The Relationship Between VDR Polymorphism And Genetic Susceptibility Of Vitiligo.

Introduction: Vitiligo is an acquired depigmenting disease on account of the loss of melanocytes. The age of onset is most frequently found in the 2nd decade of life, and the prevalence rate is 0.1～2% in the world population without predilection for sex and race. The mechanism of losing pigment cells has not yet fully understood, several theories have been proposed to explain the pathogenesis of vitiligo, involving genetic factors,neurologic factors,self-destruction of melanocyte and autoimmunity hypotheses. Genetic epidemiology and familial aggregation are not uncommon that have a role in vitiligo susceptibility. Because of multifactorial and overlapping pathogenetic theory, vitiligo is a genetically and environmentally dependent disease segregated in a simple Mendelian pattern. Substantial new data further implicate immune mechanisms in the pathogenesis of vitiligo and indicate that vitiligo may share common linkages with other autoimmune diseases, including thyroid disease, diabetes, pernicious anaemia, rheumatoid arthritis, lupus erythematosus and perhaps alopecia areata et al. Based on all of the evidence, vitiligo may be considered an autoimmune disorders, with many linked possibility contributing to increased susceptibility to pathogenesis of vitiligo, and several genes that have a role in regulating immunity have been associated with susceptibility to vitiligo. Histologically, the predominant finding in the depigmented areas of vitiligo is an appearance of dendritic cell and lymphocytes infiltrates, but no B cell. These lymphocytes express skin homing receptors CLA(cutaneous lymphocyte antigen), indicating that these cells were'en route'to the skin producing cytotoxic effect. Both dendritic cells and lymphocytes promote a Th1 response with secretion of TNF-αand IFN-γ. Recent studies and commentaries link vitamin D with inflammation response, a hallmark of active autoimmune disease. The role of vitamin D affects Th1 cell differentiation and proliferation, developing its biological effects through the vitamin D receptor (VDR). In a not dissimilar way, it is demonstrated that the functions of vitamin D hormone through its receptor can regulate the T cell-mediated immune responses. Consequently, polymorphism of VDR has been implicated in several autoimmune diseases.Generally speaking, PCR-RFLP(polymerase chain reaction-restriction fragment length polymorphism) is one of available technology can detect actual DNA sequence variants owing to variation of restriction enzyme sites in different individuals and has potential use for the detection of polymorphism. PCR-sequence specific primers can detect these related variations, so the gene polymorphism distributions of different people can be compared.Objective: In the present study, the association between the susceptibility to vitiligo in Chinese patients and the polymorphisms in exon 2, intron 8 and exon 9 of vitamin D receptor genes was studied. The possible interactions of the VDR gene in terms of family history, clinical expression and with other autoimmune diseases about vitiligo were also investigated, which might illuminate the pathogenesis of vitiligo as well as provide index for the diagnose and prognosis of vitiligo.Methods: This study adopted case-control design. In northwest vitiligo patients and unrelated Chinese Han nationality population were recruited. Genomic DNA was extracted from peripheral blood samples. Genotypes were detected using PCR-RFLP techniques and data was contrastedIn this study, all genotyping of 749 vitiligo patients and the 763 control population was performed using PCR-RFLP. the frequencies of the distribution of FokI locus( exon 2),BsmI,ApaI locus(intro 8) and TaqI locus( exon 9) of VDR gene and haplotype were compared usingχ2 test for P value, odds ratio (OR) and 95% confidence interval(CI) determined the influence of host genetic factors on incidence of vitiligo and the association between any haplotype and vitiligo clinical phenotype. Our findings suggested that the VDR polymorphism may play a significant role in the development of vitiligo and provide theoretical basis for the pathogenesis.Results:1.The univariate analysis showed a significant difference in BsmI,ApaI and TaqI polymorphism between vitiligo patients and healthy controls. The bb,aa and tt genotype frequencies in vitiligo patients group were higher than healthy controls group. It seemed that individual carrying bb,aa and tt genotype would be more susceptible to vitiligo. And there was no significant difference in FokI polymorphisms between two groups. After adjusting the confounding by logistic regression analysis, the bb,aa and tt genotype frequencies in vitiligo patients group remained higher than healthy controls group. Compared these study population, carrying bb,aa and tt genotype would increase the risk of vitiligo indeed.2. It seemed to be strongly apparent linkage disequilibrium between the FokI locus and BsmI locus,BsmI locus and ApaI locus,BsmI locus and TaqI locus, with respective D'values were high. The frequencies of fbaT and FbaT haplotypes composed of FokI,BsmI,ApaI and TaqI locus in vitiligo group were higher than that in asymptomatic healthy controls. That is to say a significantly increased risk was associated with the combined genotypes containing 2 fbaT and FbaT haplotypes, and the distributions of fbAT,FbAT和FbaT haplotypes were with the statistical difference between the study population.3. According to different onsets of vitiligo, the results of study showed: a positive family history of vitiligo had significantly association with VDR ApaI and TaqI polymorphism. Among the large cohort of separate clinical types, predominant difference was identified with the BsmI和ApaI polymorphism between segmental vitiligo,no-segmental vitiligo and controls. When the patients were stratified by the presence of an autoimmune disorder, distributions of BsmI and ApaI polymorphism were different between two study groups.Conclusions: VDR gene polymorphism may play an important role in the genetic susceptibility to the severity and development of vitiligo. When the patients were classified by the clinical groups, genotype frequencies between patients and control showed significantly different, and the distributions of VDR polymorphism were various since region,race and heredity background difference. It was the first observation of VDR gene polymorphism associated with the pathogenesis of vitiligo in the northwest of china; VDR gene may also be a marker to estimate the stage and prognosis of the vitiligo.