Host genetics and population structure effects on parasitic disease

Host genetic factors exert significant influences on differential susceptibility to many infectious diseases. In addition, population structure of both host and parasite may influence disease distribution patterns. In this study, we assess the effects of population structure on infectious disease in two populations in which host genetic factors influencing susceptibility to parasitic disease have been extensively studied. The first population is the Jirel population of eastern Nepal that has been the subject of research on the determinants of differential susceptibility to soil-transmitted helminth infections. The second group is a Brazilian population residing in an area endemic for Trypanosoma cruzi infection that has been assessed for genetic influences on differential disease progression in Chagas disease. For measures of Ascaris worm burden, within-population host genetic effects are generally more important than host population structure factors in determining patterns of infectious disease. No significant influences of population structure on measures associated with progression of cardiac disease in individuals who were seropositive for T. cruzi infection were found

Genetic analysis localizes a novel locus on chromosome 4q for the glaucoma endophenotype, cup-to-disc ratio: The Jiri Eye Study

Purpose: Glaucoma is a heterogeneous disease influenced by genetic risk factors. However, not all genetic risk factors have been identified. The aim of this project is to localize genetic factors influencing known glaucoma endophenotypes: intraocular pressure (IOP), central corneal thickness (CCT), and vertical cup-to-disc ratio (VCDR). Methods: This family-based study design utilizes phenotypic and genomic data from a single well-characterized pedigree residing in the Jiri region of Nepal. Measures of IOP, CCT and VCDR were obtained by Goldmann applanation tonometry, OCT, and slit lamp biomicroscopy, respectively. Using a genome-wide genotype data set (~550,000 SNPs), we performed a genome-wide linkage scan for IOP, CCT, and VCDR adopting a quantitative approach in SOLAR. For localized quantitative trait locus (QTL) signals, we screened all SNPs within the 1-LOD (95% confidence) interval using the classical measured genotype approach to association analysis and allowing for non-independence amongst the pedigree members. Results: For this study, phenotypic and genotype data from 1,163 (55% female) members of the Jirel population were available. The mean age of the sample is 43.8 (SD=15.7) years. IOP (h2=19%, p=6.1×10-5), CCT (h2=57%, p=1.6×10-26), and VCDR (h2=48%, p=9.7×10-22) were significantly heritable. We localized a significant QTL for VCDR on chromosome 4 (LOD=3.05 at 86.83 Mb). The top association signal within this QTL was for an intronic SNP (rs4148155; p=2.01×10-6, b=0.24) in the ABCG2 (ATP binding cassette subfamily G member 2) gene, which satisfied our QTL-specific Bonferroni-corrected significance criterion (p\u3c6.59×10-5). ABCG2 is a known stem cell marker, which is positively expressed in clonal human trabecular meshwork stem cells. Another positional candidate gene of note is SCD5 (Stearoyl-CoA desaturase 5), which is shown to suppress neurite outgrowth, a marker of neuronal differentiation. SCD5 is of significant interest given that expression of myocilin (MYOC) also inhibits neurite outgrowth. Conclusions: To our knowledge, the VCDR QTL on chromosome 4 is a novel locus and does not overlap with other glaucoma endophenotypes or glaucoma disease status. These results highlight the importance of continued evaluation of genetic factors influencing glaucoma endophenotypes in under-studied populations, such as the Jirels, as new information may be elucidated

Chronic neuropsychiatric sequelae of SARS-CoV-2: Protocol and methods from the Alzheimer\u27s Association Global Consortium

Introduction Coronavirus disease 2019 (COVID‐19) has caused \u3e3.5 million deaths worldwide and affected \u3e160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID‐19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID‐19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID‐19 to neurologic illness, both short and long term. Methods This article describes what is known so far in terms of links among COVID‐19, the brain, neurological symptoms, and Alzheimer\u27s disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer\u27s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions. Results Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe. Discussion The Alzheimer\u27s Association Global Consortium harmonized methodology is proposed as a model to study long‐term neurocognitive sequelae of SARS‐CoV‐2 infection. Key Points The following review describes what is known so far in terms of molecular and epidemiological links among COVID‐19, the brain, neurological symptoms, and AD and related dementias (ADRD) The primary objective of this large‐scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long‐term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS‐CoV‐2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS‐CoV‐2 triggers ADRD‐like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility. The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under‐represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long‐term consequences, and trends in cognitive aging, ADRD, and vascular disease. We provide a framework for current and future studies to be carried out within the Consortium. and offers a “green paper” to the research community with a very broad, global base of support, on tools suitable for low‐ and middle‐income countries aimed to compare and combine future longitudinal data on the topic. The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID‐19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high‐quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations

Risk Factors for Soil-Transmitted Helminth Infections during the First 3 Years of Life in the Tropics; Findings from a Birth Cohort.

