Association Between Genetically Elevated Omega-3 Polyunsaturated Fatty Acids and Skin Disease Risk: A Mendelian Randomization Study.

Omega-3 polyunsaturated fatty acids (PUFAs) are potential targets for the treatment of skin diseases due to their anti-inflammatory and immunomodulatory effects. By leveraging a genetic approach known as Mendelian randomization (MR), we sought to determine the causal impact of PUFAs on the likelihood of developing skin diseases among individuals of European ancestry. We integrated GWAS data from the CHARGE consortium and UK Biobank to identify genetic instruments for omega-3 PUFAs and desaturase activity, using two-sample MR to assess their associations with six skin diseases. Elevated levels of omega-3 fatty acids were found to substantially lower the probability of experiencing atopic dermatitis (0.92, 0.85,0.98), while increased DPA levels correlated with a substantial increase in the probability of squamous cell carcinoma occurrence (2.25, 1.29,3.92). Increased DHA levels were also associated with a reduced risk of atopic dermatitis (0.90, 0.84,0.96) but increased the risk of solar dermatitis (1.38, 1.09,1.73). In addition, tissue-type specific MR analysis revealed that elevated FADS1 expression in fibroblasts significantly inhibited atopic dermatitis development (β = -0.181, -0.276,-0.0853), while elevated FADS2 expression in non-sun-exposed skin tissues was associated with a reduced risk of squamous cell carcinoma (β = -0.562, -0.833,-0.029). Conversely, heightened FADS2 expression was strongly linked to a greater likelihood of developing atopic dermatitis in both sun-exposed and sun-protected skin areas (β = 0.107, 0.0348,0.179; β = 0.192, 0.114,0.0270, respectively). This study reveals the causal role of omega-3 PUFAs and FADS expression in specific tissues and blood in skin diseases. These findings underscore the potential of PUFA biosynthesis pathways as therapeutic targets for skin disease interventions.