Genetic polymorphism of the Nrf2 promoter region is associated with vitiligo risk in Han Chinese populations

Abstract

The nuclear factor erythroid‐derived two‐like 2‐antioxidant response element (Nrf2‐ARE) pathway and its downstream antioxidant enzyme heme oxygenase‐1 (HMOX1 or HO‐1) play essential roles in H2O2‐induced oxidative damage in human melanocytes. However, the link between Nrf2 promoter polymorphisms and susceptibility to oxidative stress‐related diseases such as vitiligo is unknown. This study evaluated the association of the Nrf2 and HO‐1 genes polymorphisms with vitiligo susceptibility. In this case–control study of 1136 Han Chinese vitiligo patients and 1200 controls, Nrf2 (rs35652124 and rs6721961) and HO‐1 (rs2071746) genes were genotyped by PCR‐restriction fragment length polymorphism analysis. Overall, a significantly decreased risk of vitiligo was found to be associated with Nrf2 rs35652124 CC and combined (CT+CC) genotypes [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.50–0.83 and OR, 0.84, 95% CI 0.71–0.99, respectively], as well as among subgroups: female, onset age ≤20 and never smoker. We subsequently found that Nrf2 rs35652124 C allele had higher transcriptional activity in the luciferase reporter assay compared with Nrf2 rs35652124 T allele. Furthermore, we investigated serum HO‐1 activity was associated with the rs35652124 CT+CC genotype and lower in patients than in controls (P = 0.024). Logistic regression analysis showed a dose–response relationship between lower vitiligo risk and increased HO‐1 activity in rs35652124 CT+CC genotype carriers (P trend < 0.05). These findings indicate that the C allele of rs35652124 located in the promoter region of Nrf2 gene is associated with protective effect on vitiligo in a Han Chinese population.

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

“…Indeed, the only NRF2 activator so far approved by the FDA and the EMA, dimethyl fumarate, is being marketed by Biogen for the treatment of remitting relapsing MS and psoriasis 85 . A protective role for NRF2 has been suggested in other autoimmune diseases such as systemic lupus erythematous 86,87 , Sjogren's syndrome 86 , rheumatoid arthritis 88,89 , vitiligo [90][91][92] , and STING-dependent interferonopathies 74 .…”

Vitiligo susceptibility at workplace and in daily life: the contribution of oxidative stress gene polymorphisms

“…As far as the other polymorphic genes are concerned (NRF2, HO-1, CAT, SOD), the examined studies do not allow to confirm for each a conclusive and causative role in vitiligo onset and progression. NRF2 has been recently investigated only on two polymorphisms of the gene promoter restricted to the Asian population so that the number of published results is still preliminary to define a strong association between the NRF2 SNPs and the disease (Song et al 2016). In particular, the analysis should be conducted on other ethnicities to identify the differences in the allele frequency which might be favourable for a group but unfavourable for another.…”

“…Seventeen polymorphisms have been identified and associated with disease risk (Cho et al 2015); two of these SNPs located in the gene promoter, i.e. NRF2 -653A/G rs35652124 and NRF2 -617 C/A rs6721961 (formerly -650 C/A), have been studied to assess their possible association with the disease (Song et al 2016). In East Asians, the authors observed a decreased risk of vitiligo associated with the NRF2 rs35652124 variant G allele (AG+GG genotype) as it seems the G allele is associated with increased level of proteins conferring higher protection from oxidative stress, while no evident risk was observed with NRF2 rs6721961 variant (AA homozygous genotype) probably due to the protective role of the major allele (CC).…”

“…HO-1 protein was detected in the serum of vitiligo patients with NRF2 rs35652124 AG+GG rather than in the AA genotypes. The authors attributed such HO-1 levels to the increased transcriptional activity of the NRF2 rs35652124 genotype (Song et al 2016).…”

Dysfunction of Autophagy: A Possible Mechanism Involved in the Pathogenesis of Vitiligo by Breaking the Redox Balance of Melanocytes

“…Meanwhile, several evidences demonstrated that the induction of HO-1 by activating the Nrf2-ARE pathway protected melanocytes against H 2 O 2 -induced toxicity and that upregulation of Nrf2 expression diminished the H 2 O 2 -induced apoptosis of human melanocytes [43]. Furthermore, genetic studies in Chinese Han population demonstrated that Nrf2 gene polymorphisms are associated with the susceptibility to vitiligo [44, 45]. Taken together, such evidence indicated that the Nrf2-ARE signaling pathway is altered in vitiligo melanocytes and alteration of this pathway might be involved in the pathogenesis of vitiligo.…”