Functional polymorphisms in pigmentation-related genes MC1R and DCT display population-specific association with wet age-related macular degeneration

Mika Reinisalo(University of Eastern Finland), Seppo Helisalmi(University of Eastern Finland), Ali Koskela(University of Eastern Finland), Jenni Küblbeck(University of Eastern Finland), Mikko Liukkonen(University of Eastern Finland), Maija Mutikainen(University of Eastern Finland), Angela J. Cree(University of Southampton), Helen Griffiths(University of Southampton), Andras Papp(Semmelweis University), Sanna Seitsonen(Helsinki University Hospital), Ilkka Immonen(Helsinki University Hospital), H. Soininen(University of Eastern Finland), Arto Urtti(University of Eastern Finland), Mikko Hiltunen(University of Eastern Finland), Mateusz Winiarczyk(Medical University of Lublin), Miklós Resch(Semmelweis University), J. Arjuna Ratnayaka(University of Southampton), Andrew J. Lotery(University of Southampton), Kai Kaarniranta(University of Eastern Finland), Paavo Honkakoski(University of North Carolina at Chapel Hill)
Biochemistry and Biophysics Reports
February 6, 2026
10.1016/j.bbrep.2026.102477
Cited by 0Open Access
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Abstract

Age-related macular degeneration (AMD) is among the leading causes of vision loss. Factors increasing the risk of AMD include aging, smoking, cardiovascular diseases and heritability. Although melanin pigment is known to protect retinal homeostasis, the link between pigmentation-related genes and AMD is unclear. We investigated associations between 26 variations in six pigmentation-related genes and wet AMD risk in a Finnish population, followed by replication in the United Kingdom (UK), Hungarian and Polish cohorts, totaling 775 patients and 959 controls. Associations of genetic components with smoking and body mass index (BMI) were tested in the Finnish and UK cohorts. The functionality of candidate variants in human retinal pigment epithelial (RPE) cells was evaluated using gene promoter analysis and gene silencing. Non-coding variants, rs1407995 in the dopachrome tautomerase ( DCT ) intron and rs3212351 in the melanocortin-1 receptor ( MC1R ) promoter, were associated with wet AMD in the Finnish cohort. The variant rs3212351 disrupts a binding site for transcription factor MITF and reduces MC1R expression in RPE cells. Unlike in the Finnish cohort, the data regarding the MC1R variant suggested a protective association in the Polish cohort. The incidence of AMD increased with age in all cohorts. Smoking increased AMD risk in the cohorts studied. Sex and BMI showed no associations. These findings suggest that variations in DCT and MC1R genes known to affect skin and eye pigmentation may also play a role in development of wet AMD. The observed population differences may be related to variable pigmentation traits. • Variations in pigmentation genes Dopachrome Tautomerase (DCT) and Melanocortin receptor 1 (MC1R) are associated with wet form of age-related macular degeneration (wet AMD). • Studied non-coding variants rs1407995 in the DCT intron and rs3212351 in the MC1R promoter are functional. • The observed population differences may associate with variable pigmentation traits.

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