Rajika L. Dewasurendra

Bio: Rajika L. Dewasurendra is an academic researcher from University of Colombo. The author has contributed to research in topics: Population & Malaria. The author has an hindex of 6, co-authored 10 publications receiving 217 citations.

A global network for investigating the genomic epidemiology of malaria.

Abstract: Large-scale studies of genomic variation could assist efforts to eliminate malaria. But there are scientific, ethical and practical challenges to carrying out such studies in developing countries, where the burden of disease is greatest. The Malaria Genomic Epidemiology Network (MalariaGEN) is now working to overcome these obstacles, using a consortial approach that brings together researchers from 21 countries. © 2008 Macmillan Publishers Limited. All rights reserved.

Toxocara seropositivity in Sri Lankan children with asthma.

Abstract: Background: Toxocariasis occurs in humans due to infection with Toxocara canis or T. cati, the nematode parasites of dogs and cats, respectively. The relationship between toxocariasis and asthma is complex, with some studies demonstrating that children with asthma were more likely to be Toxocara seropositive as compared to non-asthmatic children, and other studies indicating no such significant relationship. The aim of the present study was to investigate Toxocara seropositivity and its association with asthma in a selected group of Sri Lankan children. Methods: Two groups of children were studied: group 1 included 100 children with confirmed bronchial asthma who were on regular inhaler steroid treatment for asthma; group 2 included 96 children who did not have physician-diagnosed asthma or upper respiratory tract infections, attending the same hospital. Diagnosis of Toxocara seropositivity was based on IgG Toxocara Microwell Serum Elisa Kits. Enzyme-linked immunosorbent assay was regarded as positive for a reading of 0.3 optical density units. Stool samples were examined for helminth ova. Results: Toxocara seropositivity in children with asthma was 29% and this was significantly more than Toxocara seropositivity among non-asthmatic children (P < 0.001). Toxocara seropositivity was identified as a significant risk factor of asthma in a univariate model. Eosinophilia was seen in a significantly higher proportion of non-asthmatic and asthmatic children who were Toxocara seropositive. Toxocara seropositivity, however, was not identified as a significant risk factor in a multivariate model. Conclusions: The analysis confirmed previously identified risk factors for asthma but there was no association between the helminth parasitic infection, toxocariasis and bronchial asthma in children.

Genetic polymorphisms associated with anti-malarial antibody levels in a low and unstable malaria transmission area in southern Sri Lanka

Abstract: Background The incidence of malaria in Sri Lanka has significantly declined in recent years. Similar trends were seen in Kataragama, a known malaria endemic location within the southern province of the country, over the past five years. This is a descriptive study of anti-malarial antibody levels and selected host genetic mutations in residents of Kataragama, under low malaria transmission conditions.

Genetic determinants of anti-malarial acquired immunity in a large multi-centre study

Abstract: Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels. Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP)4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels. Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2. Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.

Effectiveness of a serological tool to predict malaria transmission intensity in an elimination setting

Abstract: Sri Lanka achieved the WHO certificate as a malaria free country in September 2016, thus monitoring of malaria transmission using sensitive and effective tools is an important need. Use of age-specific antibody prevalence as a serological tool to predict transmission intensity is proven to be a cost effective and reliable method under elimination settings. This paper discusses the correlation of four anti-malarial antibodies against vivax and falciparum malaria with the declining transmission intensities in two previously high malaria endemic districts i.e. Kurunegala and Moneragala of Sri Lanka. Sera was collected from 1,186 individuals from the two districts and were subjected to standard ELISA together with control sera from non-immune individuals to obtain Optical Density (OD) values for four anti-malarial antibodies i.e. anti-MSP1 and anti-AMA1 for both Plasmodium vivax and Plasmodium falciparum. The sero-positive samples were determined as mean OD + 3SD of the negative controls. The sero-prevalence was analyzed against the demographic characteristics of the population. A simple reversible catalytic model was fitted into sero-prevalence data to predict the sero-conversion and sero-reversion rates. Over 60% of the population was sero-positive for one or more antibodies except young children (<10 years). The sero-prevalence was zero in young children and very low in young adults when compared to the older age groups. The model developed for falciparum malaria that assumed the presence of a change in transmission was not significant in the Kurunegala district although significant reduction in transmission was observed when the model was used for P. vivax antibody data in that district. In Moneragala district however, all the serological markers indicated a change in transmission that has occurred approximately 15 years ago. Assessment of MSP1 and AMA1 anti-malarial antibodies of P. vivax and P. falciparum proved to be useful indicators in predicting transmission under elimination settings as prevailed in Sri Lanka. The sero-conversion rates for the two districts studied are shown to be very low or zero indicating the absence of active and/or hidden transmission confirming a “true” state of elimination at least, in the two study districts in Sri Lanka.

