New Genetic Study Finds Smoking Does Not Causally Cause Urticaria

A Mendelian randomization (MR) study found no evidence of a genetic causal association between smoking-related phenotypes and urticaria, challenging observational findings that have suggested smoking may either increase or decrease urticaria risk.¹ The findings indicate that previously reported associations may be influenced by confounding, reverse causation, or environmental factors.

Study Design and Quality Controls

The study examined 3 smoking-related phenotypes: current tobacco smoking, past tobacco smoking, and smoking or smokers in the household. Genetic data for these exposures were obtained from the Medical Research Council Integrative Epidemiology Unit Open GWAS database, while urticaria outcomes were derived from the FinnGen R12 database. All participants were of European ancestry. The 3 smoking datasets included 462,434 individuals for current smoking, 424,960 for past smoking, and 425,516 for smoking or smokers in the household. The urticaria dataset included 496,891 participants.

The investigators used inverse-variance weighted (IVW) analysis as the primary method, supplemented by MR-Egger, simple mode, weighted median, and weighted mode analyses. Genetic variants were selected using stringent criteria, including genome-wide significance thresholds, F-statistics greater than 10, and linkage disequilibrium pruning. Sensitivity analyses assessed heterogeneity, horizontal pleiotropy, and whether individual genetic variants disproportionately influenced the findings.

Primary Results Across Smoking Phenotypes

For past tobacco smoking, the IVW analysis found no significant causal association with urticaria (OR, 1.13; 95% CI, 0.97-1.31; P = .124). Similarly, current tobacco smoking was not significantly associated with urticaria (OR, 0.62; 95% CI, 0.33-1.14; P = .124). The findings were consistent across the alternative MR approaches for both smoking phenotypes.

The smoking or smokers in household phenotype produced a borderline association in the IVW analysis (OR, 4.38; 95% CI, 1.00-19.20; P = .050). However, this association was not replicated using MR-Egger, weighted median, weighted mode, or simple mode analyses. The investigators therefore considered the finding insufficient to establish a causal relationship. They noted that this dataset represents secondhand smoke exposure and may be more vulnerable to confounding from socioeconomic and household environmental factors. In addition, fewer genome-wide significant variants were available for this phenotype, requiring a less stringent P-value threshold for SNP selection.

Sensitivity analyses supported the overall robustness of the findings. Cochran's Q test showed no significant heterogeneity across the three smoking datasets. MR-Egger intercept testing and MR-PRESSO found no significant evidence of horizontal pleiotropy. Leave-one-out analyses also showed that no individual SNP had a decisive influence on the results. The MR Steiger test found no significant evidence of reverse causality.

Environmental Triggers and Clinical Nuances

The findings add to conflicting evidence surrounding smoking and urticaria. Although tobacco exposure has been proposed to influence mast cell degranulation, histamine release, immune balance, and skin barrier function, some studies have suggested that nicotine may inhibit allergic inflammation and potentially protect against urticaria.² The authors emphasized that observational studies cannot fully separate these potential effects from lifestyle and other confounding factors.

The study does not rule out smoking as an acute environmental trigger or aggravating factor for urticaria. The investigators noted that smoking intensity and duration may differ across exposure groups and that indirect effects or interactions with other risk factors cannot be excluded. Urticaria subtypes may also respond differently to tobacco exposure.

Limitations and Future Research

The study's limitations included the lack of subtype-specific urticaria analyses and restriction to European populations. The authors called for larger studies with more precisely defined smoking phenotypes, detailed exposure information, multiethnic populations, and subtype-stratified analyses. Despite the absence of a demonstrated genetic causal relationship with urticaria, they emphasized that smoking cessation remains an essential component of overall health management.

References

1. Qiu Y, Sun X. No Evidence for a Genetic Causal Association Between Smoking and Urticaria: A Mendelian Randomization Study. Clin Cosmet Investig Dermatol. 2026;19:624506. Published 2026 Aug 21. doi:10.2147/CCID.S624506

2. Hjern A, Hedberg A, Haglund B, Rosén M. Does tobacco smoke prevent atopic disorders? A study of two generations of Swedish residents. Clin Exp Allergy. 2001;31(6):908-914. doi:10.1046/j.1365-2222.2001.01096.x