Association Analyses Identify Three Susceptibility Loci for Vitiligo in the Chinese Han Population

Abstract

To identify susceptibility loci for vitiligo, we extended our previous vitiligo genome-wide association study with a two-staged replication study that included 6,857 cases and 12,025 controls from the Chinese Han population. We identified three susceptibility loci, 12q13.2 (rs10876864, P(combined)=8.07 × 10(-12), odds ratio (OR)=1.18), 11q23.3 (rs638893, P(combined)=2.47 × 10(-9), OR=1.22), and 10q22.1 (rs1417210, P(combined)=1.83 × 10(-8), OR=0.88), and confirmed three previously reported loci for vitiligo, 3q28 (rs9851967, P(combined)=8.57 × 10(-8), OR=0.88), 10p15.1 (rs3134883, P(combined)=1.01 × 10(-5), OR=1.11), and 22q12.3 (rs2051582, P(combined)=2.12 × 10(-5), OR=1.14), in the Chinese Han population. The most significant single-nucleotide polymorphism in the 12q13.2 locus is located immediately upstream of the promoter region of PMEL, which encodes a major melanocyte antigen and has expression loss in the vitiligo lesional skin. In addition, both 12q13.2 and 11q23.3 loci identified in this study are also associated with other autoimmune diseases such as type 1 diabetes and systemic lupus erythematosus. These findings provide indirect support that vitiligo pathogenesis involves a complex interplay between immune regulatory factors and melanocyte-specific factors. They also highlight similarities and differences in the genetic basis of vitiligo in Chinese and Caucasian populations.

Altered E-Cadherin Levels and Distribution in Melanocytes Precede Clinical Manifestations of Vitiligo

“…Several studies have detected serum antibodies directed against melanocyte antigens in vitiligo patients and a correlation has been found between such antibodies and disease activity (Richmond et al, 2013). Genetic investigations have implicated at least 30 susceptibility loci, encoding melanocyte components, including MC1R, TYR and OCA2, immunoregulatory proteins targeting the innate and adaptive immunity, including HLA, PTPN22 and NLRP1, and cell adhesion molecules, including DDR1 (Jin et al, 2012;Jin et al, 2011;Silva de Castro et al, 2010;Tang et al, 2013). Normally pigmented skin of vitiligo patients shows micro-depigmentation and vacuolization of melanocytes and/or keratinocytes (Tobin et al, 2000).…”

Association analysis revealed one susceptibility locus for vitiligo with immune-related diseases in the Chinese Han population

“…In one recent vitiligo GWAS, we identified an associated SNP rs10876864 at 12q13.2 in Chinese Han population (Tang et al 2013). This current associated SNP rs2456973 has strong LD with the reported SNP rs10876864 (r 2 =0.959, D'=1.00 in the CHB+JPT panel in 1000 genomes pilot 1), which indirect indicates the association with vitiligo for rs2456973.…”

A comprehensive association analysis confirmsZMIZ1to be a susceptibility gene for vitiligo in Chinese population

“…To increase statistical power and improve the coverage of genetic variants for discovery, we performed the imputation analysis in the discovery dataset of 1117 vitiligo cases and 3437 controls that was generated by combining the previously published vitiligo GWAS dataset8 9 (including 1117 cases and 1701 controls) and a new GWAS dataset of additional 1736 Chinese healthy controls. A total of 263 genotyped SNPs spanning the 400 kb region of the ZMIZ1 locus (104 SNPs) and the 500 kb surrounding region (159 SNPs) were used for imputation.…”

“…The discovery dataset for the initial fine mapping analysis consists of the previously published Chinese vitiligo GWAS dataset of 1171 cases and 1701 controls8 9 and an unpublished GWAS dataset of 1736 Chinese healthy controls that were generated by using illumina 660K and Omni Zhonghua arrays. The independent validation cohort included 7458 vitiligo patients and 7542 normal controls of Chinese Han origin that were matched by gender, age and geographic region.…”

“…Recently, four large-scale genome-wide association studies (GWASs) of generalised vitiligo were performed in Caucasians6 7 and Chinese populations 8 9. As a result, 28 susceptibility loci were discovered at genome-wide significance, and many of these loci were also shown to be associated with other autoimmune diseases.…”