Association ofNLRP1genetic variants and mRNA overexpression with generalized vitiligo and disease activity in a Gujarat population

Abstract

SummaryBackground It has been suggested that NLRP1 is involved in susceptibility to a wide range of autoimmune diseases including generalized vitiligo (GV). Genetic polymorphisms in the gene encoding NLRP1 (previously known as NALP1) have previously been shown to be associated with GV and there is speculation about their involvement in the regulation of NLRP1 expression. Objectives To explore NLRP1 polymorphisms and investigate their association with NLRP1 mRNA expression and disease activity in patients with GV. Methods Polymerase chain reaction (PCR)-restriction fragment length polymorphism and TaqMan single nucleotide polymorphism (SNP) genotyping techniques were used to genotype NLRP1 A/G (rs2670660), T/C (rs6502867) and A/T (rs12150220) polymorphisms in 537 patients with GV and 645 controls in Gujarat. NLRP1 mRNA levels were measured in the whole blood of 122 patients with GV and 175 controls using real-time PCR. Results The NLRP1 rs2670660 and rs6502867 polymorphisms were found to be in significant association with GV, minor alleles of these SNPs being prevalent in active cases of GV. The rs12150220 polymorphism was found have a marginal association with GV. The frequency of susceptible haplotype 'GCT' was significantly higher in patients with GV and increased the risk of vitiligo twofold. A significant increase in NLRP1 mRNA expression was observed in patients with GV and patients with active GV. NLRP1 mRNA expression was increased in patients with GV with the susceptible GG (rs2670660) and CC (rs6502867) genotypes. Patients with the susceptible GG (rs2670660) and CC (rs6502867) genotypes had early age of onset of GV. Moreover, patients in the age at onset group of 1-20 years showed increased expression of NLRP1 mRNA compared with the older age groups. Female patients showed a significant increase in NLRP1 mRNA and early age at onset of GV compared with male patients. Conclusions Our results suggest that NLRP1 rs2670660 and rs6502867 polymorphisms may be genetic risk factors for susceptibility to and progression of GV. The upregulation of NLRP1 mRNA in patients with susceptible genotypes advocates the crucial role of NLRP1 in GV.

Association of Neuropeptide Y (NPY), Interleukin-1B (IL1B) Genetic Variants and Correlation of IL1B Transcript Levels with Vitiligo Susceptibility

“…NLRP1 is a key regulator of the innate immune system, particularly in the skin and the NLRP1 inflammasome promotes caspase 1 dependent cleavage of IL1B precursor in to bioactive IL1B, resulting in IL1B secretion and downstream inflammatory responses. Interestingly, our recent study shows significant association of NLRP1 promoter variants with GV and NLRP1 overexpression in patients compared to controls; which might lead to increased IL1B production in vitiligo patients [67].…”

“…Our previous studies suggest that susceptibility to generalized vitiligo involves a number of immune regulatory genes such as cytotoxic T-lymphocyte associated antigen-4 ( CTLA 4), human leukocyte antigen ( HLA ), interleukin-4 ( IL 4), tumor necrosis factor-α ( TNFA ), tumor necrosis factor-β ( TNFB ), interferon-gamma ( IFNG ), melanocyte proliferating gene 1 ( MYG1 ), and NACHT leucine-rich-repeat protein 1 ( NLRP1 ) [59]–[67]. For the first time we report an association between IL1B promoter polymorphism and vitiligo along with higher transcript levels of IL1B in vitiligo patients as compared to controls.…”

Interleukin-1 Beta—A Friend or Foe in Malignancies?

“…Besides gain-of-function mutations of inflammsome proteins, a functional NLRP1 promoter polymorphism resulting in elevated gene expression was associated with increased susceptibility towards rheumatoid arthritis [80] and generalized vitiligo [81]. …”

Could ER Stress Be A Major Link Between Oxidative Stress And Autoimmunity In Vitiligo?

“…NACHT leucine-rich repeat protein 1 (NLRP1), known to be involved in inflammation and apoptosis [170,171], modulates the response of cells towards proinflammatory cytokines such as IL1β, IFNγ and TNFα. Recently, we have found increased expression of NLRP1 in vitiligo patients [172]. Bassiouny et al [173] have found increased level of IL17 and its positive correlation with disease pregression in both the lesional skin and sera of vitiligo patients.…”

“…Most vitiligo susceptibility loci encode melanocyte components, and antioxidant and immune-regulatory proteins [40,246]. For example, associations have been established between vitiligo pathogenesis and polymorphisms in tyrosinase (TYR) [247], catalase (CAT) [65], glutathione peroxidase (GPX) [65], melanocortin 1 receptor (MC1R) [248], major histocompatibility complex (MHC) [249], NACHT leucine-rich repeat protein 1 (NLRP1) [172] [252]. Both protective and susceptibility-increasing effects have been found in the case of different polymorphisms in these genes [253,254].…”