Helicobacter pylori (H. pylori) is a Gram-negative bacterium involved in the development of gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue. Unexplained iron deficiency anemia, idiopathic thrombocytopenic purpura and vitamin B12 deficiency have also been related to H. pylori infection, whereas for other extra-gastric diseases, the debate is still open. In this review, we evaluate and discuss the potential involvement of H. pylori infection in the pathogenesis of several respiratory diseases. A MEDLINE search of all studies published in English from 1965 to 2021 was carried out. Controversial findings have been reported in patients with bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, lung cancer, tuberculosis, cystic fibrosis, and sarcoidosis. Most of the available literature is concerned with case-control studies based on seroprevalence, with a small sample size and low consideration of confounders, which represents a potential issue. So far, there is no clear evidence of a causal association between H. pylori infection and respiratory diseases, and larger studies with appropriate epidemiological design are required.

• Helicobacter pylori
• asthma
• chronic obstructive pulmonary disease
• respiratory diseases

• Johne's disease
• Mycobacterium avium subsp. paratuberculosis
• genome-wide association study
• host resistance and susceptibility
• innate immunity
• livestock
• single nucleotide polymorphisms

• Allele
• HLA
• Indonesia
• global disease

• HLA-DPA
• HLA-DPB
• HLA-DQB
• Xinjiang Uygur
• susceptibility
• tuberculosis

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• China
• Female
• HLA-DP alpha-Chains/genetics
• HLA-DP beta-Chains/genetics
• HLA-DQ Antigens/genetics
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Tuberculosis, Pulmonary/genetics

• Adolescent
• Adult
• Animals
• BCG Vaccine/immunology
• BCG Vaccine/therapeutic use
• CD4-Positive T-Lymphocytes/immunology
• Child
• Child, Preschool
• Coinfection
• Disease Susceptibility/immunology
• Humans
• Infant
• Infant, Newborn
• Interferon-gamma/immunology
• Mycobacterium tuberculosis/immunology
• Mycobacterium tuberculosis/isolation & purification
• Risk Factors
• Tuberculosis, Multidrug-Resistant/epidemiology
• Tuberculosis, Multidrug-Resistant/microbiology
• Tuberculosis, Multidrug-Resistant/mortality
• Tuberculosis, Multidrug-Resistant/prevention & control
• Vaccination

• MC_EX_MR/K011944/1 Medical Research Council
• MC_EX_MR/P024270/1 Medical Research Council
• MC_UP_A900_1122 Medical Research Council
• MR/R007942/1 Medical Research Council
• MR/K023446/1 Medical Research Council
• SRF-2009-02-07 Department of Health
• MC_UU_00026/2 Medical Research Council

• M. africanum
• HLA
• Mali
• West Africa
• tuberculosis

Tuberculosis (TB) is still remains the major threat for human health worldwide. Several case-control, candidate-gene, family studies and genome-wide association studies (GWAS) suggested the association of host genetic factors to TB susceptibility or resistance in various ethnic populations. Moreover, these factors modulate the host immune responses to tuberculosis. Studies have reported genetic markers to predict TB development in human leukocyte antigen (HLA) and non-HLA genes like killer immunoglobulin-like receptor (KIR), toll-like receptors (TLRs), cytokine/chemokines and their receptors, vitamin D receptor (VDR) and SLC11A1 etc. Highly polymorphic HLA loci may influence antigen presentation specificities by modifying peptide binding motifs. The recent meta-analysis studies revealed the association of several HLA alleles in particular class II HLA-DRB1 with TB susceptibility and valuable marker for disease development especially in Asian populations. Case-control studies have found the association of HLA-DR2 in some populations, but not in other populations, this could be due to an ethnic specific association of gene variants. Recently, GWAS conducted in case-control and family based studies in Russia, Chinese Han, Morocco, Uganda and Tanzania revealed the association of genes such as ASAP1, Alkylglycerol monooxygenase (AGMO), Forkhead BoxP1 (FOXP1), C-terminal domain phosphatase 1 (UBLCP1) and intergenic SNP rs932347C/T with TB. Whereas, SNP rs10956514A/G were not associated with TB in western Chinese Han and Tibetan population. In this review, we summarize the recent findings of genetic variants with susceptibility/resistance to TB.

