Polyunsaturated fatty acids and risk of melanoma: A Mendelian randomisation analysis

Abstract

Melanoma is the deadliest form of skin cancer, mainly affecting populations of European ancestry. Some observational studies suggest that particular diets reduce melanoma risk, putatively through an increase in polyunsaturated fatty acid (PUFA) consumption. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To date, a randomized controlled trial has not been carried out to examine the relationship between PUFAs and melanoma. Hence, we performed a Mendelian randomisation (MR) study to evaluate the link between PUFAs and melanoma. To perform MR, we used summary results from the largest risk genome-wide association study (GWAS) meta-analysis of melanoma, consisting of 12,874 cases and 23,203 controls. As instrumental variables we selected SNPs associated with PUFA levels from a GWAS meta-analysis of PUFA levels, from the CHARGE consortium. We used the inverse variance weighted method to estimate a causal odds ratio. To aid interpretation, we established a benchmark "large" predicted change in PUFAs in which, for example, an increase in docosahexaenoic acid (DPA) of 0.17 units (equal to 1 standard deviation) moves a person from the 17 percentile to the median. Raising PUFA levels by a large amount (increasing DPA by 0.17 units) only negligibly changed melanoma risk: odds ratio [OR] = 1.03 (95% confidence interval [CI] = 0.96-1.10). Other PUFAs yielded similar results as DPA. Our MR analysis suggests that the effect of PUFA levels on melanoma risk is either zero or very small.

Mendelian Randomization Study for Genetically Predicted Polyunsaturated Fatty Acids Levels on Overall Cancer Risk and Mortality

“…Observational study findings are inconclusive regarding the association of PUFAs and melanoma risk (56,57). Our meta-analyzed results combining the estimates from Liyanage and colleagues (38) suggested that there is no association between PUFAs and melanoma after the adjustment for multiple testing (AA: OR, 1.03; 95% CI, 1.00-1.07; Supplementary Table S6).…”

“…Similarly, for melanoma, we obtained more precise estimates of OR by combining our study with a previously published study by Liyanage and colleagues (AA, metaanalysis OR, 1.03; 95% CI, 1.00-1.07; ref. 38; Supplementary Table S6). MR estimates for the association of 1 SD increase in PUFAs on common cancers.…”

“…We examined previously published results to assess if our selected SNP instruments had pleiotropic effects on selected potential confounders (height, BMI, and educational attainment; refs. 31,37,38). The result of the pleiotropy assessment can be found in Supplementary Tables S7-S9.…”

“…Height is an established all cancer risk factor (26) and if our PUFA SNP instruments affect height, there is the potential for these SNPs to affect all cancer risk through a horizontal pleiotropy pathway (i.e., not via PUFA). However, when we examined this previously (38), our selected SNPs either affect height via PUFA (vertical pleiotropy) or have such a tiny effect on height ( Supplementary Table S7) that it was very unlikely that our conclusions would be altered. Similarly for the other potential confounders, BMI and educational attainment, our selected SNPs have only a tiny effect on the trait ( Supplementary Tables S8 and S9), limiting the effect these could have on our causal estimates.…”

On the use of genetic information in causal inference for human complex diseases: a collection of studies on cancers

“…For the entirety of my candidature, I have also worked on the genetics of other complex traits and outcomes such as addiction, illicit substance use, psychiatric disorders, other malignant cancers and a series of eye-related diseases [156,[339][340][341]. A list of these investigations that were not covered in this thesis was added to Appendix B. I did not expand on any of these projects for several reasons.…”