Human leukocyte antigen associations with protection against tuberculosis infection and disease in human immunodeficiency virus-1 infected individuals, despite household tuberculosis exposure and immune suppression

Seedat, Faheem; James, Ian; Loubser, Shayne; Waja, Ziyaad; Mallal, S.; Hoffmann, Christopher J.; Tiemessen, Caroline T.; Chaisson, Richard E.; Martinson, Neil

doi:10.1016/j.tube.2020.102023

Cited by 7 publications

(4 citation statements)

References 45 publications

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“…Our findings align with previous studies showing the association between HLA class II region and TB (See supplemental information for more detailed description) (Goldfeld et al, 1998;Terán-Escandón et al, 1999;Ravikumaret et al, 1999;Amirzargar et al, 2004;Kim et al, 2005;Sveinbjornsson et al, 2016;Oliveira-Cortez et al, 2016;Qi et al, 2017;Tian et al, 2017;Toyo-Oka et al, 2017;Bhattacharyya, Majumder, and Pandit, 2019;Tang et al, 2019;Seedat et al, 2021;Li et al, 2021). Other genes shown to be associated with TB susceptibility in previous studies, such as ASAP1 (Thye et al, 2012), did not reach genome-wide significance in our study.…”

Section: Discussionsupporting

confidence: 92%

Large Registry Based Analysis of Genetic Predisposition to Tuberculosis Identifies Genetic Risk Factors at HLA

Tervi

Junna

Broberg

et al. 2022

Preprint

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Tuberculosis is a significant public health concern resulting in the death of over 1 million individuals each year worldwide. While treatment options and vaccines exist, a substantial number of infections still remain untreated or are caused by treatment resistant strains. Therefore, it is important to identify mechanisms that contribute to risk and prognosis of tuberculosis as this may provide tools to understand disease mechanisms and provide novel treatment options for those with severe infection. Our goal was to identify genetic risk factors that contribute to the risk of tuberculosis and to understand biological mechanisms and causality behind the risk of tuberculosis. A total of 1,895 individuals in the FinnGen study had ICD-based tuberculosis diagnosis. GWAS analysis identified genetic variants with statistically significant association with tuberculosis at the Human leukocyte antigen (HLA) region (p<5e-8) and at rs560595454 in gene INPP5A. Fine mapping the HLA-association provided evidence for one protective haplotype tagged by HLA DQB1*05:01 (p=1.82E-06, OR = 0.81 [CI 95 % 0.74-0.88]), and predisposing alleles tagged by HLA DRB1*13:02 (p=0.00011, OR = 1.35 [CI 95% 1.16-1.57]). Furthermore, genetic correlation analysis showed association with earlier reported risk factors including smoking (p<0.05). Mendelian randomization supported smoking as a risk factor for tuberculosis (inverse-variance weighted p<0.05, OR = 1.83 [CI 95 % 1.15-2.93]) with no significant evidence of pleiotropy. Our findings indicate that specific HLA alleles and INPP5A associate with the risk of tuberculosis. In addition, lifestyle risk factors such as smoking contribute to the risk of developing tuberculosis.

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Section: Discussionsupporting

confidence: 92%

Large Registry Based Analysis of Genetic Predisposition to Tuberculosis Identifies Genetic Risk Factors at HLA

Tervi

Junna

Broberg

et al. 2022

Preprint

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“…ABHD6 , our top locus using the scoring scheme we developed, produces a lipase that can degrade bis monoacylglycerol phosphate (BMP) and constitutes the major enzyme for BMP catabolism. BMP is expressed in the late endosomes and lysosomes of phagocytosing macrophages [ 12 ]. In most mammalian cells, BMP levels are low, comprising only about 1–2% of total phospholipids.…”

