|Year : 2021 | Volume
| Issue : 2 | Page : 138-144
|A study on the impact of genetic polymorphisms of cytokines TNFα, IFNγ and IL10 in South Indian leprosy patients
Venkata Karunakar Kolla1, Shehnaz Sultana1, Samuel Abraham Joshi Davala2, Vijaya Lakshmi Valluri3
1 Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad, Telangana, India
2 Department of Cell Biology, Begumpet, Hyderabad, Telangana, India
3 Bhagwan Mahavir Medical Research Centre, AC Guards, Hyderabad, Telangana, India
|Date of Web Publication||16-Apr-2021|
Vijaya Lakshmi Valluri
Scientist and HOD, Immunology and Molecular Biology Department, Bhagwan Mahavir Medical Research Centre, A. C. Guards, Hyderabad - 500 004, Telangana
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Leprosy (Hansen's disease) is a chronic, debilitating disease predominantly of the peripheral nervous system characterized by the impairment of peripheral nerves and subsequent sensory loss caused by Mycobacterium leprae. The pro- and antiinflammatory cytokine genes play a major role in nerve damage in leprosy. Aims and Objectives: The objective of the present study is to ascertain the association of cytokine gene polymorphisms TNFα -308G/A (rs 1800629), IFNγ +874A/T (rs 2430561), and IL10 -1082G/A rs 1800896 in causation with leprosy. Materials and Methods: The present study comprised 365 leprosy patients and 185 control subjects. The polymorphisms in TNFα-308, IFNγ+874, and IL10-1082 genes were typed using the amplification refractory mutation system polymerase chain reaction method (ARMS PCR). Results: The present study found significant association between IL10-1082 GA heterozygote (P < 0.02) and IFNγ+874 AA (P < 0.001) genotype and leprosy. TNFα-308GA could not establish any association with the disease. Conclusion: The identification of genetic variations in pro- and antiinflammatory cytokines that are susceptible to leprosy would assist in better understanding of the pathogenesis of leprosy and perhaps lead to new approaches for diagnosis and treatment.
Keywords: Cytokine, gene polymorphism, interferon gamma, interleukin, leprosy, tumor necrosis factor alpha
|How to cite this article:|
Kolla VK, Sultana S, Joshi Davala SA, Valluri VL. A study on the impact of genetic polymorphisms of cytokines TNFα, IFNγ and IL10 in South Indian leprosy patients. Indian J Dermatol 2021;66:138-44
|How to cite this URL:|
Kolla VK, Sultana S, Joshi Davala SA, Valluri VL. A study on the impact of genetic polymorphisms of cytokines TNFα, IFNγ and IL10 in South Indian leprosy patients. Indian J Dermatol [serial online] 2021 [cited 2021 May 11];66:138-44. Available from: https://www.e-ijd.org/text.asp?2021/66/2/138/313767
| Introduction|| |
Leprosy (Hansen's disease) is a chronic, debilitating disease predominantly of the peripheral nervous system characterized by the impairment of peripheral nerves and subsequent sensory loss caused by Mycobacterium leprae. In the year 2016, the global prevalence of leprosy was 171,948 with a registered prevalence rate of 0.23 per 10,000 people. India is among the 22 global priority countries and accounts for 60% of the new cases every year. Even with proper multidrug therapy (MDT) that can eliminate the pathogen Mycobacterium leprae, nerve damage can still occur during the administration of therapy and the consequences are deformities and disabilities associated with leprosy.
Based on the human host immune response against mycobacterial antigens, leprosy is mainly classified as tuberculoid and lepromatous leprosy. Cell-mediated immunity (CMI) corresponds to the expression of type 1 and 2 cytokines, that play a major role in the pathophysiology of nerve damage as in many inflammatory diseases., Effective CMI depends on the interactions between T cells and macrophage-producing cytokines, which in turn activate the antimycobacterial microbicidal mechanisms. Interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) are the crucial inflammatory cytokines that act as combative agents. Interleukin-10 (IL10) emerges as a potent antiinflammatory and immunosuppressive cytokine that regulates protective immunity towards leprosy. In human monocytes, IFNγ and IL10 antagonize each other's production and function.
In several studies, polymorphisms were identified in cytokine gene regulatory regions that are correlated to intraindividual variations in cytokine production,, that lead to altered levels of cytokines. The differential production of cytokines eventually alters the downstream signaling processes that could directly or indirectly affect nerve function perhaps leading to neurodegeneration.,, On the other hand, these cytokine gene polymorphisms have been implicated in the pathogenesis of many human and experimental autoimmune peripheral neuropathies as in leprosy, resulting in demyelination and axonal lesions. The variations in genotypes which can be either homozygous or heterozygous result in high, intermediate, or low expression levels of cytokines.
