# Exploring the Potential Association Between Inhaled Corticosteroid and Face Aging Risk: A Mendelian Randomization Study

## TL;DR

This study explores if inhaled corticosteroids, used for asthma, might cause facial aging through genetic and metabolic effects.

## Contribution

The study introduces a novel Mendelian randomization approach to investigate the causal link between inhaled corticosteroids and facial aging.

## Key findings

- MR analysis found a significant link between ICSs and face aging in Europeans.
- 5-Hydroxylysine partially mediates the relationship between ICSs and face aging.
- Novel DNA methylation sites of ORMDL3 are associated with face aging.

## Abstract

Background: Asthma is one of the most prevalent chronic diseases, affecting more than 300 million individuals globally. Inhaled corticosteroids (ICSs) are recommended as the primary therapy for managing and preventing asthma symptoms in current treatment guidelines. However, long-term use of ICSs could lead to multiple side effects, including skin changes. Methods: We identified ICS target genes using DrugBank and DGIdb databases and derived genetic instruments from cis-eQTL data in whole-blood samples (n = 31,684). GWAS data for facial aging traits (n = 423,999) and plasma metabolites (1400 metabolites, n = 8000) were analyzed. DNA methylation QTL (mQTL) data were used to explore epigenetic regulation. Mendelian randomization (MR) and colocalization analyses were performed to assess causality and shared genetic loci. Results: MR analysis suggested a significant link between genetically proxied ICSs (ORMDL3) and face aging in the European population. Further mediation analysis indicated that 5-Hydroxylysine partially mediates the relationship between ICSs and face aging. In addition, our analysis revealed the pleiotropic association of some novel DNA methylation sites of ORMDL3 with face aging, suggesting the possible regulatory mechanism that are involved in face aging. Conclusions: These findings, while exploratory, raise the hypothesis that ICSs may impact face aging through upregulation of ORMDL3 expression and 5-hydroxylysine metabolism and highlight the need for further pharmacological and clinical research to validate these potential effects.