A tale of three next generation sequencing platforms: comparison of Ion Torrent, Pacific Biosciences and Illumina MiSeq sequencers.

Abstract: Next generation sequencing (NGS) technology has revolutionized genomic and genetic research. The pace of change in this area is rapid with three major new sequencing platforms having been released in 2011: Ion Torrent’s PGM, Pacific Biosciences’ RS and the Illumina MiSeq. Here we compare the results obtained with those platforms to the performance of the Illumina HiSeq, the current market leader. In order to compare these platforms, and get sufficient coverage depth to allow meaningful analysis, we have sequenced a set of 4 microbial genomes with mean GC content ranging from 19.3 to 67.7%. Together, these represent a comprehensive range of genome content. Here we report our analysis of that sequence data in terms of coverage distribution, bias, GC distribution, variant detection and accuracy. Sequence generated by Ion Torrent, MiSeq and Pacific Biosciences technologies displays near perfect coverage behaviour on GC-rich, neutral and moderately AT-rich genomes, but a profound bias was observed upon sequencing the extremely AT-rich genome of Plasmodium falciparum on the PGM, resulting in no coverage for approximately 30% of the genome. We analysed the ability to call variants from each platform and found that we could call slightly more variants from Ion Torrent data compared to MiSeq data, but at the expense of a higher false positive rate. Variant calling from Pacific Biosciences data was possible but higher coverage depth was required. Context specific errors were observed in both PGM and MiSeq data, but not in that from the Pacific Biosciences platform. All three fast turnaround sequencers evaluated here were able to generate usable sequence. However there are key differences between the quality of that data and the applications it will support.

Genotype Imputation with Thousands of Genomes

Abstract: Genotype imputation is a statistical technique that is often used to increase the power and resolution of genetic association studies. Imputation methods work by using haplotype patterns in a reference panel to predict unobserved genotypes in a study dataset, and a number of approaches have been proposed for choosing subsets of reference haplotypes that will maximize accuracy in a given study population. These panel selection strategies become harder to apply and interpret as sequencing efforts like the 1000 Genomes Project produce larger and more diverse reference sets, which led us to develop an alternative framework. Our approach is built around a new approximation that uses local sequence similarity to choose a custom reference panel for each study haplotype in each region of the genome. This approximation makes it computationally efficient to use all available reference haplotypes, which allows us to bypass the panel selection step and to improve accuracy at low-frequency variants by capturing unexpected allele sharing among populations. Using data from HapMap 3, we show that our framework produces accurate results in a wide range of human populations. We also use data from the Malaria Genetic Epidemiology Network (MalariaGEN) to provide recommendations for imputation-based studies in Africa. We demonstrate that our approximation improves efficiency in large, sequence-based reference panels, and we discuss general computational strategies for modern reference datasets. Genome-wide association studies will soon be able to harness the power of thousands of reference genomes, and our work provides a practical way for investigators to use this rich information. New methodology from this study is implemented in the IMPUTE2 software package.

Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis

Abstract: It has been 100 years since the first report of sickle haemoglobin (HbS). More than 50 years ago, it was suggested that the gene responsible for this disorder could reach high frequencies because of resistance conferred against malaria by the heterozygous carrier state. This traditional example of balancing selection is known as the 'malaria hypothesis'. However, the geographical relationship between the transmission intensity of malaria and associated HbS burden has never been formally investigated on a global scale. Here, we use a comprehensive data assembly of HbS allele frequencies to generate the first evidence-based map of the worldwide distribution of the gene in a Bayesian geostatistical framework. We compare this map with the pre-intervention distribution of malaria endemicity, using a novel geostatistical area-mean comparison. We find geographical support for the malaria hypothesis globally; the relationship is relatively strong in Africa but cannot be resolved in the Americas or in Asia.

Human genetic susceptibility to infectious disease

Abstract: Recent genome-wide studies have reported novel associations between common polymorphisms and susceptibility to many major infectious diseases in humans In parallel, an increasing number of rare mutations underlying susceptibility to specific phenotypes of infectious disease have been described Together, these developments have highlighted a key role for host genetic variation in determining the susceptibility to infectious disease They have also provided insights into the genetic architecture of infectious disease susceptibility and identified immune molecules and pathways that are directly relevant to the human host defence

Genome-wide and fine-resolution association analysis of malaria in West Africa

Abstract: We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.