Interactive Effects of Genetic Susceptibility and Early-Life Tobacco Smoke Exposure on the Asthma-Eczema Complex Phenotype in Children: 6-Year Follow-Up Case-Control Study.

Atopic eczema and asthma frequently co-occur, forming a distinct complex phenotype that likely arises from shared genetic pathways and early-life environmental influences. We aimed to investigate whether variants in TNS1 and NRXN1-previously identified in a genome-wide interaction study-influence susceptibility to atopic eczema and the asthma-eczema phenotype and whether early-life environmental tobacco smoke (ETS) exposure modifies these genetic effects. A total of 188 Caucasian children under 2 years at recruitment were prospectively followed up to 6 years of age. Eligibility of all participants for the study or control group was based on a questionnaire and a physician-confirmed diagnosis of eczema and asthma. Early-life ETS exposure was assessed by parental questionnaire. All participants were genotyped for TNS1 and NRXN1 SNPs. The TNS1 rs918949 [T] allele was associated with the combined asthma-eczema phenotype but not with eczema alone. Synergistic gene-environment interactions were identified for both TNS1 and NRXN1, with the highest risk of the combined asthma-eczema phenotype observed among ETS-exposed carriers of risk alleles. Our findings provide the first independent replication of evidence suggesting that TNS1 and NRXN1 may contribute to the asthma-eczema comorbidity through mechanisms that could be substantially modified by early-life ETS exposure.