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Health risks for people with red hair

In a previous article (Red hair: it’s in your genes), we discussed melanin (made by melanocytes) and the two types of melanin involved in hair and skin pigmentation: eumelanin and pheomelanin. How changes (variants) in the MC1R gene cause pheomelanin to be the dominant pigment that leads to red hair was also discussed. People with red hair often have pale or fair skin and freckles; this is also influenced by the amount of melanin. Research has shown that MC1R variants affect not only hair and skin color but also have a role in various health conditions, meaning redheads have more than their hair color in common.

Genetic cause of red hair

Redheads produce more pheomelanin due to genetic changes (called variants) in the MC1R gene found on chromosome 16. This gene provides the code for a protein called melanocortin 1 receptor that is located on melanocytes and is responsible for the type of melanin produced. When the receptor is activated or turned on, melanocytes produce eumelanin. In contrast, if the receptor is not activated the melanocytes produce pheomelanin. Variations in the MC1R gene are responsible for this deactivation, which is called a loss‑of‑function [1].

Health risks

As a group, redheads seem to be more likely to develop certain health conditions and have certain health risks. These include:

  • Increased skin cancer risk
  • Altered sensitivity to pain
  • Increased risk of Parkinson’s disease
  • Increased risk of endometriosis

Increased skin cancer risk

As mentioned above, redheads often have pale skin and freckles. Pale skin is associated with an increased risk of skin cancer. This is because eumelanin offers some protection from harmful ultraviolet (UV) light known to be a risk factor for skin cancer and redheads have much less of it than people with darker skin have.

Changes in the MC1R gene contribute to pale skin that does not tan and to UV sensitivity, thus increasing the skin cancer risk [2, 3]. These changes may affect both the ability to block UV light and to repair mutations caused by UV exposure. Research suggests that the most common MC1R variants associated with red hair, pale skin and freckles are associated with up to a four-fold increased lifetime risk of skin cancer [3], but the molecular mechanisms are not well understood. One study in 2013 reported that the MC1R variants found in redheads could not bind to PTEN, a tumor-suppressor gene. This results in elevated signaling in a cancer-causing signaling pathway and an increased cancer risk [4, 5]. The increased risk is even greater when a mutation in the BRAF gene is also present and BRAF mutations occur in up to 70% of all melanomas (a type of skin cancer) [6].

It has been reported that some MC1R variants are associated with melanoma and red hair and others are only associated with the development of melanoma, leading to speculation that MC1R variants play a role in melanoma development via pigmentation and non-pigmentation pathways [7].

Altered sensitivity to pain

It has been suggested that some redheads have an increased sensitivity to pain and that MC1R variants cause alterations in pain sensitivity. Redheads have been shown to be more sensitive to pain from heat or cold and resistant to the pain relief effects of subcutaneous lidocaine [8]. A small study has shown that redheads may also require more anesthetic [9]. Furthermore, women with two variant MC1R alleles have been shown to exhibit greater pain relief with the opioid pain medication pentazocine than other groups [10].

A recent study in 2021 in mice provided more support for the role of MC1R variants in pain sensitivity. The researchers investigated red-haired mice carrying a loss-of-function MC1R variant that is also found in redheads, and they found that these mice had a higher tolerance to pain that is affected by the number of melanocytes but not by the amount of melanin [11, 12]. The loss of function of MC1R in melanocytes resulted in lower levels of a protein called proopiomelanocortin. This in turn influences the level of a pain‑blocking hormone (beta-endorphin) and a pain-sensitizing hormone (melanocyte stimulating hormone or MSH). These hormones work to balance pain inhibition receptors (opioid receptors) and pain sensitivity receptors (melanocortin 4 receptors). In the red-haired mice, although levels of both were reduced, the MC1R variants seemed to favor opioid receptors that inhibit pain, which resulted in an increased pain threshold. However, researchers noted that the red-haired mice have additional factors unrelated to melanocytes that activate pain inhibition receptors and contribute to an overall increase in the pain threshold [11, 13].

