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Melanocyte-stimulating hormone receptor (MSH-R) (Melanocortin receptor 1) (MC1-R) [MSHR]


Genetics of facial telangiectasia in the Rotterdam Study: a genome-wide association study and candidate gene approach.

The severity of facial telangiectasia or red veins is associated with many lifestyle factors. However, the genetic predisposition remains unclear. We performed a genome-wide association study (GWAS) on facial telangiectasia in the Rotterdam Study (RS) and tested for replication in two independent cohorts. Additionally, a candidate gene approach with known pigmentation genes was performed. Facial telangiectasia were extracted from standardized facial photographs (collected from 2010-2013) of 2,842 northwestern European participants (median age 66.9, 56.8% female) from the RS. Our GWAS top hits (p-value <10 ) were tested for replication in 460 elderly women of the SALIA cohort and in 576 additional men and women of the RS. Associations of top single-nucleotide polymorphisms (SNPs) with expression quantitative trait loci (eQTL) in various tissues were reviewed (GTEx database) alongside phenotype associations in the UK biobank database. SNP-based associations between known pigmentation genes and facial telangiectasia were tested. Conditional analysis on skin color was additionally performed. Our most significant GWAS signal was rs4417318 (p-value 5.38*10 ), an intergenic SNP on chromosome 12 mapping to the SLC16A7 gene. Other suggestive SNPs tagged genes ZNF211, ZSCAN4, ICOS, and KCNN3; SNP eQTLs and phenotype associations tagged links to the vascular system. However, the top signals did not pass significance in the two replication cohorts. The pigmentation genes KIAA0930, SLCA45A2 and MC1R, were significantly associated with telangiectasia in a candidate gene approach but not independently of skin color. In this GWAS on telangiectasia in a northwestern European population, no genome-wide significant SNPs were found, although suggestive signals indicate genes involved in the vascular system might be involved in telangiectasia. Significantly associated pigmentation genes underline the link between skin color and telangiectasia.


  • GWAS
  • KIAA0930
  • MC1R
  • SLCA45A2
  • SNP
  • Telangiectasia
  • candidate gene approach
  • epidemiology
  • genetics
  • pigmentation genes
  • red veins
  • skin aging

In vitro behavior and UV response of melanocytes derived from carriers of [[CDKN2A]] mutations and MC1R variants.

Coinheritance of germline mutation in cyclin-dependent kinase inhibitor 2A ([[CDKN2A]]) and loss-of-function (LOF) melanocortin 1 receptor (MC1R) variants is clinically associated with exaggerated risk for melanoma. To understand the combined impact of these mutations, we established and tested primary human melanocyte cultures from different [[CDKN2A]] mutation carriers, expressing either wild-type MC1R or MC1RLOF variant(s). These cultures expressed the [[CDKN2A]] product p16 (INK4A) and functional MC1R. Except for 32ins24 mutant melanocytes, the remaining cultures showed no detectable aberrations in proliferation or capacity for replicative senescence. Additionally, the latter cultures responded normally to ultraviolet radiation (UV) by cell cycle arrest, JNK, p38, and p53 activation, hydrogen peroxide generation, and repair of DNA photoproducts. We propose that malignant transformation of melanocytes expressing [[CDKN2A]] mutation and MC1RLOF allele(s) requires acquisition of somatic mutations facilitated by MC1R genotype or aberrant microenvironment due to [[CDKN2A]] mutation in keratinocytes and fibroblasts.

MeSH Terms

  • Adolescent
  • Adult
  • Animals
  • Cells, Cultured
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p15
  • DNA Damage
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Male
  • Melanocytes
  • Mutation
  • Neoplasm Proteins
  • Phosphorylation
  • Receptor, Melanocortin, Type 1
  • Retinoblastoma Protein
  • Ultraviolet Rays
  • Young Adult
  • beta-Galactosidase


  • CDKN2A
  • MC1R
  • proliferation
  • replicative senescence
  • ultraviolet radiation

The MC1R Gene and Youthful Looks.

Looking young for one's age has been a desire since time immemorial. This desire is attributable to the belief that appearance reflects health and fecundity. Indeed, perceived age predicts survival [1] and associates with molecular markers of aging such as telomere length [2]. Understanding the underlying molecular biology of perceived age is vital for identifying new aging therapies among other purposes, but studies are lacking thus far. As a first attempt, we performed genome-wide association studies (GWASs) of perceived facial age and wrinkling estimated from digital facial images by analyzing over eight million SNPs in 2,693 elderly Dutch Europeans from the Rotterdam Study. The strongest genetic associations with perceived facial age were found for multiple SNPs in the MC1R gene (p < 1 × 10(-7)). This effect was enhanced for a compound heterozygosity marker constructed from four pre-selected functional MC1R SNPs (p = 2.69 × 10(-12)), which was replicated in 599 Dutch Europeans from the Leiden Longevity Study (p = 0.042) and in 1,173 Europeans of the TwinsUK Study (p = 3 × 10(-3)). Individuals carrying the homozygote MC1R risk haplotype looked on average up to 2 years older than non-carriers. This association was independent of age, sex, skin color, and sun damage (wrinkling, pigmented spots) and persisted through different sun-exposure levels. Hence, a role for MC1R in youthful looks independent of its known melanin synthesis function is suggested. Our study uncovers the first genetic evidence explaining why some people look older for their age and provides new leads for further investigating the biological basis of how old or young people look.

MeSH Terms

  • Aged
  • Aging
  • Cohort Studies
  • Female
  • Genome-Wide Association Study
  • Haplotypes
  • Humans
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Receptor, Melanocortin, Type 1
  • Skin Aging


  • GWAS
  • MC1R
  • age
  • appearance
  • facial aging
  • perceived facial age
  • skin