Fungal exposure modulates the effect of polymorphisms of chitinases on emergency department visits and hospitalizations

Abstract

Rationale: Chitinases are enzymes that cleave chitin, which is present in fungal cells. Two types of human chitinases, chitotriosidase and acidic mammalian chitinase, and the chitinase-like protein, YKL-40, seem to play an important role in asthma. We hypothesized that exposure to environmental fungi may modulate the effect of chitinases in individuals with asthma.

Objectives: To explore whether interactions between high fungal exposure and common genetic variants in the two chitinases in humans, CHIT1 and CHIA, and the chitinase 3-like 1 gene, CHI3L1, are associated with severe asthma exacerbations and other asthma-related outcomes.

Methods: Forty-eight single nucleotide polymorphisms (SNPs) in CHIT1, CHIA, and CHI3L1 and one CHIT1 duplication were genotyped in 395 subjects and their parents as part of the Childhood Asthma Management Program. Household levels of mold (an index of fungal exposure) were determined on house dust samples. We conducted family-based association tests with gene-environment interactions. Our outcome was severe exacerbation, defined as emergency department visits and hospitalizations from asthma over a 4-year period, and our secondary outcomes included indices of lung function and allergy-related phenotypes.

Measurements and main results: Of the 395 subjects who had mold levels at randomization, 24% (95 subjects) had levels that were greater than 25,000 units per gram of house dust (high mold exposure). High mold exposure significantly modified the relation between three SNPs in CHIT1 (rs2486953, rs4950936, and rs1417149) and severe exacerbations (P for interaction 0.0010 for rs2486953, 0.0008 for rs4950936, and 0.0005 for rs1417149). High mold exposure did not significantly modify the relationship between any of the other variants and outcomes.

Conclusions: Environmental exposure to fungi, modifies the effect of CHIT1 SNPs on severe asthma exacerbations.

Figure 1.

Linkage disequilibrium plot for CHIT1 demonstrating that rs2486953, rs4950936, and rs1417149 are in linkage disequilibrium with each other. Linkage disequilibrium is measured as D′, with darker gray colors indicating higher values. The number in each box represents the r² between the two corresponding SNPs.

Figure 2.

Depiction of the effect of mold level >25,000 units per gram and genotype on the outcome of hospitalizations and emergency department visits for rs2486953. E = 1 refers to exposure to a mold level of >25,000 units per gram and E = 0 refers to a mold level of ≤25,000 units per gram. G stands for genotype and there are three possibilities for the number of copies of rs2486953: 0 copies, 1 copy, or 2 copies. Y refers to the probability of having one or more hospitalizations and emergency department visits. This figure demonstrates that with exposure to a mold level of >25,000 units per gram, having two copies of the minor allele produces a much higher probability of experiencing hospitalizations and emergency department visits than with no exposure to this mold level.