# 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

## TL;DR

This study shows how genetic variants and early-life tobacco smoke exposure together increase the risk of asthma and eczema in children.

## Contribution

The study provides first replication of gene-environment interactions involving TNS1 and NRXN1 in asthma–eczema comorbidity.

## Key findings

- The TNS1 rs918949 [T] allele is linked to the asthma–eczema phenotype but not eczema alone.
- Early-life tobacco smoke exposure synergizes with TNS1 and NRXN1 risk alleles to increase disease risk.
- Findings suggest shared genetic pathways and environmental modifiers in asthma–eczema comorbidity.

## Abstract

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.