TY - JOUR
T1 - Genome-wide association study identifies CDH13 as a susceptibility gene for rhododendrol-induced leukoderma
AU - Okamura, Ken
AU - Abe, Yuko
AU - Naka, Izumi
AU - Ohashi, Jun
AU - Yagami, Akiko
AU - Matsunaga, Kayoko
AU - Kobayashi, Yui
AU - Fukai, Kazuyoshi
AU - Tanemura, Atsushi
AU - Katayama, Ichiro
AU - Masui, Yukiko
AU - Ito, Akiko
AU - Yamashita, Toshiharu
AU - Nagai, Hiroshi
AU - Nishigori, Chikako
AU - Oiso, Naoki
AU - Aoyama, Yumi
AU - Araki, Yuta
AU - Saito, Toru
AU - Hayashi, Masahiro
AU - Hozumi, Yutaka
AU - Suzuki, Tamio
N1 - Funding Information:
We are grateful to the patients with RIL and volunteers for providing saliva samples. We also thank Dr. M. Kondo, Biological Science Research, Kao Corporation, for his excellent technical advice. This work was supported by JSPS KAKENHI Grant Number JP16K10123, and in part, by Research Fund for Rhododenol‐induced leukoderma.
Publisher Copyright:
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
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U2 - 10.1111/pcmr.12904
DO - 10.1111/pcmr.12904
M3 - Article
C2 - 32558222
AN - SCOPUS:85087176809
VL - 33
SP - 826
EP - 833
JO - Pigment Cell and Melanoma Research
JF - Pigment Cell and Melanoma Research
SN - 1755-1471
IS - 6
ER -