The present study is focused on polymorphisms in the genes encoding pro- and antiinflammatory cytokines that may be responsible for nerve damage in leprosy patients. We examined three common functional SNPs (single nucleotide polymorphisms) primarily at the positions on the genes of tumor necrosis factor alpha (TNFα)-308G/A [rs 1800629], interferon gamma (IFNγ) +874A/T [rs 2430561], and interleukin (IL) 10 -1082G/A [rs 1800896] in order to ascertain their association with leprosy.
| Materials and Methods|| |
The present case control study includes 365 leprosy patients and 185 control subjects without any previous history of mycobacterial infection. The leprosy patients under treatment at Lepra Blue Peter Public Health and Research Centre (BPHRC), Hyderabad, Telangana were enrolled in the study. The study was carried out during the years 2015–2018. The sample size was calculated using the Epi info open source software, taking into consideration the prevalence of the disease with a 95% confidence level. Patients with two extreme types of leprosy, lepromatous (39%) and tuberculoid (61%), according to the Ridley and Joplin classification, were included in the study. The Institutional Ethical Committee approved the study and informed consent was obtained from all the study subjects.
Genomic DNA isolation and genotyping
Genomic DNA was isolated, using a Qiagen FlexiGene extraction kit according to the manufacturer's recommendations (QIAGEN Pty Ltd, Australia), from 300 μl of whole blood of each subject. The polymorphisms in TNFα-308, IFNγ+874, and IL10-1082 were typed using the amplification refractory mutation system polymerase chain reaction method (ARMS PCR)., In brief, the genomic DNA of each subject was amplified for SNPs using 0.5 units of Taq polymerase (Qiagen, Australia) in two different PCRs for each polymorphism; each reaction mixture for ARMS PCR consists of 40 ng of genomic DNA in a total volume of 20 μl, containing 0.8 μM of each primer, 400 μM dNTPs, 10 mM Tris-HCl (pH 9.0), 1.5 mM MgCl2, 50 mM KCl, and 0.01% gelatin. Each reaction employed a generic antisense primer and one of the two allele-specific sense primers [Table 1]. For evaluation of the PCR amplification in both reactions, one internal control was amplified using a pair of specific primers. The products were analyzed on 2% agarose gel stained with ethidium bromide and documented using a gel doc system (Biorad, USA).
All calculations were done using SPSS version 15. The differences in the distribution of genotypes and allele frequencies were analyzed using the χ2 test. Odds ratios and 95% confidence interval (95% CI) were calculated to assess the strength of the relationship between the TNFα, IFNγ, and IL10 gene polymorphisms and leprosy. A value of P < 0.05 was considered statistically significant.
| Results|| |
In the present case control study, the mean age of patients was 34.31 ± 13.26 years and that of controls was 30.65 ± 7.75 years. The association of the genotypes based on the SNPs in the genes of TNFα, IFNγ and IL10 are presented in tables shown in the successive text. Comparisons were made with controls for disease perse, disease category, and also for types of disease. Significant odds ratio values are highlighted in grey for disease susceptibility. The established levels of cytokine expression with respect to the combination of genotypes are indicated as high, intermediate, and low secretory genotypes. The high (H) secretory genotypes are IL10GG, IFNTT, and TNFAA, the low (L) secretory genotypes are IL10AA, IFNAA, and TNFGG, and the intermediate (I) secretory genotypes are IL10GA, IFNAT, and TNFGA. Henceforth, these are represented as H, I, and L for simplicity.
Gene polymorphism of TNFα-308 [rs 1800629]
Genotype frequency obtained from the TNFα-308 gene analysis in leprosy patients revealed that a majority had the GA heterozygote (98.9%) with the trend being same for both lepromatous and tuberculoid types. The homozygous GG (1%) showed the least frequency, whereas the homozygous AA genotype was absent in disease subjects. The intermediary producing heterozygous genotype GA was significantly associated with disease susceptibility of Leprosy per se and its subtypes (OR 12, 9, and 16, P < 0.02), whereas the homozygous GG, low producer genotype showed protective association (OR 0.1 and 0.08, P < 0.001) for the same. Comparison between the type of disease and allele did not show any statistical significance. The genotypic association is shown in [Table 3].