• HLA genes
• Mycobacterium tuberculosis
• Non HLA genes
• cytokine and chemokine polymorphisms
• genetic polymprhisms in TB
• host genetics

Spinal tuberculosis (STB) is the main cause of bone and joint tuberculosis. This study aimed to screen and analyze the susceptibility genes for STB using whole-exome sequencing (WES).

All exon regions of peripheral blood DNA from 6 STB patients were captured and sequenced using WES and the sequencing data were analyzed by modern bioinformatics methods to identify disease-causing mutations. Sanger sequencing was then used to validate the mutation sites in normal controls (207) and STB patients (193). The mRNA expression of the mutant gene and the serum levels of IL-6 and TNF-α were detected using qPCR or ELISA assay, respectively.

A nonsynonymous single-nucleotide polymorphism (SNP) in the gene HLA-DQA1 (rs796778515, c.592delCinsG, CAG to GAG, p.Q198E) was identified and further validated by Sanger sequencing. The percentage of the 3 genotypes C/C, C/G and G/G in STB patients and normal controls were 37.3%, 32.1%, and 30.6% and 47.8%, 33.8%, and 18.4%, respectively. Furthermore, the C>G mutation was significantly associated with the occurrence of STB. In addition, the levels of HLA-DQA1 mRNA were significantly lower in blood cells from STB patients compared with normal controls, while the serum levels of IL-6 and TNF-α were significantly higher.

The C>G mutation in the HLA-DQA1 gene was associated with the occurrence of STB. This variation may result in the decreased level of HLA-DQA1 mRNA and increased serum levels of IL-6 and TNF-α, which finally led the STB susceptibility.

Buruli ulcer (BU) is a chronic necrotizing disease of the skin and subcutaneous fat tissue. The causative agent, Mycobacterium ulcerans, produces mycolactone, a macrolide toxin, which causes apoptosis of mammalian cells. Only a small proportion of individuals exposed to M. ulcerans develop clinical disease, as surrounding macrophages may control the infection by bacterial killing at an early stage, while mycolactone concentration is still low. Otherwise, bacterial multiplication leads to in higher concentrations of mycolactone, with formation of necrotizing lesions that are no more accessible to immune cells. By typing a cohort of 96 Ghanaian BU patients and 384 endemic controls without BU, we show an association between BU and single nucleotide polymorphisms (SNPs) in iNOS (rs9282799) and IFNG (rs2069705). Both polymorphisms influence promoter activity in vitro. A previously reported SNP in SLC11A1 (NRAMP, rs17235409) tended to be associated with BU. Altogether, these data reflect the importance of IFNG signaling in early defense against M. ulcerans infection.

• Buruli ulcer
• Mycobacterium ulcerans
• immunogenetics
• infectious diseases
• single nucleotide polymorphism

• First Nations
• Genetics
• HLA
• Immunity
• TB

Tuberculosis remains a global public health problem, and its immunopathogenesis is still poorly understood. In this study, 25 single nucleotide polymorphisms (SNPs) in the WNT pathway were evaluated in relation to tuberculosis risk in a Chinese Han discovery set, and 6 candidate susceptible SNPs were further validated in a Chinese Tibetan cohort. Luciferase reporter assay, RT-qPCR and Western blot were used to assess the functionality of the important WNT polymorphisms. Five polymorphisms were associated with tuberculosis susceptibility after Bonferroni correction: SFRP1 rs4736958, CTNNB1 rs9859392, rs9870255 and rs3864004 showed decreased tuberculosis risk; SFRP1 rs7832767 was related to an increased risk (OR = 1.81, 95% CI = 1.30–2.52, p = 0.010). Patients with TT genotype of rs4736958 and rs7832767 correlated with higher CRP concentrations (p = 0.003, <0.001, respectively). Functional assays revealed that mutant alleles of rs9859392 (G), rs9870255 (C) and rs3864004 (A) were associated with significantly decreased transcriptional activity, lower CTNNB1 mRNA expression and p-β-catenin level, which were consistent with their effects of decreasing TB risk. Our results provide evidences that WNT pathway polymorphisms influence tuberculosis susceptibility and host immune response to Mycobacterium tuberculosis, suggesting that these variations may serve as novel markers for identifying the risk of developing tuberculosis.

