Pigmentation and the cutaneous response to ultraviolet radiation

Abstract

Variation in pigmentation of hair and skin is one of the most striking forms of human diversity. Human pigmentation and sun sensitivity is a complex trait. The melanocortin 1 receptor gene (MC1R) (OMIM 15555) has been shown to be a key determinant of hair and skin colour. Recently a number of other genes have been implicated in human pigmentation. This thesis presents the relationship between human pigmentary phenotypes and genetic variation at MC1R and 34 other candidate loci from 159 individuals. The relationship between experimentally induced cutaneous erythemal and facultative pigmentary response to UVB radiation and MC1R and other pigmentation genotypes was investigated in a subset of 98 individuals. Some of this work involved the development of novel methods of assaying phenotype. I present a detailed description of human pigmentation and facultative pigmentation with respect to a number of key variables (e.g. sex, site, freckling, skin type) and seek to explain the variation in pigmentation in relation to these factors. The effect of MC1R on hair colour is large, but MC1R explains a smaller amount of the variation for skin colour. I found that a number of loci including MC1R, oculocutaneous albinism type 2 OCA2 (OMIM 611409), KIT oncogene ligand KITLG (OMIM 184745) and the Hermansky-Pudlak syndrome 3 HPS3 (OMIM 606118) are determinants of pigmentary phenotype. Some of these findings are in keeping with previous work and some are novel. I present data showing novel SNPs in genes Hermansky-Pudlak syndrome 3 (HPS3) and KIT ligand (KITLG) to be associated with human skin and hair colour variation. Association of HPS3 to eye colour was also found and has to be confirmed in another population. The possible putative mechanisms for the novel association finding in HPS3 are discussed. I am in the process of confirming these positive significant findings in collaboration with another laboratory in Denmark. Further experiments are proposed to confirm other associations and phenotypes.