The melanocortin-1-receptor gene is the major freckle gene
2001

Abstract
Ephelides and solar lentigines are different types of pigmented skin lesions. Ephelides appear early in childhood and are associated with fair skin type and red hair. Solar lentigines appear with increasing age and are a sign of photodamage. Both lesions are strong risk indicators for melanoma and non-melanoma skin cancer. Melanocortin-1-receptor (MC1R) gene variants are also associated with fair skin, red hair and melanoma and non-melanoma skin cancer. The purpose of this study was to investigate the relationship between MC1R gene variants, ephelides and solar lentigines. In a large case-control study, patients with melanoma and non-melanoma skin cancer and subjects without a history of skin cancer were studied. In all participants, the presence of ephelides in childhood and solar lentigines by physical examination was assessed according to strict definitions. The entire coding sequence of the MC1R gene was analyzed by single-strand conformation polymorphism analysis followed by sequence analyses. Carriers of one or two MC1R gene variants had a 3- and 11-fold increased risk of developing ephelides, respectively (both P < 0.0001), whereas the risk of developing severe solar lentigines was increased 1.5- and 2-fold (P = 0.035 and P < 0.0001), respectively. These associations were independent of skin type and hair color, and were comparable in patients with and without a history of skin cancer. The population attributable risk for ephelides to MC1R gene variants was 60%, i.e. 60% of the ephelides in the population was caused by MC1R gene variants. A dosage effect was found between the degree of ephelides and the number of MC1R gene variants. As nearly all individuals with ephelides were carriers of at least one MC1R gene variant, our data suggest that MC1R gene variants are necessary to develop ephelides. The results of the study also suggest that MC1R gene variants play a role, although less important, in the development of solar lentigines.

INTRODUCTION
Ephelides are small pigmented spots of the skin commonly occuring in the Caucasian population, more frequently in fair-skinned individuals with red or light-blond hair (1). The spots are best visible after sun exposure and in summer. Ephelides appear early in childhood and partly vanish with age. Fair skin, red hair and ephelides are indicators for an increased risk of malignant melanoma and non-melanoma skin cancer (2–4). Ephelides must be distinguished from solar lentigines which occur more frequently with increasing age and can be considered as a sign of photodamage (5).

MC1R gene variants and solar lentigines and compared this association with the former one.

Degree of freckling is associated with presence of MC1R gene variants
A significant association was found between the degree of ephelides in childhood and the presence of MC1R gene variants (P < 0.0001) (Fig. 1). This association showed a clear dosage effect]
Assessment of skin type and hair color
In assessing skin type, the subjects’ own assessments of their propensity to sunburn and ability to tan were ascertained at interview. Skin type was recorded according to the classification of Fitzpatrick (39) as follows: always burn, never tan (skin type I), always burn, then tan (skin type II), always tan, sometimes burn (skin type III) and always tan, never burn (skin type IV). Original or natural hair color was also ascertained by history at 20 years of age and classified into five categories: red, light blond, dark blond, brown or black.