Abstract
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.
Highlights
Vitiligo is an acquired, non-contagious disease in which progressive, patchy, multifocal loss of pigmentation of skin, overlying hair, and often mucous membranes results from loss of melanocytes from the involved areas [1]
The five promoter polymorphisms of Tumor Necrosis Factor (TNF)-a were found to be in significant association with generalized vitiligo patients (p,0.0001) when genotypes were compared using chi-squared test-362 contingency table with Bonferroni’s correction for multiple testing (Table 1)
2238A and 2308A alleles were found to increase the risk of generalized vitiligo by 6.35 and 4.326 fold respectively [odds ratio (OR) = 6.35; 95% confidence interval (CI) = 5.320– 7.590; Odds ratio (OR) = 4.326; 95% CI = 3.623–5.165] (Table 1)
Summary
Non-contagious disease in which progressive, patchy, multifocal loss of pigmentation of skin, overlying hair, and often mucous membranes results from loss of melanocytes from the involved areas [1]. It affects 0.2–1% of the world population [2]. In India, the incidence of vitiligo is found to be 0.5% [3]. The autoimmune destruction of melanocytes can be explained by the abnormalities in both humoral and cell-mediated immunity [6,7]. The autoimmune hypothesis gains further support from immunotherapy studies of melanoma patients [8]
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