Arg160Trp Allele of Melanocortin-1 Receptor Gene Might Protect Against Vitiligo[dagger], The

ABSTRACT

Melanocortin-1 receptor (MC1R) and agouti signaling protein (ASIP) play pivotal roles in the regulation of human pigmentation. We aimed to study whether single nucleotide polymorphisms (SNPs) of the MC1R and ASIP genes contribute to the pathogenesis of the polygenic pigment skin disorder, vitiligo. The PCR-amplified, full-length MC1R gene was studied with sequence analysis, and the 3' untranslated region (3' UTR) SNP of ASIP was detected using restriction fragment length polymorphism. The allele frequency of the ASIP SNP did not show any difference between the skin type, hair color and eye color-matched 97 vitiligo patients and the 59 healthy control individuals. As one of the MC1R polymorphisms showed significantly higher incidence among fair-skinned individuals (Fitzpatrick I + II, n = 140) than among dark-skinned individuals (Fitzpatrick III + IV, n = 90), both vitiligo patients and controls were divided into two groups and the frequency of the MC1R alleles was studied separately in fair-skinned and dark-skinned subgroups of diseased and healthy groups. C478T, one of the MC1R SNPs studied in 108 fair-skinned vitiligo patients and in 70 fair-skinned healthy control individuals, showed a significant difference (P = 0.0262, odds ratio [95% confidence interval] = 3.6 [0.0046-0.1003]) in allele frequency between the two groups: the allele frequency was higher in the control group, suggesting protection against vitiligo. Computer prediction of antigenicity has revealed that the Arg160Trp amino acid change caused by this SNP results in a decrease in antigenicity of the affected peptide epitope.

INTRODUCTION

Vitiligo is a common pigmentation disorder affecting both genders and approximately 1% of the population. It is characterized by patterned depigmentation where melanocytes are focally destroyed in the skin. Family studies indicate that genetic factors might play a crucial role in the pathogenesis of vitiligo, but the exact pathomechanism of the disease is still unknown. There are two principal hypotheses concerning the etiology of the disease: the "self-destruct" model suggests that inherent biochemical and/or structural abnormalities of the patient melanocytes initiate their own cytolysis, while the autoimmune model proposes an inappropriate immune response to melanocytes. The first model is supported by the findings of Casp et al. (1) who have recently demonstrated the association of a catalase gene polymorphism with vitiligo. At the same time, however, a growing body of evidence suggests association of polymorphisms of genes encoding immunoregulatory proteins, such as CTLA4 (2) and the genes of the LMP/TAP cluster of the major histocompatibility complex (MHC), with the disease (3).

As targets of the destructive autoimmune processes in vitiligo are melanocytes, it is plausible to hypothesize that melanocyte-specific autoantigens could play a role in the pathogenesis of the disease. Such autoantigens might arise from proteins exclusively expressed in melanocytes, e.g. proteins responsible for the formation of human pigmentation. Na et al. studied the allele frequencies of single nucleotide polymorphisms (SNPs) in human pigmentation regulatory genes of Korean vitiligo patients (4). The allele frequencies of five SNPs in the melanocortin-1 receptor (MC1R) gene and one SNP in the agouti signaling protein (ASIP) gene were determined in Korean vitiligo patients and in healthy Korean individuals. One MC1R and one ASIP polymorphism showed higher, although not statistically different, allele frequencies in Korean vitiligo patients compared to healthy Korean individuals. It was also demonstrated that the allele frequencies of all MC1R SNPs identified at the time exhibited great differences among different human populations (5). Therefore it is plausible to hypothesize that the contribution of different allelic variants of the MC1R gene to vitiligo pathogenesis might be different in geographically and anthropologically distant populations, such as the Korean and Hungarian.

MSHR (encoded by the MC1R gene) and ASIP are key regulators of human pigmentation. MSHR is the receptor of the α-melanocyte stimulating hormone (α-MSH). The binding of α-MSH to its receptor, MSHR, initiates a cAMP-mediated signal transduction pathway leading to the synthesis of eumelanin. Several loss-of-function MC1R mutations that block cAMP synthesis and thus the synthesis of eumelanin have been characterized in humans. The functional analysis of natural MC1R variants has been reviewed recently by Garcia-Borron et al. (6). SNPs of the MC1R gene are associated with red hair and/or fair skin in humans as well as with susceptibility to melanoma and nonmelanoma skin cancer (7-11). The binding of ASIP to MSHR blocks the α-MSH-initiated signal transduction and, thus, the production of eumelanin. The 3' UTR g.8818A/G polymorphism of ASIP leads to the destabilization of ASIP mRNA, resulting in a decrease in ASIP protein abundance and less potent antagonist activation of α-MSH-MSHR binding. The 3' UTR g.8818A/G polymorphism is significantly associated with dark hair and brown eyes (12).