A case-control study on association of proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1) polymorphisms and their transcript levels in vitiligo from Gujarat

Abstract

BackgroundAutoimmunity has been implicated in the destruction of melanocytes from vitiligo skin. Major histocompatibility complex (MHC) class-II linked genes proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1), involved in antigen processing and presentation have been reported to be associated with several autoimmune diseases including vitiligo.ObjectivesTo explore PSMB8 rs2071464 and TAP1 rs1135216 single nucleotide polymorphisms and to estimate the expression of PSMB8 and TAP1 in patients with vitiligo and unaffected controls from Gujarat.MethodsPSMB8 rs2071464 polymorphism was genotyped using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) and TAP1 rs1135216 polymorphism was genotyped by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 378 patients with vitiligo and 509 controls. Transcript levels of PSMB8 and TAP1 were measured in the PBMCs of 91 patients and 96 controls by using qPCR. Protein levels of PSMB8 were also determined by Western blot analysis.ResultsThe frequency of ‘TT’ genotype of PSMB8 polymorphism was significantly lowered in patients with generalized and active vitiligo (p = 0.019 and p = 0.005) as compared to controls suggesting its association with the activity of the disease. However, TAP1 polymorphism was not associated with vitiligo susceptibility. A significant decrease in expression of PSMB8 at both transcript level (p = 0.002) as well as protein level (p = 0.0460) was observed in vitiligo patients as compared to controls. No significant difference was observed between patients and controls for TAP1 transcripts (p = 0.553). Interestingly, individuals with the susceptible CC genotype of PSMB8 polymorphism showed significantly reduced PSMB8 transcript level as compared to that of CT and TT genotypes (p = 0.009 and p = 0.003 respectively).ConclusionsPSMB8 rs2071464 was associated with generalized and active vitiligo from Gujarat whereas TAP1 rs1135216 showed no association. The down-regulation of PSMB8 in patients with risk genotype ‘CC’ advocates the vital role of PSMB8 in the autoimmune basis of vitiligo.

Contribution of Antigen-Processing Machinery Genetic Polymorphisms to Atopic Dermatitis

“…Another SNP, in the LMP7 gene, not examined here, was associated with vitiligo in Indians from Gujarat [ 32 ], and a LMP2 SNP, also not tested by us, was found associated with vitiligo in Saudi Arabia [ 33 ]. For LMP7 rs2071543 , associated here with AD, it was reported that individuals with the TT genotype had a 3.5-fold higher ovarian cancer risk in Chinese people and 10-fold higher colon cancer risk in Germans than TG and GG genotypes [ 34 ].…”

“…A little bit more is known on the TAP1 rs1135216 associations with diseases. The rs1135216*G (Gly637) allele was described to be strongly associated with vitiligo in a Saudi Arabian population [ 33 ], although not in Gujarati Indians [ 32 ]. It was also reported to increase the risk of pulmonary tuberculosis in Iranians [ 37 ], recurrent respiratory papillomatosis in Mexicans [ 38 ] and leprosy in Indians [ 39 ].…”

Association of elevated homocysteine levels and Methylenetetrahydrofolate reductase ( MTHFR ) 1298 A > C polymorphism with Vitiligo susceptibility in Gujarat

“…A number of studies have identified potential genetic susceptibility loci in the genes involved in immunoregulation (CTLA4, NLRP1, MYG1, ICAM1, HLA), cytokines (TNFA, TNFB, IL4, IFNG, IL1B), antigen processing and presentation (PSMB8), redox homeostasis (SOD, CAT, GPX1) etc. to be associated with vitiligo susceptibility [42][43][44][45][46][47][48][49][50][51][52][53]. Homocysteine has gained a significant attention of researchers working on vitiligo since the last decade.…”

The Role of MicroRNAs in Vitiligo: Regulators and Therapeutic Targets

“…Genetic polymorphisms include single-nucleotide polymorphisms (SNPs), nucleotide insertions, deletions, inversions and chromosomal translocations 9 10 . Many studies have identified that several SNPs, such as the NRF2 rs35652124 , PSMB8 rs2071464 and inducible nitric oxide synthase ( NOS2 ) gene polymorphism, were all associated with increased susceptibility to vitiligo 11 12 . Most SNPs could target promoter regions of genes that play critical regulatory roles in vitiligo pathogenesis.…”