Genome-wide association study in Europeans (N=176,678) reveals genetic loci for tanning response to sun exposure

Repeated exposure to the sun is well known to be associated with increased risk of all skin cancers, including cutaneous malignant melanoma (CMM), basal cell carcinoma and squamous cell carcinoma, and these types of cancer are more common in fair-skinned, rather than darker-skinned, people. The tanning response after exposure to sunlight is also well known to be mainly determined by melanin pigmentation, which aims at protecting the skin from DNA photo-damage. Genome-wide association studies (GWAS) on European populations have previously identified several DNA variants in or near seven genes –– ASIP (agout-signaling protein), EXOC2, (exocyst-complex component-2) HERC2 (ECT- and RLD-domain-containing E3 ubiquitin protein ligase-2), IRF4 (interferon regulatory factor-4), MC1R (melanocortin-1 receptor), SLC45A2 (solute-carrier family 45, member-2), and TYR (tyrosinase). These seven genes are known to be associated with both pigmentation-related traits (e.g. hair, eye or skin color) and skin cancer.

Authors [see attached] chose to investigate further the genetic basis of skin-tanning and the effect on skin cancer susceptibility (i.e. by starting with a much larger cohort –– that should ‘find’ additional significant genetic loci) –– by performing large-scale GWAS using data from the UK Biobank (N = 176,678 subjects of European ancestry). They identified significant associations with tanning ability at 20 loci –– confirming previously identified associations at six of these previous loci, and reporting 14 novel loci (ten of these loci have never before been associated with pigmentation-related phenotypes).

In addition to identifying and replicating genes previously associated with ease of skin-tanning or pigmentation-related phenotypes (traits), authors (intriguingly to me) demonstrated a genetic correlation between ease of skin-tanning as well as risk of non-melanoma skin cancer with DNA variants at the AHR/AGR3 locus. These two genes –– AHR (aryl hydrocarbon receptor) and AGR3 (anterior-gradient-3, protein disulfide isomerase family member) reside next to one another on human chromosome 7p21.1.

The former gene, AHR (first discovered by yours truly and Alan Poland in 1974) is known to be associated with “reception of environmental, as well as endogenous, signals”, resulting in a cascade of downstream events programmed to respond to those incoming signals (in ways to promote cell and organism survival). In the case of “sunlight” as the signal, undoubtedly the “genetic response” includes cell cycle genes and DNA-repair genes [recently reviewed in: Progr Lipid Res 2o17; 67: 38].

I didn’t know if it was possible until I tried –– but I see it IS possible to download from that journal article and paste below Table 1 and Figures 8 & 9 from that elegant review. 🙂 As can be see, as a member of the bHLH/PAS family, AHR participates (lends a helping hand) in for virtually all fundamental/developmental and critical-life functions in the living organism.

Table 1

Summary of organs, systems, cell functions, and developmental biology in which AHR-signaling is involved.

Location AHR-signaling pathway involvement

Central nervous system Development of brain and nervous system; Neurogenesis; Neuronal cell development; Cardiorespiratory brainstem development in ventrolateral medulla; “Brain-gut-microbiome”

Eye Ciliary body formation and function; Thyroid-associated eye disease

Gastrointestinal tract Development of GI tract; Rectal prolapse during aging; “Brain-gut-microbiome”

Heart Development of heart organ; Cardiovascular physiology; Atherogenesis; Cardiomyogenesis; Cardiorespiratory function

Hematological system Development of blood cell-forming system; Hematopoiesis; Activation or suppression of erythroid development

Immune system Immune system development; The immune response; Innate immunity; Pro-inflammatory response; Anti-inflammatory response; Immunomodulatory effects

Inner ear Development of the cochlea

Kidney Development of the kidney; Hypertension

Liver Development of liver organ; Hyperlipidemia; Glucose and lipid metabolism; Hepatic steatosis

Musculoskeletal system Transmesoderm → osteoblast transition; Bone formation; Osteoclastogenesis

Pancreas Development of pancreas; Beta-cell regulation; Pancreatic fibrosis

Endocrine system Serum lowered testosterone levels; Infertility; Mammary gland duct cell epithelial hyperplasia; Degenerative changes in testis; Gerrm-cell apoptosis; Endometriosis

Reproductive system Development of male and female sex organs; Spermatogenesis; Fertility

Respiratory tract Development of respiratory tract; Disruption of GABA-ergic transmission defects; Cardiorespiratory function

Vascular system Angiogenesis; Atherosclerotic plaque formation

Skin Barrier physiology; Atopic dermatitis

Cellular functions Cell migration; Cell adhesion; Circadian rhythmicity

DNA changes DNA synthesis; DNA repair; DNA-adduct formation; Mutagenesis

Oxidative stress Mitochondrial ROS formation; Anti-oxidant protection against ROS formation; Mitochondrial H2O2 production; Crosstalk with hypoxia and HIFsignaling pathways; Transforming growth factor- signaling pathways; MID1-PP2A-CDC25B-CDK1 signaling pathway regulating mitosis

Tumor cells Growth suppression; Tumor initiation; Tumor promotion

ES cell basic functions Ectoderm → epithelium transition; Cell adhesion; Cell-cycle regulation; Apoptosis; Cavitation during morula →blastula formation; Activator of Rho/Rac GTPases; WNT-signaling pathways; Homeobox-signaling pathways

Other basic functions Transgenerational inheritance; Epigenetic effects; Chromatin remodeling; Histone modification; Aging-related and degenerative diseases

Nature Commun 2o18; 9: 1684

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