|Table 3: Significance of genotype/alleles of three cytokine genes with respect to disease category|
Click here to view
Gene polymorphism of IFNγ+874 [rs 2430561]
The heterozygous AT genotype frequency in leprosy patients was 44% and 61% in controls. The homozygous AA genotype is more frequent (33%) in patients than in controls (18%), whereas the proportion of homozygous TT genotype is nearly equal in both patients (22%) and controls (20%). The genotypic analysis of IFNγ+874 in Leprosy per se for both types of leprosy with control population revealed the susceptibility towards the low-producer A/A genotype (OR 2.2, P < 0.001), whereas a similar trend has shown protective association of the intermediate AT genotype (OR 0.4-0.5, P < 0.01). Allele “A” has shown susceptibility to Leprosy per se and lepromatous only (OR1.3–1.4, P < 0.04). However, the high producer TT has not shown significance towards any of the disease types and no association has been found within the type of disease [Table 3].
Gene polymorphism of IL10-1082 [rs 1800896]
The intermediate cytokine producer heterozygous GA showed significant association with Leprosy per se and tuberculoid type only (OR 1.5–1.6, P < 0.02), whereas the homozygous high-producer GG genotype showed a protective association specifically to tuberculoid type only (OR 0.3, P < 0.007). Comparison within the types of leprosy has led the high-producer GG susceptible towards the lepromatous end (OR 2.7, P < 0.02). None of the other combinations attained statistical significance towards the disease [Table 3].
Combination of genotypes with respective to secretion level
In [Table 2], the combination of IL10-1082 with IFNγ+874, H+I has shown a protective association toward Leprosy per se and tuberculoid (OR 0.2–0.3, P < 0.02). Whereas I+L has shown three times more susceptibility toward disease and types (OR 3, P < 0.01), I + H has shown susceptibility with tuberculoid type only. The combination of IL10-1082 with TNFα-308, I/I has shown susceptibility with disease and disease types (OR 1.9–2, P < 0.01), whereas L+L and H+I have shown protective association toward Leprosy per se and tuberculoid type (OR 0.08–0.28, P < 0.04) [Table 4]. The IFNγ+874 and TNFα-308 combination has shown susceptibility only towards “I” combinations. There was no H+H or L+L combination. The H+I and L+I combination showed disease susceptibility when compared to control, whereas H+I alone showed a protective association toward lepromatous leprosy when compared to tuberculoid type (OR 0.4, P < 0.01). The I+L and I+I combination in Leprosy per se and I+I in tuberculoid type show protective association [Table 4].
|Table 4: Significance of cytokine secretor level shared with two cytokines with respective to disease category|
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The comparison of all the three cytokines IL10-1082+, IFNγ+874+, and TNFα-308 is shown in [Table 5]. ILI, IHI, and LLI showed susceptibility towards Leprosy per se (OR 2–3, P < 0.03) and protective association towards HII, a similar trend was shown in tuberculoid type also except “ILI” which was not associated. Only “ILI” has shown 5-fold susceptibility towards lepromatous end (P < 0.0003). The comparison between the two extreme ends of leprosy, lepromatous and tuberculoid types had shown significant susceptibility towards “ILI” combination only [Table 5].
|Table 5: Significance of cytokine secretor level combined with three cytokines with respective to disease category|
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| Discussion|| |
Leprosy is a chronic infectious disease with cytokine gene polymorphisms playing an important role in host genetic factors. Genetic variations within the coding and noncoding sequences of cytokine genes modify the efficiency of transcription and production of cytokines. Genome-wide association studies revealed some genetic risk factors involved with leprosy. The present study focused on three cytokine gene polymorphisms in patients with leprosy with an aim to understand their role in the clinical outcome of the disease. To the best of our knowledge, this is the first study from South Indian population demonstrating the association of TNFα-308, IFNγ+874, and IL10-1082 gene polymorphisms with leprosy and two extreme variations of the disease as well. Polymorphism in the promoter region -308 of the TNFα gene has been ascribed to polymorphism within the regulatory region or signal sequences of the cytokine gene. TNF plays an important role in the pathogenesis of acute inflammatory leprosy reactions which is responsible for outcomes that characterize leprosy. The molecular mechanism of interaction between the TNF gene polymorphism and risk of leprosy has not yet been elucidated. While Uglialoro et al. reported that A allele of -308 polymorphism does not influence TNF gene transcription. Oliveira et al. reported that the minor A allele is related to low levels of TNF mRNA in the peripheral blood total leukocytes of leprosy patients. A meta-analysis could not find any association between the TNF -308 G>A polymorphism and leprosy. Case control studies based on TNF -308 G>A polymorphism and leprosy risk resulted in inconsistent results. Few investigators reported a positive association of TNF -308 polymorphism with leprosy, while others have shown negative association, which might be due to the small sample size and ethnicity. In the present study, allele distribution at -308 was similar among the leprosy patients and healthy controls with a higher frequency of GA genotype in all subjects. Whereas, in another study, TNFα -308 AA genotype was associated with leprosy. Further, no significant association was found between the other homozygotic (GG, AA) polymorphisms of TNFα-308 and severity of leprosy in the present study. A recent study in Brazilian population had shown association of TNFα-308 GG genotype with leprosy. Thus, there are limited studies on these polymorphic sites in leprosy and subtypes.
