Evaluating the causality between skin tanning, radiated disorders, and basal cell carcinoma: a multivariable Mendelian randomization analysis.

The causality of ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue with basal cell carcinoma (BCC) remains unclear. Our objective was to investigate whether ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue have a relation with the occurrence and development of BCCs. In this work, independent genetic variants strongly associated (P < 5e-08) with ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for BCC was obtained from the European Bioinformatics Institute (EBI). Two-sample univariable and multivariable Mendelian randomization (MR) were performed. Sensitivity analyses were preformed via MR-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out sensitivity test. We observed positive causal effect both for ease of skin tanning [odds ratio (OR) = 2.102, 95% confidence interval (CI) = 1.915-2.306, P = 2.71e-55] and radiation-related disorders of the skin and subcutaneous (OR = 1.603, 95% CI = 1.483-1.734, P = 3.41e-32) on occurrence of BCCs based on univariable MR analyses. In the multivariable mendelian randomization (MVMR) analysis of BCC risk, we also observed a direct causal effect of ease of skin tanning (ORMVMR = 1.623, 95% CI = 1.445-1.824, PMVMR =3.41e-16) and radiation-related disorders of the skin and subcutaneous (ORMVMR = 1.208, 95% CI = 1.107-1.319, PMVMR = 2.46e-05) on BCCs. The findings suggest that the high risk of BCCs can be attributed to ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue.

Chen C ，Wan B ，Lu W ，Lu J ... -  《-》

Causal relationship between the gut microbiome and basal cell carcinoma, melanoma skin cancer, ease of skin tanning: evidence from three two-sample mendelian randomisation studies.

The present study used publicly available genome-wide association study (GWAS) summary data to perform three two-sample Mendelian randomization (MR) studies, aiming to examine the causal links between gut microbiome and BCC, melanoma skin cancer, ease of skin tanning. SNPs associated with exposures to basal cell carcinoma, melanoma skin cancer and ease of skin tanning from the genome-wide association study data of UK Biobank and MRC-IEU (MRC Integrative Epidemiology Unit), and the meta-analysis data from Biobank and MRC-IEU were used as instrumental variables (IVs). The casual estimates were assessed with a two-sample Mendelian randomisation test using the inverse-variance-weighted (IVW) method, Wald ratio, MR-Egger method, maximum likelihood, weighted median, simple mode, and weighted mode. After the application of MR analysis, diffirent effects of multiple groups of gut microbiota was observed for BCC, melanoma skin cancer and ease of skin tanning. The relationships between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning were supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning. Our study initially identified potential causal roles between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning, and highlighted the role of gut microbiome in the progression of basal cell carcinoma, melanoma skin cancer, ease of skin tanning.

Lou J ，Cui S ，Li J ，Jin G ，Fan Y ，Huang N ... -  《Frontiers in Immunology》

Evaluating the effect of tanning response to sun exposure on the risk of skin diseases through Mendelian randomization.

Background: Until now, the relevance of the tanning response to sun exposure and skin diseases has incomplete and inconsistent epidemiological observations. In this case, it is valuable to find out the causality of tanning response to sun exposure and skin diseases, and take a step further toward developing effective therapies as well as prevention methods. Methods: We investigated the causal effect of tanning response to sun exposure on 10 major skin diseases that have been studied in recent large-scale genome-wide association studies (GWASs). Significant independent genetic variants from large-scale GWAS on ease of skin tanning (N = 453,065) are selected as the effective instrumental variables (IVs). For each skin disease, we extracted the summary statistics of those IVs (or their proxies) from the corresponding skin disease-GWAS as the valid IVs. Mendelian randomization (MR) was further performed to evaluate the causal association of ease of skin tanning with each of the skin diseases using different statistical methods, including inverse-variance weighted (IVW), the weighted median, and MR-Egger. Sensitivity analysis was also conducted to evaluate the effect of horizontal pleiotropy and heterogeneity. Results: We observe significant associations between six skin diseases with tanning response to sun exposure with adjusted p-value derived by IVW less than 0.05 and with nominal p value less than 0.05 at the same time derived by either MR-Egger or weighted median. The six skin diseases include actinic keratosis (IVW FDR = 1.71E-40, MR Egger p-value = 3.46E-22), seborrhoeic keratosis (IVW FDR = 2.97E-4, MR Egger p-value = 1.06E-3), blepharochalasis (IVW FDR = 1.30E-3, MR Egger p-value = 2.91E-4), seborrhoeic dermatitis (IVW FDR = 1.29E-2, MR Egger p-value = 1.23E-2), malignant melanoma of skin (IVW FDR = 2.95E-2, MR Egger p-value = 1.91E-2), and freckles (IVW FDR = 2.95E-2, weighted median p-value = 1.02E-3). Interestingly, we find increased trends of developing all of the six skin diseases with increased tanning response to sun exposure (beta values are positive using IVW, MR-egger, and weighted median methods). We also replicate the association on three skin diseases using an independent outcome GWAS cohort, including malignant melanoma of the skin (replication IVW p-value = 2.13E-39), actinic keratosis (replication IVW p-value = 4.64E-32), and seborrhoeic keratosis (replication IVW p-value = 1.79E-3). Conclusion: Our observation shows that the tanning response to sun exposure is positively correlated with the development of skin diseases in people of European descent by Mendelian randomization studies. But randomized controlled trials are still needed to add proof to our observations.

Ping W ，Zhao Q ，Ge S ，Wang X ，Li F ，Huang X ... -  《Frontiers in Genetics》

Association between cathepsins and skin cancers: A bidirectional two-sample Mendelian randomization study.

Several cathepsins have been identified as being involved in the development of cancer. Nevertheless, the connection between cathepsins and skin cancers remained highly elusive. A bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal association between cathepsins and skin malignancies. The genome-wide association studies (GWAS) data for cathepsins, malignant melanoma (MM), and basal cell carcinoma (BCC) were obtained from European research. The primary method employed was inverse variance weighted. In addition, MR-Egger, weighted median, weighted mode, and simple mode were also executed. Sensitivity analysis was performed using Cochran's Q test, MR-Egger, and MR-PRESSO. From univariable MR (UVMR), cathepsin H, and S were determined to have a causal relationship with BCC. Additionally, cathepsin H was identified as associated with MM. Multivariable MR (MVMR) showed that after correcting for risk factors of skin carcinoma, cathepsin H was detected to be protective against BCC, whereas cathepsin S has been observed as a risk factor for BCC. No substantial pleiotropy and heterogeneity were identified in the sensitivity analysis. This study was the first to establish a direct link between cathepsins and skin malignancies. Cathepsin H and S have the potential to serve as new biomarkers for BCC, offering valuable assistance in the prompt identification, treatment, and prevention of the disease. Nevertheless, additional clinical trials are required to validate our findings.

Ma X ，Zhuang H ，Xu M ，Hou F ，Xue C ... -  《-》

Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization.

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10-4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR = .011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR = .036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.

Zhou W ，Liu G ，Hung RJ ，Haycock PC ，Aldrich MC ，Andrew AS ，Arnold SM ，Bickeböller H ，Bojesen SE ，Brennan P ，Brunnström H ，Melander O ，Caporaso NE ，Landi MT ，Chen C ，Goodman GE ，Christiani DC ，Cox A ，Field JK ，Johansson M ，Kiemeney LA ，Lam S ，Lazarus P ，Le Marchand L ，Rennert G ，Risch A ，Schabath MB ，Shete SS ，Tardón A ，Zienolddiny S ，Shen H ，Amos CI ... -  《-》