Variations in host genes encoding adhesion molecules and susceptibility to falciparum malaria in India

<p>Abstract</p> <p>Background</p> <p>Host adhesion molecules play a significant role in the pathogenesis of <it>Plasmodium falciparum </it>malaria and changes in their structure or levels in individuals can influence the outcome of infection. The aim of this study was to investigate the association of SNPs of three adhesion molecule genes, <it>ICAM1</it>, <it>PECAM1 </it>and <it>CD36</it>, with severity of falciparum malaria in a malaria-endemic and a non-endemic region of India.</p> <p>Methods</p> <p>The frequency distribution of seven selected SNPs of <it>ICAM1</it>, <it>PECAM1 </it>and <it>CD36 </it>was determined in 552 individuals drawn from 24 populations across India. SNP-disease association was analysed in a case-control study format. Genotyping of the population panel was performed by Sequenom mass spectroscopy and patient/control samples were genotyped by SNaPshot method. Haplotypes and linkage disequilibrium (LD) plots were generated using PHASE and Haploview, respectively. Odds-ratio (OR) for risk assessment was estimated using EpiInfo™ version 3.4.</p> <p>Results</p> <p>Association of the ICAM1 rs5498 (exon 6) G allele and the CD36 exon 1a A allele with increased risk of severe malaria was observed (severe versus control, OR = 1.91 and 2.66, P = 0.02 and 0.0012, respectively). The CD36 rs1334512 (-53) T allele as well as the TT genotype associated with protection from severe disease (severe versus control, TT versus GG, OR = 0.37, P = 0.004). Interestingly, a SNP of the <it>PECAM1 </it>gene (rs668, exon 3, C/G) with low minor allele frequency in populations of the endemic region compared to the non-endemic region exhibited differential association with disease in these regions; the G allele was a risk factor for malaria in the endemic region, but exhibited significant association with protection from disease in the non-endemic region.</p> <p>Conclusion</p> <p>The data highlights the significance of variations in the <it>ICAM1</it>, <it>PECAM1 </it>and <it>CD36 </it>genes in the manifestation of falciparum malaria in India. The <it>PECAM1 </it>exon 3 SNP exhibits altered association with disease in the endemic and non-endemic region.</p

Analysis of the reasons for deferral of prospective blood donors in a Tertiary Care Hospital in North India

Background: Blood donor deferral is a painful and sad experience for the donor, organizer as well as screening doctors. The rate and reasons of deferral differ from region to region and center to center. The shortage of safe blood donors is frequent, and it is important to understand the causes of deferral in voluntary donors. The aim of this study was to analyze the incidence of donor deferral, causes of deferral, and apply relevant findings to modify the recruitment strategy to decrease the temporary deferral rate. This strategy could increase the pool of voluntary donors without compromising on the quality of the blood and safety of the recipient. Materials and Methods: Data from voluntary blood donation camps held in the blood bank and outdoor camps from August 2014 to August 2015 were analyzed retrospectively. Based on the history and physical examination findings; all blood donors coming for the donation were classified into fit for donation or deferred donor. Results: A total of 24,062 subjects registered for donation during the study period (August 2014 to August 2015) out of which 4125 were deferred prior to donation. The incidence of deferral was 17.1%. Most common reasons for deferral were anemia (2107 out of 4125) accounting for 51% of deferred donors, abnormal blood pressure 6.8% (281/4125), and history of medication 18% (743/4125). Majority of them were temporary deferrals 86.1% (3822/4443). Permanent deferral accounted for 13.9% (621/4443). Most of these deferred donors were aged between 18 and 30 years old. Most common reason for deferral in males and females both was anemia with an incidence of 32.7% (900/2750) and 87.7% (1207/1375) in males and females, respectively. Discussion and Conclusion: Insight into the reasons of donor deferral is very important to avoid the permanent loss of the donor as blood donation program is the life force behind any blood bank or hospital. Deferral study also indicates the health status of the general population. Since most of the deferrals are temporary deferrals, and we should give a clear message for the reason for deferral, so that they return for donation in the future

Interferon-γ (IFNG) microsatellite repeat and single nucleotide polymorphism haplotypes of IFN-α receptor (IFNAR1) associated with enhanced malaria susceptibility in Indian populations

