Department of Genetics, University of Calcutta, Kolkata, India.
Department of Biochemistry, University of Calcutta, Kolkata, India.
Dermatology. 2024;240(3):376-386. doi: 10.1159/000536480. Epub 2024 Feb 20.
Vitiligo is a common depigmentation disorder characterized by defined white patches on the skin and affecting around 0.5% to 2% of the general population. Genetic association studies have identified several pre-disposing genes and single nucleotide polymorphisms (SNPs) for vitiligo pathogenesis; nonetheless, the reports are often conflicting and rarely conclusive. This comprehensive meta-analysis study was designed to evaluate the effect of the risk variants on vitiligo aetiology and covariate stratified vitiligo risk in the Asian population, considering all the studies published so far.
We followed a systematic and comprehensive search to identify the relevant vitiligo-related candidate gene association studies in PubMed using specific keywords. After data extraction, we calculated, for the variants involved, the study-level unadjusted odds ratio, standard errors, and 95% confidence intervals by using logistic regression with additive, dominant effect, and recessive models using R software package (R, 3.4.2) "metafor." Subgroup analysis was performed using logistic regression (generalized linear model; "glm") of disease status on subgroup-specific genotype counts. For a better understanding of the likely biological function of vitiligo-associated variant obtained through the meta-analysis, in silico functional analyses, through standard publicly available web tools, were also conducted.
Thirty-one vitiligo-associated case-control studies on eleven SNPs were analysed in our study. In the fixed-effect meta-analysis, one variant upstream of TNF-α gene: rs1800629 was found to be associated with vitiligo risk in the additive (p = 4.26E-06), dominant (p = 1.65E-7), and recessive (p = 0.000453) models. After Benjamini-Hochberg false discovery rate (FDR) correction, rs1800629/TNF-α was found to be significant at 5% FDR in the dominant (padj = 1.82E-6) and recessive models (padj = 0.0049). In silico characterization revealed the prioritized variant to be regulatory in nature and thus having potential to contribute towards vitiligo pathogenesis.
Our study constitutes the first comprehensive meta-analysis of candidate gene-based association studies reported in the whole of the Asian population, followed by an in silico analysis of the vitiligo-associated variant. According to the findings of our study, TNF-α single nucleotide variant rs1800629G>A has a risk association, potentially contributing to vitiligo pathogenesis in the Asian population.
白癜风是一种常见的色素脱失性疾病，其特征是皮肤上出现明确的白色斑块，影响全球 0.5%至 2%的人口。遗传关联研究已经确定了一些白癜风发病机制的易感基因和单核苷酸多态性（SNP）；尽管如此，这些报告往往相互矛盾，很少有结论性的。本综合荟萃分析旨在评估风险变异对亚洲人群白癜风发病机制和协变量分层白癜风风险的影响，考虑到迄今为止发表的所有研究。
我们采用系统全面的搜索方法，使用特定的关键词在 PubMed 中识别相关的白癜风候选基因关联研究。在数据提取后，我们使用 R 软件包（R，3.4.2）“metafor”中的逻辑回归，根据加性、显性和隐性模型，计算了所涉及变异的研究水平未调整的优势比、标准误差和 95%置信区间。使用基于疾病状态的逻辑回归（广义线性模型；“glm”）对亚组特异性基因型计数进行亚组分析。为了更好地理解通过荟萃分析获得的与白癜风相关的变异的可能生物学功能，还通过标准的公共可用网络工具进行了体外功能分析。
我们的研究分析了 31 项关于 11 个 SNP 的白癜风病例对照研究。在固定效应荟萃分析中，TNF-α 基因上游的一个变异体：rs1800629 被发现与加性（p = 4.26E-06）、显性（p = 1.65E-7）和隐性（p = 0.000453）模型中的白癜风风险相关。在 Benjamini-Hochberg 假发现率（FDR）校正后，rs1800629/TNF-α 在显性（padj = 1.82E-6）和隐性模型（padj = 0.0049）中以 5% FDR 显著。体外特征分析表明，优先变异具有调节性质，因此有可能导致白癜风发病。
我们的研究是对整个亚洲人群基于候选基因的关联研究的首次全面荟萃分析，随后对与白癜风相关的变异进行了体外分析。根据我们研究的结果，TNF-α 单核苷酸变异 rs1800629G>A 具有风险关联，可能导致亚洲人群的白癜风发病机制。
