Association of variants in innate immune genes with asthma and eczema

Abstract

Background The innate immune pathway is important in the pathogenesis of asthma and eczema. However, only a few variants in these genes have been associated with either disease. We investigate the association between polymorphisms of genes in the innate immune pathway with childhood asthma and eczema. In addition, we compare individual associations with those discovered using a multivariate approach. Methods Using a novel method, case control based association testing (C2BAT), 569 single nucleotide polymorphisms (SNPs) in 44 innate immune genes were tested for association with asthma and eczema in children from the Boston Home Allergens and Asthma Study and the Connecticut Childhood Asthma Study. The screening algorithm was used to identify the top SNPs associated with asthma and eczema. We next investigated the interaction of innate immune variants with asthma and eczema risk using Bayesian networks. Results After correction for multiple comparisons, 7 SNPs in 6 genes (CARD25, TGFB1, LY96, ACAA1, DEFB1, and IFNG) were associated with asthma (adjusted p-value<0.02), while 5 SNPs in 3 different genes (CD80, STAT4, and IRAKI) were significantly associated with eczema (adjusted p-value < 0.02). None of these SNPs were associated with both asthma and eczema. Bayesian network analysis identified 4 SNPs that were predictive of asthma and 10 SNPs that predicted eczema. Of the genes identified using Bayesian networks, only CD80 was associated with eczema in the single-SNP study. Using novel methodology that allows for screening and replication in the same population, we have identified associations of innate immune genes with asthma and eczema. Bayesian network analysis suggests that additional SNPs influence disease susceptibility via SNP interactions. Conclusion Our findings suggest that innate immune genes contribute to the pathogenesis of asthma and eczema, and that these diseases likely have different genetic determinants.

Myeloid differentiation protein 2 facilitates pollen- and cat dander–induced innate and allergic airway inflammation

“…37 Our data suggest that future studies should investigate whether MD2 inhibitor or antagonists, like curcumin, 38 prenylated flavonoids, 39 rifampin, 40 and Eritoran 41 can inhibit allergic disorders, particularly those induced by ragweed, Bermuda, rye, timothy, pigweed, Russian thistle, cottonwood, and cat dander extracts. Future studies should investigate whether use of specific inhibitors of MD2 pathway could be a strategy to prevent neutrophil-dominant forms of asthma, such as severe asthma.…”

MD2 Facilitates Pollen and Cat Dander-Induced Innate and Allergic Airway Inflammation

“…37 Our data suggest that future studies should investigate whether MD2 inhibitor or antagonists, like curcumin, 38 prenylated flavonoids, 39 rifampin, 40 and Eritoran 41 can inhibit allergic disorders, particularly those induced by ragweed, Bermuda, rye, timothy, pigweed, Russian thistle, cottonwood, and cat dander extracts. Future studies should investigate whether use of specific inhibitors of MD2 pathway could be a strategy to prevent neutrophil-dominant forms of asthma, such as severe asthma.…”

Effects Of Endotoxin Exposure On Childhood Asthma Risk Are Modified By A Genetic Polymorphism In ACAA1

“…Models without the interaction term for rs156265 and endotoxin quartile did not show the protective effect of endotoxin on asthma risk. None of the 5 SNPs previously associated with eczema, [15] significantly modified the effect of early life endotoxin exposure on the development of eczema by age 6. Although p values for the interaction terms did not reach statistical significance (p < 0.01) after adjustment for multiple comparisons, two SNPs in CD80 (rs7630595, rs1307124) and one in IRAK2 (rs263408) (Table 4).…”

“…The Boston Home Allergens and Asthma and the Connecticut Childhood Asthma Study cohorts were similar with respect to their geographic ascertainment area, recruitment scheme, data collection time frames, and data collection methods. In a similar manner to previous work, the two cohorts were combined for this analysis [15,17]. No evidence of population stratification was detected in the combined cohort (p-value = 0.90).…”