Genetic associations observed for functional polymorphisms, rs1800925 and rs20541, which are protective against high S. mansoni
egg counts in our Brazilian study population, support evidence for a protective effect against high infection intensity for alleles associated with atopic disease, and as previously observed in a population endemic for the S. haematobium
species of schistosomes. For the SNP rs20541, the protective effect of the T allele was identified using both family-based QTDT analysis and GEE regression, while for the SNP rs1800925, statistical significance of the protective effect at the T allele was achieved using GEE regression only. Given the MAF for SNP rs1800925 in our study, statistical power for detecting the association using regression was substantial: it was close to 80% while power was under 40% for the 247 informative trios. 
Thus, the lack of association using QTDT can be explained by insufficient power, and our finding of association for rs1800925 using GEE regression remains credible given higher statistical power inherent in regression-based methods for similar sample sizes. In the literature, in a Malian population infected with S. haematobium,
the T allele at rs1800925 was protective against higher infection levels (P
and in a subsequent investigation of the promoter region, no other marker showed a greater protective effect within the full study population. 
Also in this Malian study, in a family-based analysis, the T allele at rs20541 was found to be preferentially transmitted to offspring in the highest 10% of S. hematobium
infection intensity. 
A recent Kenyan study on a population infected with S. mansoni
showed heterozygotes at rs1800925 were resistant to reinfection, but this finding specific to the heterozygous genotype class is biologically difficult to interpret and may reflect the small sample size. 
Thus our study extends previous findings of association of the T allele at rs1800925 and the T allele at rs20541 with high S. hematobium
infection intensity to high S. mansoni
From studies in industrialized populations, considerable evidence points to some influence by variants in the IL13
promoter, in particular rs1800925 and rs20541, on risk of atopy among European and Asian ancestry cohorts. 
The T allele at rs1800925 was associated with asthma and atopy among European Americans and Europeans, 
and the T allele at rs20541 was associated with bronchial asthma among Europeans. 
The T alleles for both SNPs were the risk alleles for atopy, while we have shown these are protective against high burden of S. mansoni
infection in this highly parasitized Brazilian study of an admixed population. Our data are consistent with an evolutionary hypothesis proposing the TH2 pathway developed, at least in part, as a mechanism to protect humans (and their ancestors) from helminthic infection, and certain genetic risk factors for atopic disease are a vestige of this selective process. 
The lack of association between IL13
variants and tIgE levels in this Brazilian parasitized study population can be evaluated in the context of previous findings in industrialized populations where tIgE levels have been studied among different groups, such as atopic individuals who have been exposed to allergens, non-atopic individuals, or the general population. Specifically, in a linkage study identifying the 5q31-q33 region for tIgE levels, the signal was only present in the subset of the population among individuals where no IgE specific to antigens was detected. 
Similarly, in genetic association studies focusing on IL13
variants, associations have been identified for tIgE levels among non-atopic individuals or the general population, but rarely among atopic individuals. 
For example, in the large British 1958 Birth Cohort following 4,570 individuals from the general population, basal tIgE means significantly differed between genotypes at both rs1800925 and rs20541. 
The helminth-endemic setting of the present Brazilian study population meant tIgE levels reflected a mixture of IgE specific to S. mansoni
and IgE specific to other helminths or antigens. Basal IgE levels without any antigenic stimulation, which are conditions under which we would expect to detect association with IL13
polymorphisms based on the literature as discussed above, cannot be measured in a helminth-endemic setting by definition. Thus, the finding of no associations between IL13
polymorphisms and tIgE levels in this Brazilian study is consistent with studies conducted in populations of industrialized communities.
In our Brazilian study population, the age profile for S. mansoni
egg counts features a characteristic peak in infection intensity at 15 years, which represents acquisition of natural immunity to infection in adolescence shown previously. 
For tIgE levels, a different pattern was observed and mean values were highest among young children aged 6–9 years, and then declined with increasing age. We therefore performed association analyses across SNPs on subsets of independent individuals from the full study population comprising children under 15 years and individuals over 15 years of age. No differences in evidence for association were observed in the two subsets (data not shown).
Thus, evaluating our data in the context of the literature suggests IL-13 acts most strongly on TH2 pathway effector mechanisms (as reflected in statistical associations with S. mansoni egg counts) rather than on TH2 pathway activation (as reflected by lack of association with tIgE levels). It is also possible IL-13 acts during only early TH2 activation in an antigen-specific manner, but IgE levels specific against schistosomiasis antigens were not available in this Brazilian study.
The two quantitative traits, tIgE levels, representing TH2 pathway activation, and S. mansoni egg counts, reflecting global impact of TH2 effector mechanisms and helminthic host immunity, provided a unique opportunity for genetic dissection of the TH2 pathway in the context of schistosomiasis endemicity. In summary, we have found significant associations between two well-known functional variants and S. mansoni egg counts, and a striking lack of association with tIgE levels. Since the functional effect of both variants on the gene product, IL-13, is to increase its amount or activity, this finding suggests IL-13 functions to increase anti-helminth immunity, and functional variants may be an evolutionary vestige of selective forces that result in atopic phenotypes in modern, industrialized settings. Our evaluation of IL13 variation has demonstrated TH2 pathway genes shown to carry variants that impact on atopic disease are good candidates to evaluate determinants of host immunity to helminthic infections. Moreover, genetic association studies in schistosomiasis-endemic populations allow further fine dissection of the TH2 pathway and its role in disease, both helminthic and atopic.