No Evidence for a Genetic Causal Association Between Smoking and Urticaria: A Mendelian Randomization Study.

Background: Clinical observations have confirmed that smoking is closely associated with the onset and progression of multiple inflammatory skin disorders such as rosacea and psoriasis. Nevertheless, several observational studies have suggested that smokers may have a lower risk of urticaria. The underlying mechanism may be that nicotine binds to nicotinic acetylcholine receptors on mast cells and lymphocytes, thereby inhibiting mast cell degranulation and histamine release, alleviating type I hypersensitivity reactions and exerting a potential protective effect against urticaria. Conventional observational studies are vulnerable to confounding bias and reverse causation. In contrast, Mendelian Randomization (MR) employs genetic variants randomly allocated at conception as instrumental variables to effectively avoid such biases, rendering it an ideal analytical framework to resolve this epidemiological paradoxes. To date, no MR studies have investigated the association between smoking and urticaria. Given that both active and passive smoking impair human health and may differ in exposure routes and biological effects, the present study incorporates phenotypes of active and passive smoking simultaneously to systematically explore their causal relationships with urticaria. Methods: This study employed a two-sample MR design, utilizing genome-wide association study (GWAS) summary statistics to investigate the association between smoking and the onset of urticaria. We categorized three distinct smoking phenotypes according to smoking status as exposures, including: "Current tobacco smoking", "Past tobacco smoking" and "Smoking/smokers in household". Furthermore, the latest urticaria dataset from FinnGen database was selected as the outcome. All data included in this study were derived from European populations with consistent ethnic backgrounds. Inverse variance weighted (IVW) was the main method in this study, along with MR Egger, simple mode, weighted median, and weighted mode. Results: IVW analysis revealed no statistically significant genetic causal association between past tobacco smoking and urticaria (OR = 1.13, 95% CI 0.97-1.31, P = 0.124). Similarly, no significant causal estimate was observed for current tobacco smoking (OR = 0.62, 95% CI 0.33-1.14, P = 0.124). For Smoking/smokers in household group, the IVW analysis yielded a borderline statistically significant estimate (OR = 4.38, 95% CI 1.00-19.20, P = 0.050), whereas this association was not observed in other alternative models. Conclusion: This MR study found no evidence of a genetic causal association between smoking-related phenotypes and urticaria in individuals of European ancestry. However, this finding does not exclude the possibility that smoking acts as an acute environmental trigger or disease aggravating factor. Future studies with larger sample sizes, more precisely defined smoking phenotypes, detailed exposure information, and subtype-stratified analyses of urticaria are warranted to further validate the present results. From the perspective of clinical practice and patient health management, smoking cessation remains irreplaceably important and essential.