Association of human leukocyte antigen DRB1 polymorphism and tuberculosis: a meta-analysis

Pl, Yang; He, Xijing; Qj, Zang; Hp, Li; Wang, Guoyu; Qin, Jiaqian

doi:10.5588/ijtld.14.0930

Cited by 5 publications

(5 citation statements)

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“…All 15-mer mTCEs tested showed high affinity predicted binding to multiple DR alleles (>60%) prevalent in India (Figure 6C: refer to median percentage of each group of mTCEs binding to Group A DR alleles), with the exception of mTCEs equal in India and outside India and mTCEs enriched outside India, which showed predicted binding to only few (<35% median) DR alleles. Interestingly, HLA-DRB1 * 03, HLA-DRB1 * 04 & HLA-DRB1 * 08 have been associated with TB protection/disease (68, 69); Group-A includes HLA-DRB1 * 03:01, * 04:02, * 04:08, and * 04:10 all of which bind ≧60% (>12/20) peptides tested with high predicted binding affinity. Together, these data provide strong evidence that MHC Class II DR binding patterns likely reflect whether an mTCE is (i) exclusive to India, (ii) enriched in India but can be found infrequently globally, (iii) in equal proportion in India vs. the rest of the world or (iv) enriched outside India.…”

Section: Resultsmentioning

confidence: 99%

Evidence for Highly Variable, Region-Specific Patterns of T-Cell Epitope Mutations Accumulating in Mycobacterium tuberculosis Strains

et al. 2019

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Vaccines that confer protection through induction of adaptive T-cell immunity rely on understanding T-cell epitope (TCE) evolution induced by immune escape. This is poorly understood in tuberculosis (TB), an ancient, chronic disease, where CD4 T-cell immunity is of recognized importance. We probed 905 functionally validated, curated human CD4 T cell epitopes in 79 Mycobacterium tuberculosis (Mtb) whole genomes from India. This screen resulted in identifying 64 mutated epitopes in these strains initially using a computational pipeline and subsequently verified by single nucleotide polymorphism (SNP) analysis. SNP based phylogeny revealed the 79 Mtb strains to cluster to East African Indian (EAI), Central Asian Strain (CAS), and Beijing (BEI) lineages. Eighty-nine percent of the mutated T-cell epitopes (mTCEs) identified in the 79 Mtb strains from India has not previously been reported. These mTCEs were encoded by genes with high nucleotide diversity scores including seven mTCEs encoded by six antigens in the top 10% of rapidly divergent Mtb genes encoded by these strains. Using a T cell functional assay readout, we demonstrate 62% of mTCEs tested to significantly alter CD4 T-cell IFNγ and/or IL2 secretion with associated changes in predicted HLA-DR binding affinity: the gain of function mutations displayed higher predicted HLA-DR binding affinity and conversely mutations resulting in loss of function displayed lower predicted HLA-DR binding affinity. Most mutated antigens belonged to the cell wall/cell processes, and, intermediary metabolism and respiration families though all known Mtb proteins encoded mutations. Analysis of the mTCEs in an SNP database of 5,310 global Mtb strains identified 82% mTCEs to be significantly more prevalent in Mtb strains isolated from India, including 36 mTCEs identified exclusively in strains from India. These epitopes had a significantly higher predicted binding affinity to HLA-DR alleles that were highly prevalent in India compared to HLA-DR alleles rare in India, highlighting HLA-DR maybe an important driver of these mutations. This first evidence of region-specific TCE mutations potentially employed by Mtb to escape host immunity has important implications for TB vaccine design.

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Section: Resultsmentioning

confidence: 99%

Evidence for Highly Variable, Region-Specific Patterns of T-Cell Epitope Mutations Accumulating in Mycobacterium tuberculosis Strains

et al. 2019

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“…Accordingly, in a population from South Africa, DRB1*08: 03 allele has found to be strongly positively associated with drug-resistance, increase in lung damage and resurgence of TB [75] . Another recent meta-analysis including 19 case-control studies also confirmed the DRB1*03 protection and DRB1*08 risk effect and added DRB1*04 and DRB1*16 as markers associated with an increased infection occurrence, concluding also that both ethnicity and genotyping methods affect the association between several HLA-DRB1 alleles and TB occurrence [76] . Confirming DRB1*04, DRB1*15 and DRB1*16, and adding DRB1*09 and DRB1*10 as polymorphisms that may contribute to the risk of TB, especially in East Asian, and identifying DRB1*11 as conferring protection, a 31 studies meta-analysis fail to support a significant association between the HLA-DRB1*01, *03, *07, *08, *12, *13, and *14 gene polymorphisms and TB risk [77] .…”