The level of susceptibility to tuberculosis (TB) infection depends upon allelic variations in numerous interacting genes. In our mouse model system, the whole-genome quantitative trait loci (QTLs) scan revealed three QTLs involved in TB control on chromosomes 3, 9, and in the vicinity of the H2 complex on chromosome 17. For the present study, we have established a panel of new congenic, MHC-recombinant mouse strains bearing differential small segments of chromosome 17 transferred from the TB-susceptible I/St (H2^j) strain onto the genetic background of TB-resistant C57BL/6 (B6) mice (H2^b). This allowed narrowing the QTL interval to 17Ch: 33, 77–34, 34 Mb, containing 36 protein-encoding genes. Cloning and sequencing of the H2^j allelic variants of these genes demonstrated profound polymorphic variations compare to the H2^b haplotype. In two recombinant strains, B6.I-249.1.15.100 and B6.I-249.1.15.139, recombination breakpoints occurred in different sites of the H2-Aβ 1 gene (beta-chain of the Class II heterodimer H2-A), providing polymorphic variations in the domain β1 of the Aβ-chain. These variations were sufficient to produce different TB-relevant phenotypes: the more susceptible B6.I-249.1.15.100 strain demonstrated shorter survival time, more rapid body weight loss, higher mycobacterial loads in the lungs and more severe lung histopathology compared to the more resistant B6.I-249.1.15.139 strain. CD4⁺ T cells recognized mycobacterial antigens exclusively in the context of the H2-A Class II molecule, and the level of IFN-γ-producing CD4⁺ T cells in the lungs was significantly higher in the resistant strain. Thus, we directly demonstrated for the first time that the classical H2- Ab1 Class II gene is involved in TB control. Molecular modeling of the H2-A^j product predicts that amino acid (AA) substitutions in the Aβ-chain modify the motif of the peptide–MHC binding groove. Moreover, unique AA substitutions in both α- and β-chains of the H2-A^j molecule might affect its interactions with the T-cell receptor (TCR).

Many genes of the host regulate interactions with Mycobacterium tuberculosis and determine the level of susceptibility to, and severity of, tuberculosis (TB). Identification of these genes and their alleles is continuing and contributes new knowledge about the host-pathogen interactions. So far, forward genetic approaches (from phenotype to gene) have identified several chromosomal segments involved in genetic control of TB in mice (quantitative trait loci—QTL), but only one particular gene, Ipr1, has been identified. Here, we report the identification of a second TB-controlling gene. On the basis of a pair of mouse inbred strains with polar susceptibility to TB infection (susceptible I/St and more resistant C57BL/6) we established a panel of recombinant strains carrying small segments of Chromosome 17 from I/St on the genetic background of C57BL/6. A combination of genetic mapping, gene sequencing, TB phenotypes assessment and immunological approaches demonstrates that the H2-Ab1 gene encoding the beta-chain of the Class II heterodimer H2-A determines susceptibility to TB infection. The importance of allelic polymorphisms in Class II genes encoding antigen-presenting molecules in susceptibility to infection has been suspected. This is the first prove of this role obtained by the methods of classical forward genetics.

• Alleles
• Animals
• Antigen-Presenting Cells/immunology
• Chromosome Mapping
• Disease Models, Animal
• Genetic Association Studies
• Haplotypes
• Humans
• Mice
• Mycobacterium tuberculosis/immunology
• Mycobacterium tuberculosis/pathogenicity
• Quantitative Trait Loci/genetics
• Receptors, Antigen, T-Cell, alpha-beta/genetics
• Recombination, Genetic
• T-Lymphocytes/immunology
• T-Lymphocytes/pathology
• Tuberculosis/genetics
• Tuberculosis/microbiology
• Tuberculosis/pathology

• CD4+
• CD8+
• HIV co-infection
• IL-10-producing immunosuppressive and Treg cells
• TB
• Th1 and Th17 cells

We analyzed for association between the Family with sequence similarity 46, member A (FAM46A) gene (located on chromosome 6q14.1), BCL2-Associated Athanogene 6 (BAG6) gene (located on chromosome 6p21.3) and tuberculosis in Croatian Caucasian. We genotyped the FAM46A rs11040 SNP, FAM46A VNTR and BAG6 rs3117582 polymorphisms in a case-control study with 257 tuberculosis patients and 493 healthy individuals in a Croatian Caucasian population. We found that genotype FAM46A 3/3 (three VNTR repeats homozygote) was associated with susceptibility to tuberculosis (p<0.0015, P_corr.<0.029, Odds ratio = 2.42, 95% Confidence Interval = 1.34–4.3). This association suggests that the protein domain encoded by the VNTR might be important for the function of the FAM46A protein, which, in turn, could be relevant in developing tuberculosis. In addition, we found that FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotype 132 (G-3-C) is associated with susceptibility to tuberculosis (p<0.012, p_corr.<0.024, Odds ratio 3.45, 95% Confidence Interval = 1.26–9.74). This may suggests that the interaction between the FAM46A and BAG6 proteins may be involved in tuberculosis etiology. We found also that infection of human macrophages with heat-killed M. tuberculosis (H37Rv) led to over-expression of FAM46A (VNTR 3/4) transcript. This is the first study to show associations between the FAM46A gene VNTR polymorphisms, FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotypes and any disease.

