Association between exposure to farming, allergies and genetic variation in CARD4/NOD1

Background: Caspase recruitment domain protein (CARD) 4 has been recently identified as an intracellular pattern recognition receptor that interacts with muropeptides found in common Gram-negative bacteria. We therefore aimed to explore whether the previously observed inverse association between exposure to microbial products and asthma and allergies in childhood is modified by genetic variation in CARD4. Methods: We genotyped 668 children [mean age 9.3 (SD 1.5) years] enrolled in the cross-sectional ALEX study for seven haplotype tagging single nucleotide polymorphisms in CARD4. We studied the association of asthma, hay fever and allergen-specific serum immunoglobulin E with exposure to a farming environment and with levels of endotoxin and muramic acid measured in house dust samples. We tested whether these associations differed between the genotypes of the polymorphisms under study. Results: A strong protective effect of a farming environment on allergies was only found in children homozygous for the T allele in CARD4/-21596, but not in children carrying the minor allele (C). Among the former, farmers' children had a significantly lower frequency of sensitization against pollen (5.8%), hay fever (1.7%) and atopic asthma symptoms (1.7%) compared with children not living on a farm (19.4%, 13.0% and 7.6%, P < 0.01, < 0.01 and < 0.05, respectively). Conversely, no significant difference in prevalence of these phenotypes by farming status was found among children with a C allele in CARD4/-21596 (14.3%, 7.1% and 8.0%vs 16.5%, 9.0% and 5.7%, respectively). Conclusions: Polymorphisms in CARD4 significantly modify the protective effect of exposure to a farming environment.