Skin type, melanoma, and melanocortin 1 receptor variants.

We were interested to read the recent paper by Ichii-Jones et al (1998) published in the Journal of Investigative Dermatology. The authors searched for particular variants of the melanocortin 1 receptor (MC1R) using restriction fragment length polymorphism analysis and performed a case control study with skin type and melanoma. Essentially the authors failed to find any significant relationship between the particular variants they examined and phenotype. We would contend that there are strong associations between particular variants of the MC1R and skin type and possibly with melanoma. We suggest two reasons that may have contributed to the apparent discrepancy between the authors’ results and those previously published by ourselves and others (Valverde et al, 1995, 1996; Box et al, 1997; Smith et al, 1998). There are over 20 known variants of the MC1R. In our original Nature Genetics paper (Valverde et al, 1995) we detected some but not all of these. As was appropriate for an initial survey, putative associations required confirmation and Ichii-Jones et al’s paper is a welcome contribution to this. Subsequent work by ourselves and by others has shown that three particular variants, the Arg151Cys, Arg160Trp, and Asp294His variants, are strongly associated with red hair with a majority of individuals with red hair being either compound heterozygotes or homozygotes for one of these three alleles. To this extent red hair approximates to a Mendelian recessive model (Smith et al, 1998). Importantly the relative risks for red hair and possession of one of these alleles are actually quite high (8–15-fold). We would therefore suggest that the results of IchiiJones et al can be accounted for in two ways. First, previous study by ourselves failed to find any association between the codon 92 variant or the codon 84 variant and skin type or hair color (Valverde et al, 1996). This was confirmed in the study by Box et al (1997) and more recently by Smith et al (1998). The failure of Ichii-Jones et al to detect a statistically significant association between the Asp294His variant and hair color or skin type is perhaps more surprising. One possibility is that Ichii-Jones et al carried out much of their phenotypic assessment in busy outpatients where (as they state) insufficient time meant that not all clinical data were obtained from all patients. Furthermore the authors report that many different individuals carried out the skin typing and assessment of hair color. We think use of standardized hair charts together with a more rigorous assessment of skin type is preferable. We suspect that this is the likely explanation for their failure to detect a relation between the 294 variant and hair color or skin type. The recent publication of evidence of functional impairment of the Arg151Cys variant (Frändberg et al, 1998) together with our own unpublished observations on the Asp294His and Arg151Cys, strongly support a role for these particular variants in the red hair/skin type I phenotype. In their study, Ichii-Jones et al (1998) reported that allele frequencies were not different in melanoma cases and controls for any of the three MC1R variants investigated, but that after correction for imbalances in age, gender, and skin type, the association of the Asp84Glu allele with increased risk of melanoma