title: miR-196a-2 rs11614913 polymorphism is associated with vitiligo by affecting heterodimeric molecular complexes of Tyr and Tyrp1.
abstract: Tyrosinase and tyrosinase-related protein 1 (Tyr-Tyrp1) complex plays a critical role in the synthesis of melanin intermediates, which involves the production of reactive oxygen species (ROS) and contributes to the development of vitiligo. Based on our previous observation that rs11614913 single nucleotide polymorphism (SNP) in miR-196a-2 could affect the risk of vitiligo by influencing Tyrp1, we hypothesized that the same SNP could also regulate the level of Tyr in vitiligo. The aim of this study was to evaluate the potential association between rs11614913 SNP in miR-196a-2 and serum Tyr level in vitiligo and the regulatory role of miR-196a-2 in the expression of Tyr in melanocytes. The serum Tyr level was detected in 116 patients with vitiligo and 116 controls by ELISA plate assay. The expression level of Tyrp1 and Tyr in PIG1(normal melanocyte cell lines) cells was analyzed by western blotting. The ROS level and apoptosis rate in PIG1 cells transfected with si-Tyr or control siRNA were tested by flow cytometry. The results show that the individuals with TT+TC genotypes in miR-196a-2 and higher Tyr level in serum had an increased risk of vitiligo compared with those who had the CC genotype and lower Tyr level (P < 0.001). Furthermore, the rs11614913 C allele in miR-196a-2 enhanced its inhibitory regulation on the expression of Tyr, the down-regulation of which in melanocytes successfully reduced the intracellular ROS levels and the apoptosis rate. In conclusion, our findings suggest that miR-196a-2 polymorphisms can regulate the Tyr levels, which influences the susceptibility of vitiligo.
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: T-T
authors.initials: TT
authors.lastname: Cui
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: X-L
authors.initials: XL
authors.lastname: Yi
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: W-G
authors.initials: WG
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: C
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: F-B
authors.initials: FB
authors.lastname: Zhou
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Jian
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: T-W
authors.initials: TW
authors.lastname: Gao
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, China. lichying@fmmu.edu.cn.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Li
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, China. kaifmmu@fmmu.edu.cn.
authors.forename: K
authors.identifier: http://orcid.org/0000-0003-2963-005X
authors.initials: K
authors.lastname: Li
mesh_terms: D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D014820:Vitiligo / Q000235:genetics*
chemical_list: C542543:MIRN196 microRNA, human; D008543:Melanins; D008562:Membrane Glycoproteins; D035683:MicroRNAs; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D010088:Oxidoreductases; C489799:TYRP1 protein, human; D014442:Monophenol Monooxygenase
keywords: ROS; Single nucleotide polymorphism; Tyrosinase; Tyrosinase-related protein 1; Vitiligo; miR-196a-2