Dataset Information

Interleukin 10 gene polymorphisms and development of post kala-azar dermal leishmaniasis in a selected sudanese population.

ABSTRACT:

Background

Post kala-azar dermal leishmaniasis (PKDL) is a cutaneous form of disease that develops at variable times after individuals have received treatment for clinical visceral leishmaniasis (VL). The study aimed to investigate the possible role of interleukin 10 (IL-10) and development of PKDL.

Methods

77 families composed of 41 complete case-parent trios and 36 case-parent pairs from the Masalit ethnic group were genotyped for 3 IL10 promoter polymorphisms: -1082A/G, -819C/T and -592C/A.

Results

Single point analysis using the transmission disequilibrium test showed no evidence of association between any of these IL10 promoter single nucleotide polymorphisms (SNPs) and development of PKDL. Haplotype analysis performed using TRANSMIT showed borderline significance between PKDL and the haplotype AA across -592C/A and -1082A/G (p = 0.053). Haplotypes GCC (0.33) and ATA (0.30) were the common haplotypes in this Sudanese population. Allele frequencies for the 3 SNPs differed significantly in Sudan compared to other African (Gambian, Malawian, YRI) populations.

Conclusion

There is no evidence for an association between 3 SNPs in the IL10 gene promoter and susceptibility to PKDL in the Masalit ethnic group in Sudan, although some evidence for haplotype association was observed.

SUBMITTER: Farouk S

PROVIDER: S-EPMC2951725 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Publications

Interleukin 10 gene polymorphisms and development of post kala-azar dermal leishmaniasis in a selected sudanese population.

Farouk S S Salih M A MA Musa A M AM Blackwell J M JM Miller E N EN Khalil E A EA Elhassan A M AM Ibrahim M E ME Mohamed H S HS

Public health genomics 20091229 6

<h4>Background</h4>Post kala-azar dermal leishmaniasis (PKDL) is a cutaneous form of disease that develops at variable times after individuals have received treatment for clinical visceral leishmaniasis (VL). The study aimed to investigate the possible role of interleukin 10 (IL-10) and development of PKDL.<h4>Methods</h4>77 families composed of 41 complete case-parent trios and 36 case-parent pairs from the Masalit ethnic group were genotyped for 3 IL10 promoter polymorphisms: -1082A/G, -819C/T ...[more]

PMID: 20051670

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Project description:BackgroundLittle is known about the parasite/host factors that lead to Post Kala-azar Dermal Leishmaniasis (PKDL) in some visceral leishmaniasis (VL) patients after drug-cure. Studies in Sudan provide evidence for association between polymorphisms in the gene (IFNGR1) encoding the alpha chain of interferon-γ receptor type I and risk of PKDL. This study aimed to identify putative functional polymorphisms in the IFNGR1 gene, and to determine whether differences in expression of interferon-γ (IFNG) and IFNGR1 at the RNA level are associated with pathogenesis of VL and/or PKDL in Sudan.MethodsSanger sequencing was used to re-sequence 841 bp of upstream, exon1 and intron1 of the IFNGR1 gene in DNA from 30 PKDL patients. LAGAN and SYNPLOT bioinformatics tools were used to compare human, chimpanzee and dog sequences to identify conserved noncoding sequences carrying putative regulatory elements. The relative expression of IFNG and IFNGR1 in paired pre- and post-treatment RNA samples from the lymph nodes of 24 VL patients, and in RNA samples from skin biopsies of 19 PKDL patients, was measured using real time PCR. Pre- versus post-treatment expression was evaluated statistically using the nonparametric Wilcoxon matched pairs signed-rank test.ResultsTen variants were identified in the 841 bp of sequence, four of which are novel polymorphisms at -77A/G, +10 C/T, +18C/T and +91G/T relative to the IFNGR1 initiation site. A cluster of conserved non-coding sequences with putative regulatory variants was identified in the distal promoter of IFNGR1. Variable expression of IFNG was detected in lymph node aspirates of VL patients before treatment, with a marked reduction (P = 0.006) in expression following treatment. IFNGR1 expression was also variable in lymph node aspirates from VL patients, with no significant reduction in expression with treatment. IFNG expression was undetectable in the skin biopsies of PKDL cases, while IFNGR1 expression was also uniformly low.ConclusionsUniformly low expression of IFN and IFNGR1 in PKDL skin biopsies could explain parasite persistence and is consistent with prior demonstration of genetic association with IFNGR1 polymorphisms. Identification of novel potentially functional rare variants at IFNGR1 makes an important general contribution to knowledge of rare variants of potential relevance in this Sudanese population.

