# The сontribution of FOXO family transcription factor genes (FOXO1, FOXO3) to chronic obstructive pulmonary disease

## TL;DR

This study finds that genetic variations in FOXO1 and FOXO3A genes are linked to COPD and its severity, offering potential for new diagnostic and treatment strategies.

## Contribution

First-time identification of significant associations between FOXO1 and FOXO3A gene polymorphisms and COPD risk and phenotypes.

## Key findings

- FOXO1 (rs12585277) and FOXO3A (rs2253310) gene variants are significantly associated with COPD.
- Genotype-dependent variations in smoking index and lung function were observed for these gene loci.
- A COPD risk model including these gene variants, smoking index, and age showed high predictive accuracy.

## Abstract

Chronic obstructive pulmonary disease (COPD) is a multifactorial disease of the respiratory system and is the third leading cause of death worldwide. In the framework of the most relevant concepts of COPD pathogenesis, the key focus is on accelerated cellular senescence. FOXO family transcription factors are important hub components of cellular senescence signaling pathways. The objective of the study is to identify the association of FOXO1 (rs12585277, rs9549240), and FOXO3A (rs2253310, rs3800231) genes polymorphic variants with COPD and disease phenotypes. DNA samples from COPD patients (N = 710) and healthy individuals (N = 655) were used, polymorphic loci were analyzed by real-time PCR. For the first time, significant associations of FOXO1 (rs12585277) and FOXO3A (rs2253310) gene polymorphic loci with COPD and disease phenotypes were shown. Association with COPD was established with FOXO1 (rs12585277) (Padj = 0.0018, OR = 1.44 for the AG genotype) and FOXO3A (rs2253310) (Padj = 5.926 × 10–7, OR = 1.99 for the GG genotype). A significant genotype-dependent variation of smoking index (in pack/years), vital capacity and forced vital capacity was revealed for FOXO1 (rs9549240, rs12585277) and FOXO3A (rs2253310) loci. Multiple regression and ROC analysis identified highly informative COPD risk model, which included polymorphic variants of the FOXO1 (rs12585277) and FOXO3A (rs2253310) genes, smoking index and age (P = 5.25 × 10–93, AUC = 0.864). The multivariate regression model of the COPD “frequent exacerbator” phenotype included the AG genotype of FOXO1 (rs12585277), smoking index and age (AUC = 0.897, P = 4.1 × 10–86). FOXO family transcription factors involved in autophagy, oxidative stress and cellular homeostasis may provide a platform for a new diagnostic and treatment strategy for COPD as potential biomarkers and targets for therapy.