Genetic haplotypes of Th-2 immune signalling link allergy to enhanced protection to parasitic worms

Parasitic worm infection, allergy and asthma involve increased IgE production, eosinophil activity, mucus secretion and smooth muscle reactivity, effected through Th-2 immune signalling. These pathological features of allergic disorder, common in developed countries, appear to be protective features in resistance to parasitic worm infections prevalent in many developing countries. We investigated how genetic variation in the Th-2 signalling transduction molecule STAT6 relates to these clinical disorders, using immune phenotyping by serum IgE levels and haplotyping nine STAT6 genetic variants in a rural Chinese population, where Ascaris infection is prevalent, and an urban UK population where Ascaris is largely unknown but asthma and allergy are prevalent. We show for the first time that STAT6 haplotypes relate clearly to IgE levels, allergy and worm burden. The haplotypes segregated into two groups: those with raised IgE/Iow worm burden tended to have increased risk of allergic disorder, whereas low IgE/high worm burden tended to have a reduced risk of allergies. By estimating the mean worm burden for each haplotype in China and the relative risk of asthma for the matching haplotype in the UK, we draw a cross-population comparison and show a negative correlation between worm burden and expected risk of asthma. These data imply that the origin of common up-regulating variants of Th-2 signalling, involving STAT6, promotes asthma and allergy in developed countries, whereas in developing countries it protects against parasitic worm infections. Selective evolutionary mechanisms, driven by parasitic worm infection, may underlie the genetic contribution to risk of allergy and asthma in humans.