Sex-Dependent Association of SMAD3 Gene Polymorphisms With Asthma and Allergy Risk in Russian Children

Despite significant advances in identifying susceptibility genes for bronchial asthma (BA), the immunogenetic and other molecular mechanisms underlying disease risk and progression remain incompletely understood. This study aimed to investigate the association between two common single-nucleotide polymorphisms (SNPs), rs17293632 and rs2033784, located within the SMAD3 (SMAD family member 3) gene-previously identified in genome-wide association studies-and susceptibility to atopic asthma and allergen sensitivity in Russian children.

This study included DNA samples from 999 unrelated children from the Kursk region, comprising 526 patients with BA (316 boys and 210 girls) and 473 healthy children. SNP genotyping was performed using the MassARRAY-4 system.

Both SNPs were associated with an increased risk of BA under the additive genetic model (p ≤ 0.001). In the sex-stratified analysis, the rs17293632 (odds ratio (OR) = 1.79, 95% confidence interval (CI): 1.15-2.77; p = 9.0 × 10^-4) and rs2033784 (OR = 1.80, 95% CI: 1.28-2.52; p = 6.0 × 10^-4) variants were exclusively associated with asthma risk among girls, whereas no significant associations were observed in boys. The rs17293632T-rs2033784G haplotype was associated with an increased risk of asthma in girls (OR = 2.01, 95% CI: 1.38-2.92, p = 3.0 × 10^-4). Notably, SMAD3 gene polymorphisms were associated with an increased risk of asthma exclusively among children living in urban environments (p ≤ 0.0001). Polymorphisms in the SMAD3 gene have also been linked to specific allergies, including those to horsehair, chicken eggs, beef, wheat, oatmeal, barley, and foxtail.

The present study of Russian children confirmed that the rs17293632 and rs2033784 polymorphisms of the SMAD3 gene are significant genetic markers associated with BA and allergies. However, an association between these SMAD3 variants and asthma was observed only among girls, marking the first time this association has been reported. Further research is necessary to determine whether the SMAD3 gene constitutes a viable therapeutic target for treating asthma and allergic diseases.