Browsing by Author "Pradeep K. Patra"

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A rare non-synonymous c.102C>G SNP in the IFNB1 gene might be a risk factor for cerebral malaria in Indian populations
(2013) Aditya Nath Jha; Vipin Kumar Singh; Rajender Singh; Sudhanshu S. Pati; Pradeep K. Patra; Lalji Singh; Kumarasamy Thangaraj
Interferon beta1 (IFNB1) is a type I interferon that is mainly known for its antiviral activity, but it also regulates a number of anti-inflammatory and immunomodulatory functions. Studies on mouse models of cerebral malaria have established that IFNB1 regulates severe malaria pathogenesis and increases overall survival against malaria. It down-regulates pro-inflammatory cytokines: TNF, IFNG and ICAM-1, resulting in decreased adherence of Plasmodium falciparum parasitized RBC to capillary wall, entry into the brain and delayed onset of death. Therefore, we hypothesized that variations in IFNB1 gene could regulate malarial pathogenesis. We re-sequenced the complete IFNB1 gene along with 900bp of 5' up-stream and 500bp of 3'-UTR in 437 individuals from malaria endemic regions of the Orissa and Chhattisgarh states of India. The subjects comprised of 173 cases of severe malaria, 101 of mild malaria, and 156 ethnically matched asymptomatic controls. Data were statistically compared between cases and controls for their possible association with P. falciparum malarial outcome. Two single nucleotide polymorphisms (SNPs): a synonymous c.153C>T (rs1051922) and a non-synonymous substitution c.102C>G (rs139262191, p.Ser34Arg) were identified. The genotype and allele distribution of c.153C>T did not differ significantly between the study groups [mild, χ22=4.10, p-value<0.13 and severe χ22=0.06, p-value<0.97]. Interestingly, the rare non-synonymous SNP (rs139262191) was observed only in malaria patients. The differences between all cases and controls did not reach statistical significance, however, a statistically significant difference was observed between the asymptomatic control group and the cerebral malaria group [OR=20.32, 95% CI=1.08-382.63, p-value=0.044]. Moreover, the genotypes between cerebral malaria positive and negative groups were not significantly different [OR=5.58, 95% CI=0.61-50.97, p-value=0.123]. Our findings suggest that the IFNB1 variant, p.Ser34Arg, might be a risk factor for cerebral malaria in Indian populations. © 2013 Elsevier B.V.
IL-4 Haplotype -590T, -34T and Intron-3 VNTR R2 Is Associated with Reduced Malaria Risk among Ancestral Indian Tribal Populations
(2012) Aditya Nath Jha; Vipin Kumar Singh; Namrata Kumari; Ashish Singh; Justin Antony; Hoang van Tong; Sakshi Singh; Sudhanshu S. Pati; Pradeep K. Patra; Rajender Singh; Nguyen L. Toan; Le H. Song; Amal Assaf; Iara J. T. Messias-Reason; Thirumalaisamy P. Velavan; Lalji Singh; Kumarasamy Thangaraj
Background: Interleukin 4 (IL-4) is an anti-inflammatory cytokine, which regulates balance between TH1 and TH2 immune response, immunoglobulin class switching and humoral immunity. Polymorphisms in this gene have been reported to affect the risk of infectious and autoimmune diseases. Methods: We have analyzed three regulatory IL-4 polymorphisms; -590C>T, -34C>T and 70 bp intron-3 VNTR, in 4216 individuals; including: (1) 430 ethnically matched case-control groups (173 severe malaria, 101 mild malaria and 156 asymptomatic); (2) 3452 individuals from 76 linguistically and geographically distinct endogamous populations of India, and (3) 334 individuals with different ancestry from outside India (84 Brazilian, 104 Syrian, and 146 Vietnamese). Results: The -590T, 34T and intron-3 VNTR R2 alleles were found to be associated with reduced malaria risk (P<0.001 for -590C>T and -34C>T, and P = 0.003 for VNTR). These three alleles were in strong LD (r2>0.75) and the TTR2 (-590T, -34T and intron-3 VNTR R2) haplotype appeared to be a susceptibility factor for malaria (P = 0.009, OR = 0.552, 95% CI = 0.356 -0.854). Allele and genotype frequencies differ significantly between caste, nomadic, tribe and ancestral tribal populations (ATP). The distribution of protective haplotype TTR2 was found to be significant (χ23 = 182.95, p-value <0.001), which is highest in ATP (40.5%); intermediate in tribes (33%); and lowest in caste (17.8%) and nomadic (21.6%). Conclusions: Our study suggests that the IL-4 polymorphisms regulate host susceptibility to malaria and disease progression. TTR2 haplotype, which gives protection against malaria, is high among ATPs. Since they inhabited in isolation and mainly practice hunter-gatherer lifestyles and exposed to various parasites, IL-4 TTR2 haplotype might be under positive selection. © 2012 Jha et al.
MBL2 variations and malaria susceptibility in Indian populations
(2014) Aditya Nath Jha; Pandarisamy Sundaravadivel; Vipin Kumar Singh; Sudhanshu S. Pati; Pradeep K. Patra; Peter G. Kremsner; Thirumalaisamy P. Velavan; Lalji Singh; Kumarasamy Thangaraj
Human mannose-binding lectin (MBL) encoded by the MBL2 gene is a pattern recognition protein and has been associated with many infectious diseases, including malaria. We sought to investigate the contribution of functional MBL2 gene variations to Plasmodium falciparum malaria in well-defined cases and in matched controls. We resequenced the 8.7 kb of the entire MBL2 gene in 434 individuals clinically classified with malaria from regions of India where malaria is endemic. The study cohort included 176 patients with severe malaria, 101 patients with mild malaria, and 157 ethnically matched asymptomatic individuals. In addition, 830 individuals from 32 socially, linguistically, and geographically diverse endogamous populations of India were investigated for the distribution of functional MBL2 variants. The MBL2-221C (X) allelic variant is associated with increased risk of malaria (mild malaria odds ratio [OR]=1.9, corrected P value [PCorr]=0.0036; severe malaria OR=1.6, PCorr=0.02). The exon1 variants MBL2*B (severe malaria OR=2.1, PCorr=0.036; mild versus severe malaria OR=2.5, PCorr=0.039) and MBL2*C (mild versus severe malaria OR=5.4, PCorr=0.045) increased the odds of having malaria. The exon1 MBL2*D/*B/*C variant increased the risk for severe malaria (OR=3.4, PCorr=0.000045). The frequencies of low MBL haplotypes were significantly higher in severe malaria (14.2%) compared to mild malaria (7.9%) and asymptomatic (3.8%). The MBL2*LYPA haplotypes confer protection, whereas MBL2*LXPA increases the malaria risk. Our findings in Indian populations demonstrate that MBL2 functional variants are strongly associated with malaria and infection severity. © 2014, American Society for Microbiology.