It is clear that MC1R variants and pigmentation level affect the pain threshold, which has implications for the management of pain in individuals with red hair. Moreover, changes in the pathways involved in balancing the level of hormones that result in decreased plasma MSH may also explain pain variations among non-red-haired individuals.

Increased risk of Parkinson’s disease

A possible association between Parkinson’s disease and increased incidence of melanoma has led researchers to assess the role of variants in the MC1R gene in Parkinson’s disease, and several studies have reported an association between red hair and Parkinson’s disease. One study examined the relationship between hair color and Parkinson’s disease risk among more than 130,000 participants in two large American studies, the Health Professionals Follow-up Study and the Nurses’ Health Study [14]. It found that the relative risk for Parkinson’s disease increased with decreasing darkness of hair color, and that those with red hair had a two-fold higher risk of Parkinson’s disease compared to those with black hair. Furthermore, the association was particularly strong for people under 70 years old.

Researchers also reported that participants homozygous for a particular MC1R variant allele had a significantly increased risk of Parkinson’s disease [14]. Studies in mice carrying the same loss-of-function MC1R variants found in some redheads showed they have increased susceptibility to dopaminergic toxins and develop dopaminergic deficits in adulthood [15]. This correlates with Parkinson’s disease in man; the symptoms of Parkinson’s disease are due to low levels of dopamine and the onset is usually later in life.

It is unclear whether MC1R variantscontribute to the increased risk of Parkinson’s disease due to their effect on pigmentation or via some other mechanism, but some research suggests MC1R may have a neuro‑protective role [15].

Increased risk of endometriosis

A possible increased risk of endometriosis has been reported in women with red hair; however, it may be linked to fertility status. A study of 90,065 women published in 2006 showed that women with red hair who had not been infertile were more likely to have endometriosis than women with other color hair were. In contrast, women with naturally red hair who were infertile had a decreased rate of endometriosis [16].

Other health implications for people with red hair

As well as the above-mentioned health risks associated with having red hair, there may be other implications too:

  • Decreased risk of prostate cancer
  • More efficient vitamin D synthesis

Decreased risk of prostate cancer

An article published in 2013, reported that redheaded men were significantly less likely to develop prostate cancer than brown-haired men were. Redheads had approximately half the risk of brown-haired men. The study did not provide a definitive mechanism for this, but suggested that MC1R variants may influence prostate cancer development directly (through genetic or regulatory mechanisms or other genes, including pigmentation genes) or indirectly (through the interactions with ultraviolet light or vitamin D) [17].

More efficient vitamin D synthesis

Redheads may be more efficient at synthesizing their own vitamin D than people with other hair colors. One small study found that redheads had higher levels of a vitamin D precursor in their blood and suggested that this may be an evolutionary adaptation allowing for sufficient synthesis of provitamin D under lower intensity light conditions such as found in Northern Europe [18]. Vitamin D is good for your bones, immunity and your mood. However, this advantage is outweighed by the tendency to burn and the increased skin cancer risk, meaning redheads should be especially careful about sun exposure and always use a high sun protection factor (SPF) sun cream.

Conclusion

While there has been a lot of research looking at the health risks associated with having red hair, it is clear that researchers have more to explore. An awareness of these health risks and an understanding of the causes, will potentially lead to more support for redheads and others who may be at risk and even to the development of new treatments.

References

[1] National Library of Medicine, Medline Plus. Is hair color determined by genetics? Retrieved 8 August 2022 from https://medlineplus.gov/genetics/understanding/traits/haircolor/

[2] Young R. 6 July 2001. Preventing UV-associated cancers by altering skin pigmentation. Retrieved 27 July 2022 from https://news.harvard.edu/gazette/story/2021/07/altering-skin-pigmentation-can-prevent-uv-cancer/

[3] D’Orazio J et al. UV radiation and the skin. Int J Mol Sci 2013 14(6):12222-48. doi: 10.3390/ijms140612222. PMID: 23749111; PMCID: PMC3709783. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709783/

