Abstract
Helminth infections and allergic diseases are associated with IgE hyperresponsiveness but the genetics of this phenotype remain to be defined. Susceptibility to Ascaris lumbricoides infection and antibody levels to this helminth are associated with polymorphisms in locus 13q33-34. We aimed to explore this and other genomic regions to identify genetic variants associated with the IgE responsiveness in humans. Forty-eight subjects from Cartagena, Colombia, with extreme values of specific IgE to Ascaris and ABA-1, a resistance marker of this nematode, were selected for targeted resequencing. Burden analyses were done comparing extreme groups for IgE values. One-hundred one SNPs were genotyped in 1258 individuals of two well-characterized populations from Colombia and Sweden. Two low-frequency coding variants in the gene encoding the Acidic Mammalian Chitinase (CHIA rs79500525, rs139812869, tagged by rs10494133) were found enriched in high IgE responders to ABA-1 and confirmed by genetic association analyses. The SNP rs4950928 in the Chitinase 3 Like 1 gene (CHI3L1) was associated with high IgE to ABA-1 in Colombians and with high IgE to Bet v 1 in the Swedish population. CHIA rs10494133 and ABDH13 rs3783118 were associated with IgE responses to Ascaris. SNPs in the Tumor Necrosis Factor Superfamily Member 13b gene (TNFSF13B) encoding the cytokine B cell activating Factor were associated with high levels of total IgE in both populations. This is the first report on the association between low-frequency and common variants in the chitinases-related genes CHIA and CHI3L1 with the intensity of specific IgE to ABA-1 in a population naturally exposed to Ascaris and with Bet v 1 in a Swedish population. Our results add new information about the genetic influences of human IgE responsiveness; since the genes encode for enzymes involved in the immune response to parasitic infections, they could be helpful for understanding helminth immunity and allergic responses. We also confirmed that TNFSF13B has an important and conserved role in the regulation of total IgE levels, which supports potential evolutionary links between helminth immunity and allergic response.
Highlights
Upon infection with helminths humans synthesize specific IgE antibodies to parasite components as well as high levels of total IgE
ABA-1 is an excellent tool with which to investigate the genetics of the IgE response to Ascaris
Due to the high prevalence of these conditions [8, 41, 42], studies analyzing the influences of genetic variants on the IgE response to allergens from both sources can be performed simultaneously in the same population; and second, the perennial exposure to allergenic components allows selecting extreme phenotypes of IgE responses
Summary
Upon infection with helminths humans synthesize specific IgE antibodies to parasite components as well as high levels of total IgE. The intensity of this response differs among exposed individuals [1,2,3,4], which seems to be determined by environment and their genetic backgrounds. The intestinal helminth Ascaris lumbricoides infects about 0.9 billion people worldwide [8], inducing specific IgE against its proteins (e.g. the polyprotein allergen ABA-1, tropomyosin, glutathione-S-transferase) [9,10,11], high levels of total IgE and, in general, a strong Th2 response [12]. ABA-1 is an excellent tool with which to investigate the genetics of the IgE response to Ascaris
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