Cytokine IFN-γ secreted by Th1 CD4+, CD8+ T cells, and NK cells act as the body's defence system against intracellular pathogens. A Brazilian study of T allele at position + 874 of the IFNγ gene conferred a protective effect towards leprosy. However, no association was found between IFNγ+874T/A and leprosy in a Chinese study. Another Brazilian study reported that the A/A genotype and the allele IFNγ (16CA) were significantly associated with paucibacillary (PB) compared to multibacillary (MB) patients. Reynard et al. reported the association of a higher frequency of IFNγ (15CA), IFNγ (16CA), and IFNγ (17CA) alleles and the development of leprosy. The present study has a higher frequency of AT heterozygotes in IFNγ +874 polymorphism in both the case and control groups, which is similar to the frequency trend among South Brazilian population. A study from South Malawi revealed that the low-producer genotype AA had higher frequency in both groups, while the high-production TT genotype showed low frequency among all the leprosy cases and controls studied. Our results showed significant increase in the distribution of IFNγ+874 homozygous AA genotype which is significantly associated with leprosy (P < 0.0002), demonstrating that the IFNγ+874 AA genotype could be a risk factor for susceptibility to leprosy in South Indian population.
The overproduction of the inflammatory cytokine IFNγ is in turn suppressed by IL10 cytokine,, thus providing protection against the inflammatory reaction. Interleukin 10 (IL-10) is produced by monocytes and activated T cells involved in the regulation of inflammatory and immunological reactions. Turner et al. showed that gene polymorphisms of IL10 at the –1082 position from the transcriptional start site and the presence of G allele are associated with higher production of the cytokine and the presence of A allele is associated with lower production of the cytokine. According to earlier studies, the high-producer genotype of IL10 is associated with many inflammatory diseases., Several studies have been carried out on IL10 gene polymorphism and leprosy including 6–11 CA repeat microsatellite polymorphisms and three-point mutations polymorphisms such as -1082 (G/A) (rs1800896), -819 (C/T) (rs1800871) and -592 (C/A) (rs1800872). Few studies among Brazilian population on the IL10 -819T allele reported association with leprosy and another study reported a high frequency of the IL10-819TT genotype in leprosy patients. A Colombian study reported the association of the C/C and C/T genotypes in IL10-819, the C/C and C/A genotypes in the IL10-592 and -819C-592C, and -1082A-819C-592C haplotypes with leprosy. The IL10-3575A/-2849G/-2763C haplotype is associated with resistance to leprosy and development of more severe forms of the disease in a Brazilian population, whereas the IL10-3575T/-2849A/2763C haplotype is susceptible to leprosy. However, in the Indian population, the extended haplotype IL10-3575T/-2849G/-2763C/- 1082A/-819C/-592C confer resistance towards leprosy and development of more severe forms of disease, while IL10-3575T/-2849G/-2763C/-1082A/-819T/-592A haplotype is associated with the risk of severe form of the disease. Overall, the above studies suggest a definite role of SNPs in the promoter region of the IL10 gene in the pathophysiology of leprosy. The present study found a significant association of IL10-1082 GA heterozygote (P < 0.02) in leprosy patients of South Indian origin.
In conclusion, our study showed that the IL10-1082 GA genotype and the “low-producer” IFNγ+874 AA genotype are associated with the susceptibility towards leprosy in the South Indian population. The identification of genetic variations in pro- and antiinflammatory cytokines that are susceptible to leprosy would assist in better understanding of the pathogenesis of leprosy and perhaps lead to new approaches for the diagnosis and treatment.
The authors would like to thank Lepra Blue Peter Public Health and Research Centre (BPHRC) for their cooperation and support during the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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