Janardan Subedi

Genes on chromosomes 1 and 13 have significant effects on Ascaris infection

Nematode parasites show a characteristic aggregated distribution among hosts. This observation has important implications for pathogenesis, immunology, and control of these infections, but the relative roles of environment and genetics in determining these patterns have remained uncertain. This paper presents the results of the first genome scan for susceptibility to infection with roundworm (Ascaris lumbricoides). Data on 375 genetic markers were generated for each of 444 members of a genetically isolated Nepalese population, the Jirels. Ascaris worm burden as assessed by egg counts was measured in these same individuals by using the Kato Katz thick smear method. The extensive genealogical data available for the population allowed assignment of all 444 individuals to a single pedigree that contained 6,209 pairs of relatives that were informative for genetic analysis. A variance components linkage analysis resulted in the unequivocal localization of two genes (one on chromosome 1 and another on chromosome 13) with clear, significant effects on susceptibility to Ascaris infection. This is the first evidence that individual quantitative trait loci influence variation in Ascaris burden in humans.

Localization of Multiple Quantitative Trait Loci Influencing Susceptibility to Infection with Ascaris lumbricoides

A linkage-based genome scan of 1,258 members of a single pedigree of the Jirel population of Nepal localized 6 potential quantitative trait loci (QTLs) influencing susceptibility to infection with Ascaris lumbricoides, the most common soil-transmitted intestinal helminth. Three QTLs exhibited genomewide significance, including QTLs on chromosomes 13 (logarithm of the odds ratio [LOD] score, 3.37; genomewide P = .013, 8 (LOD score, 3.03; genomewide P = .031), and 11 (LOD score, 3.19; genomewide P = .020). Another QTL on chromosome 1 approached significance (LOD score, 2.72; genomewide P = .067). There was suggestive evidence of linkage for 2 additional loci on chromosomes 1 and 13.

Landscape Genetics Reveals Focal Transmission of a Human Macroparasite

Macroparasite infections (e.g., helminths) remain a major human health concern. However, assessing transmission dynamics is problematic because the direct observation of macroparasite dispersal among hosts is not possible. We used a novel landscape genetics approach to examine transmission of the human roundworm Ascaris lumbricoides in a small human population in Jiri, Nepal. Unexpectedly, we found significant genetic structuring of parasites, indicating the presence of multiple transmission foci within a small sampling area (∼14 km2). We analyzed several epidemiological variables, and found that transmission is spatially autocorrelated around households and that transmission foci are stable over time despite extensive human movement. These results would not have been obtainable via a traditional epidemiological study based on worm counts alone. Our data refute the assumption that a single host population corresponds to a single parasite transmission unit, an assumption implicit in many classic models of macroparasite transmission. Newer models have shown that the metapopulation-like pattern observed in our data can adversely affect targeted control strategies aimed at community-wide impacts. Furthermore, the observed metapopulation structure and local mating patterns generate an excess of homozygotes that can accelerate the spread of recessive traits such as drug resistance. Our study illustrates how molecular analyses complement traditional epidemiological information in providing a better understanding of parasite transmission. Similar landscape genetic approaches in other macroparasite systems will be warranted if an accurate depiction of the transmission process is to be used to inform effective control strategies.

Two Quantitative Trait Loci Influence Whipworm (Trichuris trichiura) Infection in a Nepalese Population

BACKGROUND Whipworm (Trichuris trichiura) infection is a soil-transmitted helminth infection that affects >1 billion people. It is a serious public health problem in many developing countries and can result in deficits in growth and cognitive development. In a follow-up study of significant heritability for whipworm infection, we conducted the first genome scan for quantitative trait loci (QTL) influencing the heritability of susceptibility to this important parasitic disease. METHODS Whipworm egg counts were determined for 1,253 members of the Jirel population of eastern Nepal. All individuals in the study sample belonged to a single pedigree including >26,000 pairs of relatives that are informative for genetic analysis. RESULTS Linkage analysis of genome scan data generated for the pedigree provided unambiguous evidence for 2 QTL influencing susceptibility to whipworm infection, one located on chromosome 9 (logarithm of the odds ratio [LOD] score, 3.35; genomewide P = .0138) and the other located on chromosome 18 (LOD score, 3.29; genomewide P = .0159). There was also suggestive evidence that 2 loci located on chromosomes 12 and 13 influenced whipworm infection. CONCLUSION The results of this first genome scan for T. trichiura egg counts provides new information on the determinants of genetic predisposition to whipworm infection.

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.

