Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.
PLoS One. 2012 Dec 20;7(12):e52298. doi: 10.1371/journal.pone.0052298.
Tumor Necrosis Factor (TNF)-α, is a paracrine inhibitor of melanocytes, which plays a critical role in the pathogenesis of several autoimmune diseases including vitiligo, as abnormal immune responses have frequently been observed in vitiligo patients. Moreover, vitiligo patients show higher lesion levels of TNF-α. Genetic polymorphisms in the promoter region of TNF-α are involved in the regulation of its expression. The present study explores TNF-α promoter polymorphisms and correlates them with TNF-α transcript and protein levels in vitiligo patients and controls of Gujarat along with its effect on disease onset and progression. PCR-RFLP technique was used for genotyping of these polymorphisms in 977 vitiligo patients and 990 controls. TNF-α transcript and protein levels were measured by Real time PCR and ELISA respectively. The genotype and allele frequencies for the investigated polymorphisms were significantly associated with vitiligo patients. The study revealed significant increase in TNF-α transcript and protein levels in vitiligo patients compared to controls. In particular, haplotypes: AATCC, AACCT, AGTCT, GATCT, GATCC and AGCCT were found to increase the TNF-α levels in vitiligo patients. Analysis of TNF-α levels based on the gender and disease progression suggests that female patients and patients with active vitiligo had higher levels of TNF-α. Also, the TNF-α levels were high in patients with generalized vitiligo as compared to localized vitiligo. Age of onset analysis of the disease suggests that the haplotypes: AACAT, AACCT, AATCC and AATCT had a profound effect in the early onset of the disease. Moreover, the analysis suggests that female patients had an early onset of vitiligo. Overall, our results suggest that TNF-α promoter polymorphisms may be genetic risk factors for susceptibility and progression of the disease. The up-regulation of TNF-α transcript and protein levels in individuals with susceptible haplotypes advocates the crucial role of TNF-α in autoimmune pathogenesis of vitiligo.
肿瘤坏死因子 (TNF)-α 是黑素细胞的旁分泌抑制剂，在包括白癜风在内的几种自身免疫性疾病的发病机制中起关键作用，因为白癜风患者经常出现异常免疫反应。此外，白癜风患者的 TNF-α 水平更高。TNF-α 启动子区域的遗传多态性参与其表达的调节。本研究探讨了 TNF-α 启动子多态性，并将其与古吉拉特邦白癜风患者和对照者的 TNF-α 转录本和蛋白水平相关联，以及其对疾病发病和进展的影响。采用 PCR-RFLP 技术对 977 例白癜风患者和 990 例对照者的这些多态性进行基因分型。采用实时 PCR 和 ELISA 分别测量 TNF-α 转录本和蛋白水平。所研究的多态性的基因型和等位基因频率与白癜风患者显著相关。研究表明，与对照组相比，白癜风患者的 TNF-α 转录本和蛋白水平显著升高。特别是，在白癜风患者中，AATCC、AACCT、AGTCT、GATCT、GATCC 和 AGCCT 等单体型增加了 TNF-α 水平。基于性别和疾病进展对 TNF-α 水平的分析表明，女性患者和活动期白癜风患者的 TNF-α 水平较高。此外，与局限性白癜风相比，全身性白癜风患者的 TNF-α 水平较高。疾病发病年龄分析表明，单体型 AACAT、AACCT、AATCC 和 AATCT 对疾病的早期发病有深远影响。此外，分析表明女性患者白癜风发病较早。总体而言，我们的研究结果表明，TNF-α 启动子多态性可能是疾病易感性和进展的遗传危险因素。易感性单体型个体中 TNF-α 转录本和蛋白水平的上调表明 TNF-α 在白癜风自身免疫发病机制中起着关键作用。