[4] Harvard Medical School. How Red Hair May Increase Melanoma Risk. Retrieved 27 July 2022 from https://hms.harvard.edu/news/how-red-hair-may-increase-melanoma-risk

[5] Cao J t al. MC1R is a potent regulator of PTEN after UV exposure in melanocytes. Mol Cell 2013 51(4):409-22. doi: 10.1016/j.molcel.2013.08.010. PMID: 23973372; PMCID: PMC3792490. https://doi.org/10.1016/j.molcel.2013.08.010

[6] Collins F. 4 September 2013. Why Redheads Are More Susceptible to Melanoma. Retrieved 27 July 2022 from https://directorsblog.nih.gov/2013/09/04/why-redheads-are-more-susceptible-to-melanoma/

[7] Raimondi S et al. MC1R variants, melanoma and red hair color phenotype: a meta-analysis. Int J Cancer 2008 15;122(12):2753-60. doi: 10.1002/ijc.23396. PMID: 18366057. https://onlinelibrary.wiley.com/doi/10.1002/ijc.23396

[8] Liem EB et al. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology 2005 102(3):509-14. doi: 10.1097/00000542-200503000-00006. PMID: 15731586; PMCID: PMC1692342. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1692342/

[9] Edwin B et al. Anesthetic Requirement Is Increased in Redheads. Anesthesiology 2004 101:279–283 doi: https://doi.org/10.1097/00000542-200408000-00006

[10] Mogil JS et al. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci USA 2003 100(8):4867-72. doi: 10.1073/pnas.0730053100. Epub 2003 Mar 27. PMID: 12663858; PMCID: PMC153647. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC153647/

[11] Bryant E. 20 April 2021. Study finds link between red hair and pain threshold. National Institutes of Health. Retrieved 1 August 2022 from https://www.nih.gov/news-events/nih-research-matters/study-finds-link-between-red-hair-pain-threshold

[12] Robinson KC et al. Reduced MC4R signaling alters nociceptive thresholds associated with red hair. Sci Adv 20217(14):eabd1310. doi: 10.1126/sciadv.abd1310. PMID: 33811065. https://www.science.org/doi/10.1126/sciadv.abd1310

[13] Massachusetts General Hospital. 3 April 2021. Research reveals why redheads may have different pain thresholds: Study in red-haired mice uncovers mechanisms involved and suggests new treatment strategies for pain. ScienceDaily. Retrieved 1 August 2022 from www.sciencedaily.com/releases/2021/04/210403153628.htm

[14] Gao X et al. Genetic determinants of hair color and Parkinson’s disease risk. Ann Neurol 2009 65(1):76-82. doi: 10.1002/ana.21535. PMID: 19194882; PMCID: PMC2639631. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639631/

[15] Chen X et al. The melanoma-linked “redhead” MC1R influences dopaminergic neuron survival. Ann Neurol 2017 81(3):395-406. doi: 10.1002/ana.24852. Epub 2017 Jan 23. PMID: 28019657; PMCID: PMC6085083. https://onlinelibrary.wiley.com/doi/10.1002/ana.24852

[16] Missmer SA et al. Natural hair color and the incidence of endometriosis. Fertil Steril 2006 85(4):866-70. doi: 10.1016/j.fertnstert.2005.12.008. Epub 2006 Mar 9. PMID: 16580366. https://www.fertstert.org/article/S0015-0282(05)04323-2/fulltext

[17] Weinstein SJ et al. Pigmentation-related phenotypes and risk of prostate cancer. Br J Cancer 2013 109(3):747-50. doi: 10.1038/bjc.2013.385. Epub 2013 Jul 16. PMID: 23860522; PMCID: PMC3738118. https://www.nature.com/articles/bjc2013385

[18] Flegr J et al. Increased 25(OH)D3 level in redheaded people: Could redheadedness be an adaptation to temperate climate? Exp Dermatol 2020 29(7):598-609. doi: 10.1111/exd.14119. Epub 2020 Jun 25. PMID: 32478926. https://onlinelibrary.wiley.com/doi/abs/10.1111/exd.14119

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