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. 2023 Jan 13;14(1):207.
doi: 10.3390/genes14010207.

Comparative Genetic Association Analysis of Human Genetic Susceptibility to Pulmonary and Lymph Node Tuberculosis

Abhimanyu  1   2 , Mridula Bose  1 , Astha Giri  1 , Mandira Varma-Basil  1
Affiliations

Comparative Genetic Association Analysis of Human Genetic Susceptibility to Pulmonary and Lymph Node Tuberculosis

Abhimanyu et al. Genes (Basel). .

Abstract

Background: Tuberculosis (TB) manifests itself primarily in the lungs as pulmonary disease (PTB) and sometimes disseminates to other organs to cause extra-pulmonary TB, such as lymph node TB (LNTB). This study aimed to investigate the role of host genetic polymorphism in immunity related genes to find a genetic basis for such differences.

Methods: Sixty-three, Single nucleotide polymorphisms (SNPs) in twenty-three, TB-immunity related genes including eleven innate immunity (SLCA11, VDR, TLR2, TLR4, TLR8, IRGM, P2RX7, LTA4H, SP110, DCSIGN and NOS2A) and twelve cytokine (TNFA, IFNG, IL2, Il12, IL18, IL1B, IL10, IL6, IL4, rs1794068, IL8 and TNFB) genes were investigated to find genetic associations in both PTB and LNTB as compared to healthy community controls. The serum cytokine levels were correlated for association with the genotypes.

Results: PTB and LNTB showed differential genetic associations. The genetic variants in the cytokine genes (IFNG, IL12, IL4, TNFB and IL1RA and TLR2, 4 associated with PTB susceptibility and cytokine levels but not LNTB (p < 0.05). Similarly, genetic variants in LTA4H, P2RX7, DCSIGN and SP110 showed susceptibility to LNTB and not PTB. Pathway analysis showed abundance of cytokine related variants for PTB and apoptosis related variants for LNTB.

Conclusions: PTB and LNTB outcomes of TB infection have a genetic component and should be considered for any future functional studies or studies on susceptibility to pulmonary and extra-pulmonary TB.

Keywords: cytokine; extra-pulmonary tuberculosis; genetic association; genotype; innate immunity; lymph node tuberculosis; pulmonary tuberculosis; serum; single nucleotide polymorphisms.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Some of the results were submitted to the funders as a part of the final project report. This work was part of doctoral thesis of Dr. Abhimanyu, Th 19865, University of Delhi. This work has been presented as poster at the Indian Society for Human Genetics conference by Dr Abhimanyu and at the Indian association of medical microbiologist meeting by Astha Giri.

Figures

Figure 1
Figure 1
The study groups show homogeneity forming a tight cluster showing no stratification in the samples. Figure depicts a three-dimensional plot for checking population stratification among the study groups i.e., PTB (green spheres), LNTB (Purple Spheres) and HC (green Spheres). Raw Hamming distances as multidimensional scaling (MDS) co-ordinates are plotted on X, Y and Z-axes, to visualize genetic distance between the study groups.
Figure 2
Figure 2
Cytokine levels have limited correlation with genotypes in LNTB. (A) Increased cytokine levels in LNTB (n = 50, red) vs HC (n = 84, Blue). The groups were compared using a multiple Mann-Whitney test. ***** p < 0.00001, *** p < 0.001, ** p < 0.01, * p < 0.05, (B) Heatmap of overall ANOVA p-Values of 34 SNPs in the cytokine genes with the corresponding cytokine levels. Shades of Red depict non-significant p-values and shades of blue significant p-value. Only significant variant, IL18 at rs3882891 is shown with the genotypes with their respective levels, where AA genotype individuals are highest IL18 producers and compared to CA and CC (p < 0.05) genotypes.
Figure 3
Figure 3
PTB and LNTB risk associated SNP related genes enrich in different pathways. Pathways enriched in PTB (A) and LNTB (B) through a pathway analysis based on the SNPs with significant p-values. The modules obtained from JActivemodules were used for enrichment in ClueGO App in Cytoscape. Two metrics, %Associated genes (proportion of genes in the pathway from the network of all genes) and Term p-value (enrichment p-value) is plotted here to show the abundance of the pathway with all the input genes and the p-value for the GO term obtained from WikiPathways.
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