DNA Methylation at cg18095732 Modulates ZDHHC20 Expression and Decreases Acne Vulgaris Risk

Ke Gong,1,2 Xiaotian Ji,1,* Shuhui Wu,1,* Dan Dan Zhao,1,* Mingfang Zhu1,* 1Department of Dermatology, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China; 2Department of Traditional Chinese Medicine, Cangzhou Central Hospital, Cangzhou, Hebei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingfang Zhu, Department of Dermatology, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China, Email [email protected]: Acne vulgaris is a common chronic inflammatory skin disorder involving lipid metabolism and immune dysregulation. Protein S-palmitoylation regulates lipid homeostasis, while DNA methylation has emerged as a potential contributor to acne pathogenesis. Yet, how DNA methylation and palmitoylation intersect in acne remains unclear.Methods: The objective of this study was to investigate whether palmitoylation-related genes are causally linked to acne by integrating large-scale genetic and epigenetic datasets through Mendelian randomization and complementary analyses.Results: Our MR and SMR analyses identified ZDHHC20, a gene encoding a palmitoyltransferase, as significantly and negatively associated with acne risk. Further mediation analysis revealed that hypermethylation at the CpG site cg18095732 was positively associated with ZDHHC20 expression and indirectly contributed to a reduced risk of acne. This methylation site accounted for 61.90% of the total effect via mediation. Robustness of the findings was confirmed through sensitivity analyses, which indicated no evidence of horizontal pleiotropy or heterogeneity.Conclusion: This study provides supportive evidence for a regulatory pathway in which DNA methylation at cg18095732 up-regulates ZDHHC20 and is associated with lower acne susceptibility. Our findings highlight epigenetic regulation as a potential biomarker or intervention point for inflammatory skin disorders.Plain Language Summary: Acne vulgaris, commonly known as acne, is a skin condition that causes pimples, blackheads, and inflammation. It affects many people, especially teenagers. While hormones, bacteria, and oil production are known to play roles, our understanding of the genetic and molecular causes of acne is still growing.In this study, we explored how a specific chemical change to DNA, called DNA methylation, may protect against acne. DNA methylation is a natural process where small molecules attach to DNA and affect how genes work. We focused on a particular site on the DNA, called cg18095732, and examined its relationship with a gene named ZDHHC20. This gene helps control a process called palmitoylation, which can affect how skin cells function.We used large databases and advanced genetic methods to study the connections between DNA methylation, ZDHHC20 gene activity, and acne risk. We found that higher methylation at cg18095732 was linked to increased activity of ZDHHC20 and a lower risk of acne. This suggests that DNA methylation at this site may help regulate gene function in a way that reduces acne.Our findings may offer new clues for understanding acne and developing future treatments.Keywords: acne vulgaris, DNA methylation, palmitoylation, ZDHHC20, Mendelian randomization