinal cohort study of household contacts of TB cases and the results of an individual participant data (IPD) metaanalysis of available evidence on the association between vitamin D levels and incident TB disease. Added value of this studyWe demonstrated that low vitamin D levels predicts risk of future progression to TB disease in a dose-dependent manner. Implications of all the available evidenceThese findings suggest the possibility that vitamin D supplementation among individuals at high risk for developing TB disease might play a role in TB prevention efforts.

epidemiology↗

bioRxiv2018

RESISTANCE AT NO COST: THE TRANSMISSIBILITY AND POTENTIAL FOR DISEASE PROGRESSION OF DRUG-RESISTANT M. TUBERCULOSIS

BackgroundThe future trajectory of drug resistant tuberculosis strongly depends on the fitness costs of drug resistance mutations. Here, we measured the association of phenotypic drug resistance and the risk of TB infection and disease among household contacts (HHCs) of patients with pulmonary TB.\n\nMethodsWe evaluated 12767 HHCs of patients with drug sensitive and resistant pulmonary TB at baseline, two, six, and 12 months to ascertain infection status and to determine whether they developed tuberculosis disease. We also assessed the impact of drug resistance phenotype on the likelihood that a TB strain shared a genetic fingerprint with at least one other TB patient in the cohort.\n\nFindingsAmong 3339 TB patients for whom were DST available, 1274 (38%) had TB that was resistant to at least one drug and 478 (14*3%) had multi-drug resistant (MDR) TB, i.e. TB resistant to both INH and rifampicin. Compared to HHCs of drug sensitive TB patients, those exposed to a patient with MDR-TB had an 8% (95% CI: 4-13%) higher risk of infection by the end of follow up. We found no statistically significant difference in the relative hazard of incident TB disease among HHCs exposed to MDR-TB compared to DS-TB (Adjusted HR 1*28 [(95% CI: *9-1*83]). Patients with MDR-TB were more likely to be part of a genetic cluster than were DS-TB patients.\n\nInterpretationClinical strains of MDR M. tuberculosis are neither less transmissible than drug sensitive strains nor less likely to cause disease. (ClinicalTrials.gov number, NCT00676754)\n\nFundingNational Institutes of Health: NIH/NIAID CETR U19AI109755\n\nStatementAll authors have seen the manuscript and approved the manuscript.

epidemiology↗

bioRxiv2018

Genotypic clustering does not imply recent tuberculosis transmission in a high prevalence setting: A genomic epidemiology study in Lima, Peru

BackgroundWhole genome sequencing (WGS) can elucidate Mycobacterium tuberculosis (Mtb) transmission patterns but more data is needed to guide its use in high-burden settings. In a household-based transmissibility study of 4,000 TB patients in Lima, Peru, we identified a large MIRU-VNTR Mtb cluster with a range of resistance phenotypes and studied host and bacterial factors contributing to its spread.\n\nMethodsWGS was performed on 61 of 148 isolates in the cluster. We compared transmission link inference using epidemiological or genomic data with and without the inclusion of controversial variants, and estimated the dates of emergence of the cluster and antimicrobial drug resistance acquisition events by generating a time-calibrated phylogeny. We validated our findings in genomic data from an outbreak of 325 TB cases in London. Using a larger set of 12,032 public Mtb genomes, we determined bacterial factors characterizing this cluster and under positive selection in other Mtb lineages.\n\nFindingsFour isolates were distantly related and the remaining 57 isolates diverged ca. 1968 (95% HPD: 1945-1985). Isoniazid resistance arose once, whereas rifampicin resistance emerged subsequently at least three times. Amplification of other drug resistance occurred as recently as within the last year of sampling. High quality PE/PPE variants and indels added information for transmission inference. We identified five cluster-defining SNPs, including esxV S23L to be potentially contributing to transmissibility.\n\nInterpretationClusters defined by MIRU-VNTR typing, could be circulating for decades in a high-burden setting. WGS allows for an improved understanding of transmission, as well as bacterial resistance and fitness factors.\n\nFundingThe study was funded by the National Institutes of Health (Peru Epi study U19-AI076217 and K01-ES026835 to MRF). The funding sources had no role in any aspect of the study, manuscript or decision to submit it for publication.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSUse of whole genome sequencing (WGS) to study tuberculosis (TB) transmission has proven to have higher resolution that traditional typing methods in low-burden settings. The implications of its use in high-burden settings are not well understood.\n\nAdded value of this studyUsing WGS, we found that TB clusters defined by traditional typing methods may be circulating for several decades. Genomic regions typically excluded from WGS analysis contain large amount of genetic variation that may affect interpretation of transmission events. We also identified five bacterial mutations that may contribute to transmission fitness.\n\nImplications of all the available evidenceAdded value of WGS for understanding TB transmission may be even higher in high-burden vs. low-burden settings. Methods integrating variants found in polymorphic sites and insertions and deletions are likely to have higher resolution. Several host and bacterial factors may be responsible for higher transmissibility that can be targets of intervention to interrupt TB transmission in communities.