• Adaptor Proteins, Signal Transducing/genetics
• Adult
• Alleles
• Croatia
• Female
• Genetic Predisposition to Disease
• Genotype
• Haplotypes
• Homozygote
• Humans
• Macrophages/microbiology
• Male
• Middle Aged
• Mycobacterium tuberculosis
• Polymorphism, Single Nucleotide
• Polynucleotide Adenylyltransferase
• Proteins/genetics
• Tandem Repeat Sequences
• Tuberculosis/genetics

Background. To explore the potential role of natural-resistance-associated macrophage protein 1 (NRAMP1) gene, vitamin D receptor (VDR) gene, (human leukocyte antigen, (HLA-DRB1) HLA) -DRB1 gene, and HLA-DQB1 gene polymorphisms in susceptibility to tuberculosis (TB) in the Chinese Kazakh population. Methods. A case-control study was performed on the Chinese Kazak population. Genetic polymorphisms of NRAMP1 gene (3′UTR) and VDR gene (TaqI and FokI) were analysed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing analysis in TB patients and healthy controls. Genetic polymorphisms of HLA-DRB1 gene and HLA-DQB1 gene in the two groups were detected with polymerase chain reaction-sequence-specific primers (PCR-SSPs) technique and sequencing analysis. Results. There was statistically significant difference in the 3′UTR polymorphism between the TB patients and healthy controls in the Chinese Kazak population (P = 0.002; OR = 1.859; 95% CI = 1.182–2.926). Significant difference was observed in the FokI polymorphism between the TB patients and healthy controls (P = 0.001; OR = 1.530; 95% CI = 1.007–2.325). It does not disclose any significant association between the disease and TaqI (P > 0.05). Alleles HLA-DRB1∗04 and HLA-DQB1∗0201 occurred more frequently in patients than in controls (P = 0.011 and 0.002; OR = 1.889 and 1.802; 95% CI = 1.153–3.095 and 1.230–2.639, resp.). Conclusions. Polymorphisms in the NRAMP1 gene, VDR gene, HLA-DRB1 gene, and HLA-DQB1 gene are statistically associated with susceptibility to TB in the Chinese Kazakh population.

• Innate immunity
• MBL2
• Polymorphisms
• Pulmonary
• Tuberculosis

• Adult
• Age Factors
• Alleles
• Case-Control Studies
• Chromosomes, Human, Pair 8
• Female
• Genetic Linkage
• Genetic Loci
• Genetic Predisposition to Disease
• Genotype
• High Mobility Group Proteins/genetics
• Humans
• Linkage Disequilibrium
• Madagascar
• Male
• Morocco
• Mycobacterium tuberculosis/isolation & purification
• Polymorphism, Single Nucleotide
• Tuberculosis, Pulmonary/genetics
• Tuberculosis, Pulmonary/microbiology
• White People

• U01 AI088685 NIAID NIH HHS
• 5UL1RR024143-04 NCRR NIH HHS
• 268777 European Research Council
• R01 AI089970 NIAID NIH HHS
• U01AI088685 NIAID NIH HHS
• UL1 RR024143 NCRR NIH HHS
• 1R01AI089970-01 NIAID NIH HHS

• AIDS-Related Opportunistic Infections/epidemiology
• AIDS-Related Opportunistic Infections/genetics
• AIDS-Related Opportunistic Infections/immunology
• Africa/epidemiology
• Antitubercular Agents/therapeutic use
• Brazil/epidemiology
• CD8-Positive T-Lymphocytes/immunology
• Female
• Genetic Predisposition to Disease
• HIV-1/genetics
• Humans
• India/epidemiology
• Male
• Polymorphism, Genetic
• Tuberculosis/epidemiology
• Tuberculosis/genetics
• Tuberculosis/immunology