Attitudes towards helminthic infection in the Jirel population of eastern Nepal

Intestinal worm infections, including roundworm, hookworm, and whipworm, are major international health concerns, affecting approximately one fourth of the worlds population. Many intervention schemes have been attempted to control these infections in heavily exposed populations, but success has been limited because individuals are readily reinfected upon renewed exposure. Few data are available concerning peoples health beliefs about soil-transmitted helminthic infections in such populations. The purpose of this study was to assess health beliefs about common helminthiasis in a population experiencing moderate to high rates of infection. The focal population for the study was the Jirel population, a tribal group distributed across nine villages in the Jiri Region of Dolakha District, eastern Nepal. The results indicate that beliefs about the types, causes, and treatments of helminthic infections have been developed and reinforced by experience and empirical evidence. Peoples frequent inability to confirm the efficacy of drug therapy by observing worms in stools has led to dissatisfaction with biomedical approaches. Carefully planned education programs are required to alter prevailing attitudes and improve control of soil-transmitted helminthiasis in the region.

Genetic Influences on Plasma Cytokine Variation in a Parasitized Population

The soil-transmitted helminths are the most common helminthic infections, affecting about one-fourth of the worlds population. There is a significant genetic component to susceptibility to infection with these organisms. Substantial changes in plasma cytokine levels are associated with helminthic infections, and there may be significant genetic components to this cytokine variation. Six plasma cytokine levels were assessed for 367 members of a single pedigree from the Jirel population of eastern Nepal. This population experiences moderate rates of infection with geohelminths. Sex, age, helminthic infection, infection with Giardia, and presence of a household latrine were considered as covariates in all analyses of the cytokine data. The analyses of the single Jirel pedigree revealed significant heritabilities for IFN-;gg (h2-0.654_0.096), TNF-;ga (h2-0.458_0.101), IL-2 (h2-0.583_0.101), IL-4 (h2-0.700_0.095), IL-5 (h2-0.676_0.087), and IL-10 (h2-0.597_0.093). The ratios of IL-4 to IFN-;gg and of IL-10 to IFN-;gg were used as indicators of the degree of type 2 bias in immunological response; analyses of these variables indicated that approximately 40-60% of the variation (h2-0.400-0.577) in these derived measures of relative type 2/type 1 response is due to genetic factors.

Mental Illness and Disability among Elders in Developing Countries The Case of Nepal

Objective: This article attempts to document the prevalence of psychiatric disorders among elders in a rural village in Nepal. In addition, we investigate the relationship between psychiatric illness and functional disability to assess the impact of disorder on social functioning. Method: A semistructured interview checklist to diagnose six disorders was used (N = 182). In addition, elders older than age 60 were examined to assess the functional impact of mental health conditions by measuring functional disability. Results: Eighteen percent of elders seem to have a diagnosable psychiatric disorder. Furthermore, in general these elders were also less likely to receive assistance with the disabilities they report, compared with those who do not experience a psychiatric disorder. Discussion: Documenting the extent of psychiatric disorder among elders in developing societies sensitizes health planners to the growing reality of aging in their societies and the need for expanded physical and psychiatric health care services.

Measuring Community Mental Health in Developing Societies: Evaluation of a Checklist Format in Nepal:

Background: There is growing recognition of the importance of mental health problems in developing countries. In large part, however, we have very limited epidemiological data at national and/or community levels about the prevalence of mental illnesses. Aims: The purpose of this paper is to describe the reliability and validity characteristics of an assessment tool that may be useful for conducting community-level surveys (particularly in rural communities of developing countries) to obtain prevalence rates of mental illnesses. Methods: We used a sample of adults residing in a rural village in Nepal to assess disorders with a modified version of the DSM-III-R Checklist. We evaluated construct validity, scale reliability, convergent validity and discriminant validity. Results: There is strong evidence for the construct validity of generalized anxiety and depression in our sample. By contrast, the symptoms associated with mania and schizophrenia were not empirically distinct. Convergent validity is acceptable. As a test of validity characteristics, the pattern of sociodemographic correlations suggests that the specific social origins of disorder in Nepal will require further investigation. Conclusion: The first step in obtaining high quality information on the distribution of mental illness in developing countries is to establish some reliable and valid indicators of disorder. The checklist format for assessing disorder appears to meet this objective and offers the possibility that community-level prevalence studies can be reasonably conducted.

Lay Explanations and Self-Management of Diabetes in Kathmandu, Nepal

Objectives: This research explores the lay explanations and self-management of diabetes among residents in greater Kathmandu, Nepal. Methods: Interviews were done with 300 respondents drawn from diabetes patient listings and members of a national diabetes club. Sociodemographic and health-related data were collected with two standardized instruments: the Illness Perception Questionnaire and the Summary of Diabetes Self-Care Activities. Hierarchical ordinary least squares regression analyses were employed to examine predictors of self-management of diabetes. Results: Across seven equations, R 2 values ranged from .020 to .221, and with the exception of one domain of self-management (blood sugar testing), one or more lay explanatory factors entered each equation. Discussion: Respondents from this sample appear to hold lay explanations of diabetes that are similar to those of their peers in developed nations. Findings are discussed, including the caveat that these mostly male, relatively educated, and urban-residing adults with diabetes are not necessarily representative of Nepali society.