Pro-inflammatory cytokines IFNγ and IFNα function through their cellular receptors IFNγR1 and IFNαR1, respectively to mediate immune processes during malaria infection. A total of 21 SNPs, 2 ins/del polymorphisms and a microsatellite repeat, selected on the basis of their reported association with infectious diseases including malaria in world populations, were analysed for association with Plasmodium falciparum malaria susceptibility in a case-control study with adult patients and ethnically-matched controls drawn from a disease meso- to hyperendemic and a nonendemic region of India. Among the five IFNG SNPs tested, an intron 3 and a 3′UTR SNP associated with disease in the endemic region. In addition, large (CA)<SUB>n</SUB> repeats of IFNG intron 1 associated with protection from severe malaria in the endemic region (severe vs. control, odds ratio = 0.21, 95% CI = 0.08–0.52, P = 1.3 × 10<SUP>-4</SUP>). The TA11CAG haplotype (rs2069705 T/C, rs2430561 A/T, rs3138557 (CA)<SUB>n</SUB>, rs2069718 T/C, rs2069727 A/G, rs2069728 G/A) carrying a short CA<SUB>11</SUB> repeat also exhibited very strong association with severe malaria, particularly in the endemic region (severe vs. control, OR = 14.56, 95% CI = 3.39–85.81, P = 3 × 10<SUP>-5</SUP>). One SNP each from the IFNA8 and IFNA17 of IFNA gene cluster had a protective effect in the non-endemic region but not in the endemic region. A promoter and an intron 2 SNP of IFNAR1 were risk factors for disease and the IFNAR1 haplotype GCCAGG (rs2843710 C/G, rs2850015 C/T, +6993 C/T, rs2243594 A/G, rs1012335 G/C, rs2257167 G/C) carrying both the risk alleles strikingly associated with disease manifestation in the endemic region (severe vs. control, OR = 27.14, 95% CI = 3.12–1254, P = 2 × 10<SUP>-5</SUP>; non-severe vs. control, OR = 61.87, 95% CI = 10.08–2521, P = 1 × 10<SUP>-8</SUP>). The data indicates dissimilar contribution of cytokine and cytokine receptor variants to disease in populations residing in areas of differential malaria endemicity

<i>FADS1</i> and <i>FADS2</i> expression across 44 human tissues.

<p>Boxplots of <i>FADS1</i> (top) and <i>FADS2</i> (bottom) mRNA expression (log₁₀RPKM—y axis) are shown across tissues (x-axis) from GTEx; outliers are shown as circles; median expression is represented as the center line.</p

rs174548 genotype associations with <i>FADS1</i> and <i>FADS2</i> across tissues.

<p>Nominal associations (effect size and 95% confidence interval) between rs174548 genotypes (G, alt allele vs C, ref allele) with <i>FADS1</i> (A) and <i>FADS2</i> (B) are shown across GTEx tissues. The effect size of the eQTLs was defined as the slope of the linear regression, comparing the alt allele (G) to the reference allele (C).</p

<i>FADS1</i> and <i>FADS2</i> expression by rs174548 genotype.

<p><i>FADS1</i> (A) <i>FADS2</i> (B) rank normalized gene expression (Y-axis) by rs174548 genotype (G: alt allele, C: ref allele) in the five tissues with significant (FDR<0.05) associations between rs174548 and <i>FADS1</i> and <i>FADS2</i> in the same tissues.</p

Tissue-specific impact of <i>FADS</i> cluster variants on <i>FADS1</i> and <i>FADS2</i> gene expression

