Tianwen Gao

Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC

We conducted a genome-wide association study of generalized vitiligo in the Chinese Han population by genotyping 1,117 cases and 1,429 controls. The 34 most promising SNPs were carried forward for replication in samples from individuals of the Chinese Han (5,910 cases and 9,916 controls) and Chinese Uygur (713 cases and 824 controls) populations. We identified two independent association signals within the major histocompatibility complex (MHC) region (rs11966200, Pcombined = 1.48 × 10−48, OR = 1.90; rs9468925, Pcombined = 2.21 × 10−33, OR = 0.74). Further analyses suggested that the strong association at rs11966200 might reflect the reported association of the HLA-A*3001, HLA-B*1302, HLA-C*0602 and HLA-DRB1*0701 alleles and that the association at rs9468925 might represent a previously unknown HLA susceptibility allele. We also identified one previously undescribed risk locus at 6q27 (rs2236313, Pcombined = 9.72 × 10−17, OR = 1.20), which contains three genes: RNASET2, FGFR1OP and CCR6. Our study provides new insights into the genetic basis of vitiligo.

Genetic Variation of Promoter Sequence Modulates XBP1 Expression and Genetic Risk for Vitiligo

Our previous genome-wide linkage analysis identified a susceptibility locus for generalized vitiligo on 22q12. To search for susceptibility genes within the locus, we investigated a biological candidate gene, X-box binding protein 1(XBP1). First, we sequenced all the exons, exon-intron boundaries as well as some 5′ and 3′ flanking sequences of XBP1 in 319 cases and 294 controls of Chinese Hans. Of the 8 common variants identified, the significant association was observed at rs2269577 (p_trendu200a=u200a0.007, ORu200a=u200a1.36, 95% CIu200a=u200a1.09–1.71), a putative regulatory polymorphism within the promoter region of XBP1. We then sequenced the variant in an additional 365 cases and 404 controls and found supporting evidence for the association (p_trendu200a=u200a0.008, ORu200a=u200a1.31, 95% CIu200a=u200a1.07–1.59). To further validate the association, we genotyped the variant in another independent sample of 1,402 cases and 1,288 controls, including 94 parent-child trios, and confirmed the association by both case-control analysis (p_trendu200a=u200a0.003, ORu200a=u200a1.18, 95% CIu200a=u200a1.06–1.32) and the family-based transmission disequilibrium test (TDT, pu200a=u200a0.005, ORu200a=u200a1.93, 95% CIu200a=u200a1.21–3.07). The analysis of the combined 2,086 cases and 1,986 controls provided highly significant evidence for the association (p_trendu200a=u200a2.94×10−6, ORu200a=u200a1.23, 95% CIu200a=u200a1.13–1.35). Furthermore, we also found suggestive epistatic effect between rs2269577 and HLA-DRB1*07 allele on the development of vitiligo (pu200a=u200a0.033). Our subsequent functional study showed that the risk-associated C allele of rs2269577 had a stronger promoter activity than the non-risk G allele, and there was an elevated expression of XBP1 in the lesional skins of patients carrying the risk-associated C allele. Therefore, our study has demonstrated that the transcriptional modulation of XBP1 expression by a germ-line regulatory polymorphism has an impact on the development of vitiligo.

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

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.

Association between FOXP3 polymorphisms and vitiligo in a Han Chinese population

Vitiligo is an autoimmune chronic depigmentation disorder caused by melanocyte loss. Previous studies found that CD4+CD25+ regulatory T‐cell (Treg) dysfunction was involved in the pathogenesis of vitiligo and that gene polymorphisms in forkhead box P3 (FOXP3) – a master regulator of Treg development and function – were associated with susceptibility to some autoimmune disorders. Therefore, we hypothesized that functional polymorphisms of the FOXP3 gene might be associated with vitiligo via dysregulation of Treg cells.

The association of vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D levels with generalized vitiligo

Summary Backgroundu2002 Vitiligo is an acquired depigmentation autoimmune disorder that has been described as being associated with lower levels of 25‐hydroxyvitamin D [25(OH)D]. Genetic variations within the vitamin D receptor (VDR) gene could lead to significant receptor dysfunction, and could further affect the formation of the biologically active 25(OH)D. Therefore, we hypothesized that VDR polymorphisms might be involved in vitiligo by affecting the formation of 25(OH)D.

