In a study of the association with eye color (227220) with haplotype-tagging SNPs proximal to intron 1 of the OCA2 gene (611409) that span the intergenic region and encompass the 3-prime end of the upstream gene HERC2, Sturm et al. (2008) identified a SNP in intron 86 of HERC2, rs12913832, that was strongly associated with eye color in 3011 European individuals (P = 2 x 10(-78)). Individuals carrying the CC genotype had only a 1% probability of having brown eyes, while those with the TT genotype had an 80% probability. Haplotype analysis combining the 3 SNPs in OCA2 identified by Duffy et al. (2007) (611409.0013) with rs12913832 followed by multiple ordinal logistic regression showed that the HERC2 SNP alone was the best predictor of eye color. Sturm et al. (2008) concluded that the conserved region around rs12913832 represents a regulatory region controlling constitutive expression of OCA2, and that the C allele of rs12913832 leads to decreased expression of OCA2, particularly within iris melanocytes, by abrogation of the binding site for HLTF (603257) that regulates transcription of OCA2. Sturm et al. (2008) also demonstrated that the OCA2 coding SNP R419Q (611409.0012) acts as a penetrance modifier of rs12913832.
In a 3-generation Danish family segregating blue and brown eye color, Eiberg et al. (2008) used fine mapping to identify a 166-kb candidate region within the HERC2 gene. Further studies of SNPs within this region among 144 blue-eyed and 45 brown-eyed individuals identified 2 SNPs, rs1129038 and the strongly conserved rs12913832, that showed significant associations with the blue-eyed phenotype (p = 6.2 x 10(-46)). A common founder haplotype containing these SNPs was identified among blue-eyed persons from Denmark, Turkey, and Jordan. In vitro functional expression studies in human colon carcinoma cells showed that what the authors referred to as the 'G' allele of rs12913832, present in blue-eyed individuals, had an inhibitory effect on OCA2 promoter activity.
Visser et al. (2012) found that HLTF, LEF1 (153245), and MITF (156845) bound to the enhancer region surrounding rs12913832 in darkly pigmented human melanocytes carrying the T allele of rs12913832. Binding was associated with long-range chromatin looping between the enhancer and the OCA2 promoter, leading to elevated OCA2 expression. In contrast, lightly pigmented melanocytes carrying the C allele of rs12913832 showed reduced enhancer binding, chromatin looping, and OCA2 expression.