<div><p>Omega-6 (n-6) and omega-3 (n-3) long (≥ 20 carbon) chain polyunsaturated fatty acids (LC-PUFAs) play a critical role in human health and disease. Biosynthesis of LC-PUFAs from dietary 18 carbon PUFAs in tissues such as the liver is highly associated with genetic variation within the fatty acid desaturase (<i>FADS)</i> gene cluster, containing <i>FADS1</i> and <i>FADS2</i> that encode the rate-limiting desaturation enzymes in the LC-PUFA biosynthesis pathway. However, the molecular mechanisms by which <i>FADS</i> genetic variants affect LC-PUFA biosynthesis, and in which tissues, are unclear. The current study examined associations between common single nucleotide polymorphisms (SNPs) within the <i>FADS</i> gene cluster and <i>FADS1</i> and <i>FADS2</i> gene expression in 44 different human tissues (sample sizes ranging 70–361) from the Genotype-Tissue Expression (GTEx) Project. <i>FADS1</i> and <i>FADS2</i> expression were detected in all 44 tissues. Significant cis-eQTLs (within 1 megabase of each gene, False Discovery Rate, FDR<0.05, as defined by GTEx) were identified in 12 tissues for <i>FADS1</i> gene expression and 23 tissues for <i>FADS2</i> gene expression. Six tissues had significant (FDR< 0.05) eQTLs associated with both <i>FADS1</i> and <i>FADS2</i> (including artery, esophagus, heart, muscle, nerve, and thyroid). Interestingly, the identified eQTLs were consistently found to be associated in opposite directions for <i>FADS1</i> and <i>FADS2</i> expression. Taken together, findings from this study suggest common SNPs within the <i>FADS</i> gene cluster impact the transcription of <i>FADS1</i> and <i>FADS2</i> in numerous tissues and raise important questions about how the inverse expression of these two genes impact intermediate molecular (such a LC-PUFA and LC-PUFA-containing glycerolipid levels) and ultimately clinical phenotypes associated with inflammatory diseases and brain health.</p></div

Distinct cytokine profiles define immune response to falcipatum malaria in region of high and low transmission

The immune effector response to Plasmodium falciparum infection involves a finely-tuned interplay between different cell types and cytokines. However, the processes by which they mediate the development of clinical immunity, in areas of different endemicity, are poorly understood. We analyzed circulating levels of pro-inflammatory (TNF, IFN-γ, IL-12, IL-16) and anti-inflammatory (IL-4, IL-10, IL-13) cytokines in control and patient groups drawn from a P. falciparum-endemic and a non-endemic region of India. The endemic region control population exhibited a lower pro- to anti-inflammatory cytokine ratio, indicating a shift towards a high basal Th2 response. Levels of IL-10 contributed most towards the region-specific difference in basal cytokine response. IL-10 was also the strongest predictor of disease in the endemic region, while IL-12, along with IL-10 and IL-6, contributed most to disease outcome in the non-endemic region. A low, mean IFN-γ/IL-10 ratio was associated with disease severity in the endemic region (p &#60; 0.0001). In contrast, a low mean IL-12/IL-10 ratio correlated with disease outcome in the non-endemic region (p &#60; 0.0001). In the endemic region, IL-13 correlated negatively with IFN-γ in severe patients (Spearman's ρ: -0.49; p : 0.013), while in the non-endemic region, IL-13 correlated negatively with IL-6 in severe malaria patients (Spearman's ρ: -0.485; p : 0.001). In conclusion, levels of pro- and anti-inflammatory cytokines and the relative balance between the Th1 and Th2 response, illustrates how populations residing in areas of varying disease endemicity may respond to P. falciparum-induced immune challenge

HLA alleles and sustained peanut consumption promote IgG4 responses in subjects protected from peanut allergy

We investigated the interplay between genetics and oral peanut protein exposure in the determination of the immunological response to peanut using the targeted intervention in the LEAP clinical trial. We identified an association between peanut-specific IgG4 and HLA-DQA1*01:02 that was only observed in the presence of sustained oral peanut protein exposure. The association between IgG4 and HLA-DQA1*01:02 was driven by IgG4 specific for the Ara h 2 component. Once peanut consumption ceased, the association between IgG4-specific Ara h 2 and HLA-DQA1*01:02 was attenuated. The association was validated by observing expanded IgG4-specific epitopes in people who carried HLA-DQA1*01:02. Notably, we confirmed the previously reported associations with HLA-DQA1*01:02 and peanut allergy risk in the absence of oral peanut protein exposure. Interaction between HLA and presence or absence of exposure to peanut in an allergen- and epitope-specific manner implicates a mechanism of antigen recognition that is fundamental to driving immune responses related to allergy risk or protection