Project description:BackgroundPost Kala-azar Dermal Leishmaniasis (PKDL) is a dermal sequel of visceral leishmaniasis (VL), poses a significant threat to the success of ongoing kala-azar elimination program, due to its potential role in sustaining transmission cycles and complicating disease management strategies. In VL, neutrophils have been identified as the 'first line of defence', having multiple roles in disease pathogenesis, but their role in PKDL, if any, still remains elusive; presenting a critical gap in knowledge, and was the aim of this study.Methodology/principal findingsIn a cohort of PKDL patients, CD66b+ neutrophils were quantified in skin biopsies, followed by immunostaining of FFPE sections to identify activated neutrophils (CD66b+/CD64+) and degranulated (CD66b+/MPO+), along with expression of neutrophil elastase (NE), matrix metalloprotease 9 (MMP9) and collagen I. Plasma levels of neutrophil chemo-attractants CXCL8/1/2/5, CCL2 and 20 and cytokines, (IL-6, IFN-γ, IL-4, IL-10, TNF-α, IL-17 and IL-22, 23) were evaluated by a multiplex assay, while lesional expression of IL-8, IL-10 and IL-17 was evaluated by immunohistochemistry. As compared to healthy individuals (control skin samples), PKDL cases at the lesional sites had an increased number of activated CD66b+ neutrophils (positive for CD64+, MPO+ and NE+). The plasma levels of neutrophil chemo-attractants, pro-inflammatory and regulatory cytokines were raised as was circulating and lesional IL-8, along with an enhanced lesional expression of IL-10 and IL-17A. An increase in circulatory and lesional MMP9 was accompanied by decreased collagen I, suggesting disintegration of matrix integrity.Conclusions/significanceTaken together, in PKDL, activated neutrophils possibly contribute towards modulating the lesional landscape. Understanding this involvement of neutrophils in patients with PKDL, particularly in the absence of an animal model, could offer better understanding of the disease pathogenesis and provide insights into novel therapeutic strategies for the ongoing elimination program.

Project description:BackgroundThe potential reservoirs of visceral leishmaniasis (VL) in South Asia include asymptomatic and relapsed cases of VL, along with patients with post kala-azar dermal leishmaniasis (PKDL). Accordingly, accurate estimation of their parasite load is pivotal for ensuring disease elimination, presently targeted for 2023. Serological tests cannot accurately detect relapses and/or monitor treatment effectiveness, and therefore, parasite antigen/nucleic acid based detection assays remain the only viable option. An excellent option is the quantitative polymerase chain reaction (qPCR) but the high cost, technical expertise and time involved precludes its wider acceptability. Accordingly, the recombinase polymerase amplification (RPA) assay operated in a mobile suitcase laboratory has emerged not simply as a diagnostic tool for leishmaniasis but also to monitor the disease burden.Methodology/principal findingsUsing total genomic DNA isolated from peripheral blood of confirmed VL cases (n = 40) and lesional biopsies of PKDL cases (n = 64), the kinetoplast-DNA based qPCR and RPA assay was performed and parasite load expressed as Cycle threshold (Ct) and Time threshold (Tt) respectively. Using qPCR as the gold standard, the diagnostic specificity and sensitivity of RPA in naïve cases of VL and PKDL was reiterated. To assess the prognostic potential of the RPA, samples were analyzed immediately at the end of treatment or ≥6 months following completion of treatment. In cases of VL, the RPA assay in terms of cure and detection of a relapse case showed 100% concordance with qPCR. In PKDL following completion of treatment, the overall detection concordance between RPA and qPCR was 92.7% (38/41). At the end of treatment for PKDL, 7 cases remained qPCR positive, whereas RPA was positive in only 4/7 cases, perhaps attributable to their low parasite load.Conclusions/significanceThis study endorsed the potential of RPA to evolve as a field applicable, molecular tool for monitoring parasite load, possibly at a point of care level and is worthy of consideration in resource limited settings.

Dataset Information

Interleukin 10 gene polymorphisms and development of post kala-azar dermal leishmaniasis in a selected sudanese population.

Background

Methods

Results

Conclusion

Publications

Interleukin 10 gene polymorphisms and development of post kala-azar dermal leishmaniasis in a selected sudanese population.

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