Section: Pulmonary Tuberculosismentioning

confidence: 92%

HLA Loci and Respiratory Infectious Diseases

Spínola

2016

Journal of Respiratory Research

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The HLA system harbour a wide set of genes that plays an important role in the regulation and action of the immune system against invading pathogens, making them natural candidates for research on the genetic susceptibility for respiratory infections. Thus, along past decades, this topic has been subject to intense research and, consequently, several alleles of those loci have been implicated in the ability, more or less effective, to tackle and control invading pathogens in the respiratory system. Current editorial introduce, revise, summarize and comment the major advances in the role of HLA genes for the development of, and protection against, respiratory infectious disease. A general picture is drawn and new challenges on the field are relocated, especially those that might enlighten respiratory diseases aetiology and, thus, contribute in advances for diagnosis and treatment.

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“…Finally, the few existing HLA association studies in individuals of African ancestry indicate considerable deviation from the effects in other groups, the majority of which were identified in individuals of European or Asian populations (Fingerlin et al, 2015;Malkova et al, 2020;Tong et al, 2015;Yang et al, 2016). This study probed for HLA associations with outcomes of Mtb exposure in individuals from a densely populated region of Kampala, Uganda (Mchenry et al, 2021;Stein et al, 2018Stein et al, , 2019, whereas associations with sarcoidosis outcomes were assessed in Americans of African ancestry (ACCESS Research Group, 1999;Baughman et al, 2001;Rybicki et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Variants within the human leukocyte antigen (HLA) genomic region are associated with both active tuberculosis disease (Tong et al, 2015; Yang et al, 2016) and sarcoidosis (Fingerlin et al, 2015). The class II HLA loci: DRB1, DQB1, and DPB1 are of particular concern due to their central role in antigen recognition and presentation to helper T cells via antigen‐presenting cells, which is the initial mechanism leading to granuloma formation and persistence that characterizes both tuberculosis disease and sarcoidosis (Grunewald et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest‐neighbor feature selection

Dawkins

Garman

Cejda

et al. 2022

Genetic Epidemiology

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Tuberculosis and sarcoidosis are inflammatory diseases characterized by granulomas that may occur in any organ but are often found in the lung. The panoply of classical human leukocyte antigen (HLA) alleles associated with occurrence and/or severity of both diseases varies considerably across studies. This heterogeneity of results, due to variation in factors like ancestry and disease subphenotype, as well as the use of simple modeling strategies to elucidate likely complex relationships, has made conclusions about underlying commonalities difficult. Here we perform HLA association analyses in individuals of African ancestry, using a greater resolution to include subphenotypes of disease and employing more comprehensive analytical techniques. Using a novel application of nearest‐neighbor feature selection to score allelic importance, we investigated HLA allele association with Mycobacterium tuberculosis exposure outcomes in the first analysis of both latent Mycobacterium tuberculosis infection and active disease compared with those who, despite long‐term exposure to active index cases, have neither positive diagnostic tests nor display clinical symptoms. We also compared persistent to resolved sarcoidosis. This led to the identification of novel HLA associations and evidence of main effects and interaction effects. We found strikingly similar main effects and interaction effects at HLA‐DRB1, ‐DQB1, and ‐DPB1 in those resistant to tuberculosis (either latent or active) and persistent sarcoidosis.

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Association of human leukocyte antigen DRB1 polymorphism and tuberculosis: a meta-analysis

Abstract: These results reinforce the importance of HLA-DRB1 alleles in the development of infectious diseases.

Cited by 5 publications

References 0 publications

Evidence for Highly Variable, Region-Specific Patterns of T-Cell Epitope Mutations Accumulating in Mycobacterium tuberculosis Strains

Evidence for Highly Variable, Region-Specific Patterns of T-Cell Epitope Mutations Accumulating in Mycobacterium tuberculosis Strains

HLA Loci and Respiratory Infectious Diseases

Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest‐neighbor feature selection

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