Section: Discussionmentioning

confidence: 99%

“…These individuals, who may resist or clear MTB infection, or acquire infection with a non-IFNγ−centric T-cell response, have been termed resisters (RSTRs) [ 6 , 7 ]. Estimates of prevalence of RSTR varies as a function of follow-up time and method of diagnostics (i.e., tuberculin skin test (TST) and/or interferon gamma release assay (IGRA)), with current estimates in high-exposure settings ranging from 7-25% [ 6 , [8] , [9] , [10] , [11] , [12] ]. This phenotype is important for understanding pathogenesis and is relevant in designing potential vaccines and prevention strategies against TB, as it can provide insight into how individuals respond to prevent infection by MTB, a critical first step to developing disease [ 7 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Resistance to TST/IGRA conversion in Uganda: Heritability and Genome-Wide Association Study

et al. 2021

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Background Pulmonary tuberculosis (TB) is one of the most deadly pathogens on earth. However, the majority of people have resistance to active disease. Further, some individuals, termed resisters (RSTRs), do not develop traditional latent tuberculosis (LTBI). The RSTR phenotype is important for understanding pathogenesis and preventing TB. The host genetic underpinnings of RSTR are largely understudied. Methods In a cohort of 908 Ugandan subjects with genome-wide data on single nucleotide polymorphisms, we assessed the heritability of the RSTR phenotype and other TB phenotypes using restricted maximum likelihood estimation (REML). We then used a subset of 263 RSTR and LTBI subjects with high quality phenotyping and long-term follow-up to identify DNA variants genome-wide associated with the RSTR phenotype relative to LTBI subjects in a case-control GWAS design and annotated and enriched these variants to better understand their role in TB pathogenesis. Results The heritability of the TB outcomes was very high, at 55% for TB vs. LTBI and 50.4% for RSTR vs. LTBI among HIV- subjects, controlling for age and sex. We identified 27 loci associated with the RSTR phenotype (P<5e-05) and our annotation and enrichment analyses suggest an important regulatory role for many of them. Interpretation The heritability results show that the genetic contribution to variation in TB outcomes is very high and our GWAS results highlight variants that may play an important role in resistance to infection as well as TB pathogenesis as a whole.

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“…Human MHC molecules are also known as human leukocyte antigen (HLA). The HLA gene is located at the end of the short arm of human chromosome 6 and is divided into three regions: HLA Class I, HLA Class II, and HLA Class III ( 101 ). HLA genes with antigen presentation function are classic HLA genes located in HLA class I and HLA class II regions.…”

Section: The Development Of Bioinformatics Technology Has Laid the Fo...mentioning

confidence: 99%

Peptide-Based Vaccines for Tuberculosis

Gong

Pan²,

Cheng

et al. 2022

Front. Immunol.

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Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. As a result of the coronavirus disease 2019 (COVID-19) pandemic, the global TB mortality rate in 2020 is rising, making TB prevention and control more challenging. Vaccination has been considered the best approach to reduce the TB burden. Unfortunately, BCG, the only TB vaccine currently approved for use, offers some protection against childhood TB but is less effective in adults. Therefore, it is urgent to develop new TB vaccines that are more effective than BCG. Accumulating data indicated that peptides or epitopes play essential roles in bridging innate and adaptive immunity and triggering adaptive immunity. Furthermore, innovations in bioinformatics, immunoinformatics, synthetic technologies, new materials, and transgenic animal models have put wings on the research of peptide-based vaccines for TB. Hence, this review seeks to give an overview of current tools that can be used to design a peptide-based vaccine, the research status of peptide-based vaccines for TB, protein-based bacterial vaccine delivery systems, and animal models for the peptide-based vaccines. These explorations will provide approaches and strategies for developing safer and more effective peptide-based vaccines and contribute to achieving the WHO’s End TB Strategy.

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Human leukocyte antigen associations with protection against tuberculosis infection and disease in human immunodeficiency virus-1 infected individuals, despite household tuberculosis exposure and immune suppression

Cited by 7 publications

References 45 publications

Large Registry Based Analysis of Genetic Predisposition to Tuberculosis Identifies Genetic Risk Factors at HLA

Large Registry Based Analysis of Genetic Predisposition to Tuberculosis Identifies Genetic Risk Factors at HLA

Resistance to TST/IGRA conversion in Uganda: Heritability and Genome-Wide Association Study

Peptide-Based Vaccines for Tuberculosis

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