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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.

Ascaris lumbricoides is the most common helminthic infection in developing nations, affecting over a quarter of the world's population (1, 2). Heavy worm loads can result in serious morbidity and even mortality as a consequence of intestinal blockage (3–7). Long-term infection with roundworm has been implicated in the development and persistence of childhood malnutrition and may have lasting effects on anthropometric measures of growth (5, 8–12).

In addition to the importance of the disease because of the worldwide scale of infection, the significance of helminthic infections has dramatically increased with the advent of HIV infections (13). Bentwich and colleagues (14, 15) have proposed that helminthic infections have deleterious effects on the ability to mount an effective immune response to other infections, particularly HIV and tuberculosis. Furthermore, they have suggested that the rapid progression to AIDS observed in developing countries may be attributable in part to helminthic coinfections (14, 15). Helminthic coinfections may also diminish the efficacy of future vaccines (13, 15). Clearly, helminthic infections can have a significant impact on epidemiological patterns of other diseases that have devastating health consequences (13).

Helminthic infections are characteristically overdispersed in human populations, with a small proportion of people harboring the majority of parasitic worms present (16, 17). Although this aggregation has been attributed most commonly to variability in exposure patterns, some have suggested the possible role of genetic factors (17, 18). A familial patterning to Ascaris infection frequently has been noted (19–21).

Our previous studies have demonstrated that there is a substantial genetic component to susceptibility to Ascaris infection in humans (22). The focal population for these studies was the Jirel population of eastern Nepal, a Tibeto–Burman language speaking hybrid group derived from Sherpas and Sunwars approximately 10–11 generations ago (23, 24). We used data on Ascaris egg counts in a single large pedigree comprising 1,261 members of the Jirel population to determine that genetic factors accounted for approximately 30% (h 2 = 0.291, P < 0.0001) of the variation in eggs per gram of feces (EPG) as assessed by the Kato–Katz thick smear method (22). Systematic environmental factors accounted for an additional 6% of the variation. This strong evidence for the role of genetic factors in determining susceptibility to Ascaris infection provided impetus for a genome scan in the same population to find the locations of specific genes involved in determining susceptibility and resistance.

Although these previous studies are compelling in their general support of the possibility of genetic factors influencing Ascaris infection, classical genetic approaches that look only at the phenotypic variability among classes of relatives are not able to unequivocally disentangle genetic factors from shared environmental components of disease susceptibility. However, modern genomic approaches to the dissection of the determinants of infectious disease susceptibility do not confound genetic and environmental effects because the genetic effects are assessed from the cosegregation of a disease trait and a specific marker locus throughout an extended pedigree. It is impossible for an environmental effect on a disease trait to mimic this segregation pattern throughout an extended pedigree. Thus, linkage analysis approaches can be used to demonstrate the roles of genes in determining patterns of variation in parasitic burden among individuals.

Ultimately, identifying the specific genes involved in susceptibility to roundworm infection may suggest new biological pathways to be targeted by pharmacological treatment and intervention mechanisms. Localization of the genes by linkage analysis is the first important step toward identifying genes influencing Ascaris infection. Additionally, this easily quantifiable infection may serve as a model disease for understanding the genetic mechanisms involved in other more complex infectious diseases.