Background: Soil-transmitted helminths (STH) infect more than 2 billion humans worldwide, causing significant morbidity in children. There are few data on the epidemiology and risk factors for infection in pre-school children. To investigate risk factors for infection in early childhood, we analysed data prospectively collected in the ECUAVIDA birth cohort in Ecuador. Methods and Findings: Children were recruited at birth and followed up to 3 years of age with periodic collection of stool samples that were examined microscopically for STH parasites. Data on social, demographic, and environmental risk factors were collected from the mother at time of enrolment. Associations between exposures and detection of STH infections were analysed by multivariable logistic regression. Data were analysed from 1,697 children for whom a stool sample was obtained at 3 years. 42.3% had at least one STH infection in the first 3 years of life and the most common infections were caused by A. lumbricoides (33.2% of children) and T. trichiura (21.2%). Hookworm infection was detected in 0.9% of children. Risk of STH infection was associated with factors indicative of poverty in our study population such as Afro-Ecuadorian ethnicity and low maternal educational level. Maternal STH infections during pregnancy were strong risk factors for any childhood STH infection, infections with either A. lumbricoides or T. trichiura, and early age of first STH infection. Children of mothers with moderate to high infections intensities with A. lumbricoides were most at risk. Conclusions: Our data show high rates of infection with STH parasites during the first 3 years of life in an Ecuadorian birth cohort, an observation that was strongly associated with maternal STH infections during pregnancy. The targeted treatment of women of childbearing age, in particular before pregnancy, with anthelmintic drugs could offer a novel approach to the prevention of STH infections in pre-school children

Spatial and Genetic Epidemiology of Hookworm in a Rural Community in Uganda

There are remarkably few contemporary, population-based studies of intestinal nematode infection for sub-Saharan Africa. This paper presents a comprehensive epidemiological analysis of hookworm infection intensity in a rural Ugandan community. Demographic, kinship, socioeconomic and environmental data were collected for 1,803 individuals aged six months to 85 years in 341 households in a cross-sectional community survey. Hookworm infection was assessed by faecal egg count. Spatial variation in the intensity of infection was assessed using a Bayesian negative binomial spatial regression model and the proportion of variation explained by host additive genetics (heritability) and common domestic environment was estimated using genetic variance component analysis. Overall, the prevalence of hookworm was 39.3%, with the majority of infections (87.7%) of light intensity (≤1000 eggs per gram faeces). Intensity was higher among older individuals and was associated with treatment history with anthelmintics, walking barefoot outside the home, living in a household with a mud floor and education level of the household head. Infection intensity also exhibited significant household and spatial clustering: the range of spatial correlation was estimated to be 82 m and was reduced by a half over a distance of 19 m. Heritability of hookworm egg count was 11.2%, whilst the percentage of variance explained by unidentified domestic effects was 17.8%. In conclusion, we suggest that host genetic relatedness is not a major determinant of infection intensity in this community, with exposure-related factors playing a greater role

Multi-parallel qPCR provides increased sensitivity and diagnostic breadth for gastrointestinal parasites of humans: field-based inferences on the impact of mass deworming

BACKGROUND: Although chronic morbidity in humans from soil transmitted helminth (STH) infections can be reduced by anthelmintic treatment, inconsistent diagnostic tools make it difficult to reliably measure the impact of deworming programs and often miss light helminth infections. METHODS: Cryopreserved stool samples from 796 people (aged 2-81 years) in four villages in Bungoma County, western Kenya, were assessed using multi-parallel qPCR for 8 parasites and compared to point-of-contact assessments of the same stools by the 2-stool 2-slide Kato-Katz (KK) method. All subjects were treated with albendazole and all Ascaris lumbricoides expelled post-treatment were collected. Three months later, samples from 633 of these people were re-assessed by both qPCR and KK, re-treated with albendazole and the expelled worms collected. RESULTS: Baseline prevalence by qPCR (n = 796) was 17 % for A. lumbricoides, 18 % for Necator americanus, 41 % for Giardia lamblia and 15% for Entamoeba histolytica. The prevalence was <1% for Trichuris trichiura, Ancylostoma duodenale, Strongyloides stercoralis and Cryptosporidium parvum. The sensitivity of qPCR was 98% for A. lumbricoides and N. americanus, whereas KK sensitivity was 70% and 32%, respectively. Furthermore, qPCR detected infections with T. trichiura and S. stercoralis that were missed by KK, and infections with G. lamblia and E. histolytica that cannot be detected by KK. Infection intensities measured by qPCR and by KK were correlated for A. lumbricoides (r = 0.83, p < 0.0001) and N. americanus (r = 0.55, p < 0.0001). The number of A. lumbricoides worms expelled was correlated (p < 0.0001) with both the KK (r = 0.63) and qPCR intensity measurements (r = 0.60). CONCLUSIONS: KK may be an inadequate tool for stool-based surveillance in areas where hookworm or Strongyloides are common or where intensity of helminth infection is low after repeated rounds of chemotherapy. Because deworming programs need to distinguish between populations where parasitic infection is controlled and those where further treatment is required, multi-parallel qPCR (or similar high throughput molecular diagnostics) may provide new and important diagnostic information

