Smoking is an independent but not a causal risk factor for moderate to severe psoriasis: A Mendelian randomization study of 105,912 individuals

Abstract

BackgroundSmoking is strongly associated with higher risk of psoriasis in several observational studies; however, whether this association is causal or can be explained by confounding or reverse causation is not fully understood. Randomized controlled trials are the gold standard when examining causality; however, when this method is not feasible, the Mendelian randomization design is an alternative. Herein genetic variants can be used as robust proxies for modifiable exposures and thereby avoiding confounding and reverse causation.In this study, we hypothesized that smoking is an independent and causal risk factor for psoriasis and tested this using a Mendelian randomization design.MethodsWe used data from the Copenhagen General Population Study including 105,912 individuals with full information on lifestyle factors, biochemistry, and genotype data. In total, 1,240 cases of moderate to severe psoriasis were included to investigate the association between smoking and psoriasis. To assess causality of the association, we used the genetic variant CHRNA3 rs1051730, where the T-allele is strongly associated with high lifelong cumulative smoking, as a proxy for smoking.ResultsIn observational analyses, the multivariable adjusted hazard ratio of developing moderate to severe psoriasis was 1.64 (95% confidence interval: 1.35-2.00) in ever smokers with ≤ 20 pack-years and 2.23 (1.82-2.73) in ever smokers with > 20 pack-years compared to never smokers. In genetic analyses, the odds ratio of developing moderate to severe psoriasis was 1.05 (0.95-1.16) per CHRNA3 rs10511730 T-allele in ever smokers.ConclusionSmoking was an independent risk factor for moderate to severe psoriasis in observational analyses. However, using a genetic variant as a robust proxy for smoking, we did not find this association to be causal.

Risk of Head and Neck Cancer in Patients with Psoriasis: A Nationwide Population-based Study

“…Although the exact pathogenesis remains unclear, alcohol consumption and smoking are recognized as risk factors for head and neck cancers ( 30 ) and are known to compromise the immune system. Nonetheless, recent studies suggest that a causal relationship between these behaviours and psoriasis has not yet been established ( 31 , 32 ). In our study, the tendency to develop head and neck cancer associated with these factors was not significant, except for a notable risk of oropharyngeal and oral cavity cancer associated with alcohol consumption.…”

Investigating causal associations among gut microbiota, metabolites, and psoriatic arthritis: a Mendelian randomization study

“…In confounding analysis, we evaluated each SNP and its proxy in the PhenoScanner GWAS database ( Kamat et al, 2019 ) 4 to carefully assess their associations with potential confounding traits (including smoking, alcohol consumption, hypertension, dyslipidemia, obesity and type 2 diabetes mellitus) among GM/metabolites and the risk of PsA, which can identify potential pleiotropic effects ( Näslund-Koch et al, 2023 ; Zhang Z. Y. et al, 2023 ). Once the SNPs were associated with these potential confounders at the threshold of P < 1 × 10 –5 , IVW was replicated after dropping these SNPs to eliminate the risk of horizontal pleiotropy in our MR findings and validate the robustness of the results.…”

Assessment of causal relationships between omega-3 and omega-6 polyunsaturated fatty acids in autoimmune rheumatic diseases: a brief research report from a Mendelian randomization study

“…During the confounding analysis, we examined each SNP and its corresponding proxy in the PhenoScanner GWAS and ensemble databases ( 38 ) to evaluate their relationships with various confounding traits, such as immune-related diseases, smoking, alcohol consumption, fasting blood glucose, chronic kidney disease, C-reactive protein levels, and type 2 diabetes mellitus, in relation to PUFAs and the risk of PsA. This thorough examination allowed us to identify potential pleiotropic effects ( 39 ). SNPs that displayed associations with these confounders at a significance level of p < 1 × 10 −5 were excluded from the analysis, and the instrumental variable weighting (IVW) method was then reapplied to ensure the elimination of horizontal pleiotropy and validate the robustness of our Mendelian randomization results.…”