Racemic RS‐4‐(4‐hydroxyphenyl)‐2‐butanol (rhododendrol; trade name: Rhododenol [RD]), which is used in topical skin‐lightening cosmetics, was unexpectedly reported in Japan to induce leukoderma or vitiligo called RD‐induced leukoderma (RIL) after repeated application. To our knowledge, no studies have investigated chemical‐induced vitiligo pathogenesis on a genome‐wide scale. Here, we conducted a genome‐wide association study (GWAS) for 147 cases and 112 controls. CDH13, encoding a glycosylphosphatidylinositol‐anchored protein called T‐cadherin (T‐cad), was identified as the strongest RIL susceptibility gene. RD sensitivity was remarkably increased by T‐cad knockdown in cultured normal human melanocytes. Furthermore, we confirmed tyrosinase upregulation and downregulation of the anti‐apoptotic molecules (BCL‐2 and BCL‐XL), suggesting that T‐cad is associated with RD via tyrosinase or apoptotic pathway regulation. Finally, monobenzyl ether of hydroquinone sensitivity also tended to increase with T‐cad knockdown, suggesting that the T‐cad could be a candidate susceptibility gene for RIL and other chemical‐induced vitiligo forms. This is the first GWAS for chemical‐induced vitiligo, and it could be a useful model for studying the disease's genetic aspects.

中文翻译：

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全基因组关联研究将 CDH13 鉴定为杜鹃醇诱导的白斑病的易感基因。

外消旋 RS-4-(4-羟基苯基)-2-丁醇（杜鹃花醇；商品名：Rhododenol [RD]），用于局部美白化妆品，在日本出人意料地被报道诱发白斑病或白癜风，称为 RD重复应用后的白皮病 (RIL)。据我们所知，还没有研究在全基因组范围内研究化学诱导的白癜风发病机制。在这里，我们对 147 例病例和 112 例对照进行了全基因组关联研究 (GWAS)。CDH13编码一种称为 T-钙粘蛋白 (T-cad) 的糖基磷脂酰肌醇锚定蛋白，被鉴定为最强的 RIL 易感基因。在培养的正常人黑色素细胞中，T-cad 敲低显着增加了 RD 敏感性。此外，我们证实了抗凋亡分子（BCL-2 和 BCL-XL）的酪氨酸酶上调和下调，表明 T-cad 通过酪氨酸酶或凋亡途径调节与 RD 相关。最后，对苯二酚敏感性的单苄基醚也倾向于随着 T-cad 敲低而增加，这表明 T-cad 可能是 RIL 和其他化学诱导的白癜风形式的候选易感基因。这是第一个用于化学诱导白癜风的 GWAS，它可能是研究该疾病遗传方面的有用模型。