Genetics of Inflammatory Mediators of Atopy and Asthma in Adults

The prevalence of atopic disorders such as asthma, allergic rhinitis and allergic conjunctivitis in many populations is close to 30% and has continued to increase in many developed countries, causing a major burden on the individuals, their health care systems, and on society. The biological bases of these disorders and of atopy in general have undergone investigation to a great extent, but many aspects still need clarification, for example in order to target novel therapies to patients who would benefit.

Our studies examined whether functional single nucleotide polymorphisms of candidate genes IL1A, IL4RA, TLR4, IL4, and NOS3 exert their effects individually on the risk or severity of atopy or asthma, or whether two polymorphisms of different candidate genes show an interactive effect. The aim was also to observe factors associated with polymorphism rs20541 of IL13 and other factors with or without allergic comorbidities such as subject-reported allergic rhinitis and allergic conjunctivitis symptoms in adult asthma patients.

A total of 1,156 asthma patients and 1,792 non-asthmatic subjects as controls participated in our studies, all of them having participated in a Finnish population- based case-control study conducted to investigate the risk factors and predictors of the outcome of adult asthma. Inclusion criteria for subjects with asthma were age over 30 years and entitlement to special reimbursement for asthma medication from the Social Insurance Institution of Finland. Allergic rhinitis and conjunctivitis were defined by questionnaire. Of the participants 245 asthma patients and 405 matched control subjects were tested for atopic status by skin prick tests and by measurement of serum IgE levels, and we also determined variety of polymorphisms of candidate genes previously linked to atopy or asthma.

We demonstrated in our non-asthma control group, which represented the general population reasonably well, an epistatic effect on atopy between IL1A and IL4RA genes. The predisposing combination was the carrier status of genotype TT of IL4RA +22446 and genotype GG of IL1A +4845. An increased risk for asthma appeared in the female carriers of allele G of TLR4 +896 and allele T of IL4 -590. Additionally, an epistatic effect of allele T of NOS3 +894 and genotype GG of IL1A +4845 influenced degree of atopy. We also showed that allele A of IL13 rs20541 affected the risk for allergic rhinitis and conjunctivitis in asthma patients. In addition, carriers of allele A of IL13 rs20541 were predisposed towards multisensitization in asthma.

Our findings suggest that gene-gene interactions affect susceptibility to atopy and asthma as well as severity of atopy in Finnish adults. Even if single nucleotide polymorphisms of candidate genes show no individual effects, two separate polymorphisms can potentiate the effects of each other, predisposing carriers of certain allele combinations to clinical manifestations. An effect of TLR and IL4 genes was apparent only in female subjects, indicating sex-dependent differences in the body’s defense mechanisms. Our results indicate that key features of adult atopic asthma phenotype may be high prevalence of the allele A of IL13 rs20541, a multisensitization pattern, and allergic rhinitis and conjunctivitis symptoms.