Causal association between polyunsaturated fatty acids and acne: a two-sample Mendelian randomization study

Background Observational studies have demonstrated a close association between polyunsaturated fatty acids (PUFAs) and acne. However, the findings of clinical trials have been inconsistent, leaving the causal relationship between PUFAs and acne unclear.Objectives To investigate the causal association between genetically proxied PUFAs and acne risk.Methods Mendelian randomization (MR) was performed using single nucleotide polymorphisms associated with PUFAs as instrumental variables. The causal associations between PUFAs and acne were estimated among 115 006 UK Biobank participants and 363 927 participants of Finnish descent.Results Genetically predicted docosahexaenoic acid (DHA) levels [beta = -0.303, 95% confidence interval (CI) -0.480 to -0.126; P = 7.74 x 10-4] and its percentage to total fatty acids (beta = -0.402, 95% CI -0.651 to -0.258; P = 5.91 x 10-6) showed a significant causal association with a decreased risk of acne. Conversely, genetically predicted percentages of linoleic acid (LA) in total fatty acids (beta = 0.768, 95% CI 0.411-0.126; P = 2.87 x 10-4) and omega-6 : omega-3 ratio (beta = 0.373, 95% CI 0.142-0.604; P = 4.48 x 10-3) were robustly associated with an increased risk of acne. These effects were attenuated after excluding a genetic variant of rs174528 located upstream of FADS1, highlighting the biologic link between FADS1 and delta-5 desaturase activity. Multivariable MR analysis indicated that PUFAs were causally associated with acne, independent of body mass index.Conclusions Our study indicates that high DHA levels and their ratios to total fatty acids have causal protective effects against acne, while high LA levels and omega-6 : omega-3 ratio are associated with increased acne risk. This association was largely attributable to the influence of genetic variants related to FADS1. Acne is a common inflammatory skin disease that affects a part of the skin called 'pilosebaceous follicles'. It affects about 9% of people of all ages worldwide. Acne can develop in childhood and persist into adulthood. It is influenced by genetics and diet. Some studies suggest a link between fats called 'PUFAs' and acne. However, the relationship remains unclear.To understand the relationship between acne and PUFAs, we analysed data from genetic research that involved 115,006 participants in the UK Biobank (a large biomedical database) and 363,927 individuals of Finnish descent. We studied small changes in DNA linked to PUFAs to see whether they play a role in causing acne. We found that a genetic predisposition to high levels of a fatty acid called 'DHA' and its percentage to total fatty acids help protect against acne. However, a genetic predisposition to a high percentage of a fatty acid called 'linoleic acid' in the total make up of fatty acids and an increased ratio of the fatty acids omega-6 to omega-3 were found to worsen acne. These associations were influenced by a gene called 'FAD1'. This gene controls the metabolism of omega-3 and omega-6.Our findings provide evidence of the effect of PUFAs on acne. They suggest that balancing the omega-6 to omega-3 ratio may be a potential target for acne prevention and treatment. Our study provides evidence of a causal effect of polyunsaturated fatty acids on acne, using a two-sample Mendelian randomization analysis based on data from large genome-wide association studies involving over 470 000 Europeans.