microbiology↗

bioRxiv2018

Progression of recent Mycobacterium tuberculosis exposure to active tuberculosis is a highly heritable complex trait driven by 3q23 in Peruvians

Among 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5-15% are expected to develop active tuberculosis (TB). Approximately half of these will progress to active TB within the first 18 months after infection, presumably because they fail to mount the initial immune response that contains the local bacterial spread. The other half will reactivate their latent infection later in life, likely triggered by a loss of immune competence due to factors such as HIV-associated immunosuppression or ageing. This natural history suggests that undiscovered host genetic factors may control early progression to active TB. Here, we report results from a large genome-wide genetic study of early TB progression. We genotyped a total of 4,002 active TB cases and their household contacts in Peru and quantified genetic heritability [Formula] of early TB progression to be 21.2% under the liability scale. Compared to the reported [Formula] of genome-wide TB susceptibility (15.5%), this result indicates early TB progression has a stronger genetic basis than population-wide TB susceptibility. We identified a novel association between early TB progression and variants located in an enhancer region on chromosome 3q23 (rs73226617, OR=1.19; P < 5x10-8). We used in silico and in vitro analyses to identify likely functional variants and target genes, highlighting new candidate mechanisms of host response in early TB progression.

genetics↗

bioRxiv2017

The Impact of Vitamin A and Carotenoids on the Risk of Tuberculosis Progression

BackgroundLow and deficient levels of vitamin A are common in low and middle income countries where tuberculosis burden is high. We assessed the impact of baseline levels of vitamins A and carotenoids on TB disease risk.\n\nMethods and FindingsWe conducted a case-control study nested within a longitudinal cohort of household contacts of pulmonary TB cases in Lima, Peru. We screened all contacts for TB disease at 2, 6, and 12 months after enrollment. We defined cases as HIV-negative household contacts with blood samples who developed TB disease at least 15 days after enrollment of the index patient. For each case, we randomly selected 4 controls from among contacts who did not develop TB disease, matching on gender and year of age. We used conditional logistic regression to estimate odds ratios (ORs) for incident TB disease by vitamin A and carotenoids levels, controlling for other nutritional and socioeconomic factors.\n\nAmong 6751 HIV-negative household contacts with baseline blood samples, 192 developed secondary TB disease during follow-up. We analyzed 180 cases with viable samples and 709 matched controls. After controlling for possible confounders, we found that baseline vitamin A deficiency was associated with a 10-fold increase in risk of TB disease among household contacts (aOR 10.42; 95% CI 4.01-27.05; p < 0.001). This association was dose-dependent with stepwise increases in TB disease risk with each decreasing quartile of vitamin A level. Carotenoid levels were also inversely associated with TB risk among adolescents.\n\nOur study is limited by the one year duration of follow up and by the relatively few blood samples available from household contacts under ten years of age.\n\nConclusionsVitamin A deficiency strongly predicted risk of incident TB disease among household contacts of TB patients. Vitamin A supplementation among individuals at high risk of TB may provide an effective means of preventing TB disease.

epidemiology↗