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

## TL;DR

This study finds that genetic variations in pigmentation-related genes MC1R and DCT are linked to wet age-related macular degeneration, with effects differing across populations.

## Contribution

The study identifies functional non-coding variants in MC1R and DCT that are associated with wet AMD risk and explores population-specific differences.

## Key findings

- Variants rs1407995 in DCT and rs3212351 in MC1R are functionally linked to wet AMD risk.
- The MC1R variant rs3212351 disrupts MITF binding and reduces MC1R expression in retinal pigment epithelial cells.
- Population-specific associations were observed, with the MC1R variant showing protective effects in the Polish cohort.

## 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.

Image 1

•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.

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.