Genetic Polymorphisms of Glutathione S-Transferase and Risk of Vitiligo in the Chinese Population

Vitiligo is a common acquired depigmenting disorder characterized by white areas on the skin. Oxidative stress is a major pathogenesis hypothesis of vitiligo. Glutathione S-transferases (GSTs) are enzymes involved in protecting cells against chemical toxicity and stress. We hypothesized that the GSTM1- and GSTT1-null genotypes and GSTP1 polymorphisms were associated with increased risk for vitiligo. In a hospital-based case-control study of 749 vitiligo patients and 763 age- and sex-frequency-matched healthy controls, GSTM1 and GSTT1 genotypes and GSTP1 (Ile104Val, Ala113Val, Gly169Asp) polymorphisms were analyzed using the multiplex PCR and PCR-restriction fragment length polymorphism technique, respectively. We found that the GSTT1-null genotype was significantly associated with the susceptibility to vitiligo and the GSTM1-null genotype also showed a trend toward vitiligo association. We further analyzed the combined effect of GSTM1-null and GSTT1-null genotypes and showed an increased risk of developing vitiligo. By contrast, no statistically significant association was found between GSTP1 polymorphisms and vitiligo risk. These results suggest that individuals with homozygous deletion of GSTT1 and/or GSTM1 have a greater predisposition to vitiligo.

Decreased methionine sulphoxide reductase A expression renders melanocytes more sensitive to oxidative stress: a possible cause for melanocyte loss in vitiligo.

Summary Backgroundu2002 Methionine is one of the major targets of reactive oxygen species (ROS). It is readily oxidized to methionine‐S‐sulphoxide and methionine‐R‐sulphoxide, which can be reduced by methionine sulphoxide reductase (MSR) A and B, respectively. MSR represents a unique repair mechanism in the skin antioxidant network. It functions both as a protein repairer and as a ROS scavenger. However, the expression and activity of MSR are significantly reduced in vitiligo.

A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with psoriasis.

Psoriasis is one of the most common inflammatory diseases of skin. MCP‐1 is an important CC‐type chemokine responsible for monocytes and T lymphocytes recruitment in inflammatory conditions. A single nucleotide polymorphism of the MCP‐1 gene in the gene regulatory region was found to be related to the expression of MCP‐1, and the associations of this polymorphism with many inflammatory diseases were conformed. However, the significance of this polymorphism in psoriasis remains unclear. Therefore, we examined this polymorphism in 507 patients with plaque‐type psoriasis and 530 healthy controls using the polymerase chain reaction–restriction fragment length polymorphism method. We also tested the serum MCP‐1 in 320 patients and 160 controls and compared the serum MCP‐1 level in patients of different genotypes. Our results showed that the frequency distribution of the AA, AG and GG genotypes between the patients and the controls was statistically different (P = 0.031); significantly increased risk for psoriasis was associated with the AG, GG and AG + GG genotype. The frequency distribution of the AA, AG and GG genotypes was also different between female psoriasis patients and controls (P = 0.025), between type I psoriasis patients and controls (P = 0.025), between psoriasis patients without positive familial history and controls (P = 0.048), and between patients with psoriasis area and severity index of ≥ 10 and controls (P = 0.041). MCP‐1 serum level was significantly higher in patients than controls (P < 0.0001). There were significant differences of serum MCP‐1 level between patients of the GG genotype and the AA genotype (P = 0.028), between patients of the AG genotype and the AA genotype (P = 0.049), and between patients of the AG + GG genotype and the AA genotype (P = 0.027). These results showed the –2518 MCP‐1 polymorphism is related to the susceptibility of plaque type psoriasis. Individuals containing the GG or AG genotype were at higher risk of psoriasis than subjects with the AA genotype.

Two new susceptibility loci 1q24.2 and 11p11.2 confer risk to severe acne

Severe acne is a chronic inflammatory skin disorder characterized by widespread inflammatory lesions including nodules, cysts and potential scarring. Here we perform the first genome-wide association study of severe acne in a Chinese Han population comprising 1,056 cases and 1,056 controls using the Illumina HumanOmniZhongHua-8 BeadChip. In an independent cohort of 1,860 cases and 3,660 controls of Chinese Han, we replicate 101 SNPs of which 3 showed consistent association. We identify two new susceptibility loci at 11p11.2 (DDB2, rs747650, P(combined)=4.41 × 10⁻⁹ and rs1060573, P(combined)=1.28 × 10⁻⁸) and 1q24.2 (SELL, rs7531806, P(combined)=1.20 × 10⁻⁸) that are involved in androgen metabolism, inflammation processes and scar formation in severe acne. These results point to new genetic susceptibility factors and suggest several new biological pathways related to severe acne.

The association of functional polymorphisms in the aryl hydrocarbon receptor (AHR) gene with the risk of vitiligo in Han Chinese populations.

Backgroundu2002 Vitiligo is an acquired depigmentation disorder resulting from selective destruction of melanocytes. The aryl hydrocarbon receptor (AHR) is vital to the regulation of melanogenesis and melanocyte proliferation and differentiation through modulating the expressions of melanogenesis‐related genes. AHR mutations may negatively affect AHR proteins and its target genes. Therefore, we hypothesized that AHR polymorphisms might be involved in vitiligo by impacting the transcriptional activities of related genes as mentioned above.