Individual Predisposition, Household Clustering and Risk Factors for Human Infection with Ascaris lumbricoides: New Epidemiological Insights

Numerous analyses have found that people infected with roundworm (Ascaris lumbricoides) are predisposed to harbor either many or few worms. Members of the same household also tend to harbor similar numbers of worms. These phenomena are called individual predisposition and household clustering respectively. In this article, we use Bayesian methods to fit a statistical model to worm count data collected from a cohort of participants at baseline and after two rounds of re-infection following curative treatment. We show that individual predisposition is extremely weak once the clustering effect of the household has been accounted for. This suggests that predisposition is of limited importance to the epidemiology of roundworm infection. Further, we show that over half of the variability in average worm counts among households is explained by household risk factors. This implies that exposures to infectious roundworm eggs shared by household members are important determinants of household clustering. We argue that these results support the hypothesis proposed in the literature that the household is a key focus of roundworm transmission

Genetic Determination and Linkage Mapping of Plasmodium falciparum Malaria Related Traits in Senegal

Plasmodium falciparum malaria episodes may vary considerably in their severity and clinical manifestations. There is good evidence that host genetic factors contribute to this variability. To date, most genetic studies aiming at the identification of these genes have used a case/control study design for severe malaria, exploring specific candidate genes. Here, we performed a family-based genetic study of falciparum malaria related phenotypes in two independent longitudinal survey cohorts, as a first step towards the identification of genes and mechanisms involved in the outcome of infection. We studied two Senegalese villages, Dielmo and Ndiop that differ in ethnicity, malaria transmission and endemicity. We performed genome-scan linkage analysis of several malaria-related phenotypes both during clinical attacks and asymptomatic infection. We show evidence for a strong genetic contribution to both the number of clinical falciparum malaria attacks and the asymptomatic parasite density. The asymptomatic parasite density showed linkage to chromosome 5q31 (LOD = 2.26, empirical p = 0.0014, Dielmo), confirming previous findings in other studies. Suggestive linkage values were also obtained at three additional chromosome regions: the number of clinical malaria attacks on chromosome 5p15 (LOD = 2.57, empirical p = 0.001, Dielmo) and 13q13 (LOD = 2.37, empirical p = 0.0014 Dielmo), and the maximum parasite density during asymptomatic infection on chromosome 12q21 (LOD = 3.1, empirical p<10−4, Ndiop). While regions of linkage show little overlap with genes known to be involved in severe malaria, the four regions appear to overlap with regions linked to asthma or atopy related traits, suggesting that common immune related pathways may be involved

A Research Agenda for Helminth Diseases of Humans: Basic Research and Enabling Technologies to Support Control and Elimination of Helminthiases

Successful and sustainable intervention against human helminthiases depends on optimal utilisation of available control measures and development of new tools and strategies, as well as an understanding of the evolutionary implications of prolonged intervention on parasite populations and those of their hosts and vectors. This will depend largely on updated knowledge of relevant and fundamental parasite biology. There is a need, therefore, to exploit and apply new knowledge and techniques in order to make significant and novel gains in combating helminthiases and supporting the sustainability of current and successful mass drug administration (MDA) programmes. Among the fields of basic research that are likely to yield improved control tools, the Disease Reference Group on Helminth Infections (DRG4) has identified four broad areas that stand out as central to the development of the next generation of helminth control measures: 1) parasite genetics, genomics, and functional genomics; 2) parasite immunology; 3) (vertebrate) host–parasite interactions and immunopathology; and 4) (invertebrate) host–parasite interactions and transmission biology. The DRG4 was established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR). The Group was given the mandate to undertake a comprehensive review of recent advances in helminthiases research in order to identify notable gaps and highlight priority areas. This paper summarises recent advances and discusses challenges in the investigation of the fundamental biology of those helminth parasites under the DRG4 Group's remit according to the identified priorities, and presents a research and development agenda for basic parasite research and enabling technologies that will help support control and elimination efforts against human helminthiases