In this prospective study including 132,302 men and women, we found that lighter hair color was associated with a higher PD risk; participants with red hair had approximately a two-fold higher risk of PD relative to those with black hair. The observed associations were independent of ethnicity, smoking, caffeine intake, and other known risk factors for PD and the associations were particularly strong for younger onset of PD (<70 y). We also found that participants homozygous for the MC1R Arg151Cys variant allele had a significantly increased risk of PD.
Our findings suggest that the higher frequency of melanoma occurring among individuals with PD may be at least in part explained by the associations of both diseases with a lighter hair color and the MC1R Arg151Cys variant allele, rather than being an adverse effect of levodopa treatment as previously suggested. 7, 8
In a recent prospective case-control study including 8090 PD cases based on the national Danish Hospital Register, Olsen et al found an increased prevalence of melanoma before a diagnosis of PD 1
. The OR was 1.44 (95% CI: 1.0, 2.0) for developing PD relative to population-based controls.1
In the PD patients who participated in the DATATOP (deprenyl and tocopherol antioxidative therapy of parkinsonism) trial, the observed incidence of melanoma during ~4.5 years of follow-up was significantly higher than expected in the general population, with a standardized event ratio of 3.3 (95%CI: 1.1, 7.8) and the increased incidence of melanoma was not associated with levodopa therapy.2
In a case-control study based on the Rochester Epidemiology Project (PD case =196), Elbaz et al reported that PD patients tended to have a higher risk of melanoma (OR=1.5, 95% CI: 0.3, 9.0).4
However, most of these studies did not control for ethnicity and other ethnicity-relevant dietary habits and lifestyle factors, which may confound the observed melanoma-PD associations.
The exact mechanisms underlying the increased risk of PD associated with light hair or MC1R gene variants is not known. However, it is plausible that pigmentation metabolism, and genes that encode these proteins, may be involved in the pathogenesis of PD. Melanin, like dopamine, is synthesized from the amino acid tyrosine. A major pathological feature of PD is an abnormal loss of neuromelanin-containing cells within the substantia nigra. Neuromelanin has a chemical structure similar to that of melanin. A large body of evidence suggests that neuromelanin could be neuroprotective by scavenging redox active metals (e.g., iron), toxic metals (e.g., mercury and lead), and organic toxic compounds(e.g., pesticides).26
However, neuromelanin synthesis could be regulated by different enzymes than those in peripheral melanogenesis. 27
Alternatively, skin melanin could have a protective role by binding environmental toxins.28
Melanin is a mixture of polymers with different physicochemical properties.29
Mammalian melanocytes can produce two basic types of melanin, brown/black eumelanin and yellow/red pheomelanin. Hair color is one of most important phenotype of pigmentation, with a recessive trait.30
The MC1R gene encodes a 317-amino acid seven-pass-transmembrane G protein coupled receptor.30
Homozygote or compound heterozygote variant MC1R genotype carriers are generally red haired because of overproduction of pheomelanin.30, 31
Difference in pigmentation also reflects differences in ethnicity as well as ancestry. This could explain partially the observed relationship between hair color, MC1R polymorphism and PD risk. Africans and Asians carry less MC1R variants responsible for red hair and in some studies, 32-34
but not all,35, 36
Africans or Asians were found to have a lower PD prevalence than Caucasians. However, the difference in PD prevalence could be due to ascertainment biases or differences in demographic structure. 34, 36
Two studies, 37, 38
which compared PD incident rates among different ethnic groups living in the same region, generated conflicting results. Among members of the Kaiser Permanente Medical Care Program of Northern California, Van Den Eeden et al. found that PD incidence was lower in African Americans compared with non-Hispanics Whites and Hispanics, 37
whereas Mayeux et al. reported that Blacks had a significant higher incident rate of PD relative to Whites living in Northern Manhattan, 38
although the period of follow-up (three years) of the latter study was rather short to obtain stable estimates of PD incidence. Even among individuals of the same race, however, a lighter skin color was associated with a higher PD risk.39
In a case-control study including 509 newly diagnosed PD in Northern California, Tanner et al found that darker skin color was inversely associated with PD risk among Caucasians (OR=0.46; 95% CI: 0.28, 0.78) and African-Americans (OR=0.60; 95% CI: 0.38, 0.94).39
Although the association between hair color and PD risk remained significant after further controlling for ethnicity and major ancestry, a possibility of residual confounding cannot be ruled out.
Alternately, the MC1R gene variants could also contribute excessive PD via mechanisms other than its effects on pigmentation. For example, α-melanocyte-stimulating hormone (α-MSH), the MC1R ligand, has anti-inflammatary effects in the brain and immune modulating effects. 40, 41
It reduces NFκB activity and therefore, down-regulates production of nitric oxide, oxygen peroxide, and several cytokines, such as IL-6.40, 41
These have been suggested to have an unfavorable role in PD.42-44
MC1R has been detected in human periaqueductal gray matter,45
and the MC1R red-hair variants have been associated with a higher risk and severity of multiple sclerosis.46
Administration of α-MSH (intraperitoneally) has also been shown to prevent damage in brainstem ischemia and rescues neurons from excitotoxic cell death induced by kainic acid.47-49
These studies, together with our findings, suggest that MC1R or related genes could have a role in neurodegenerative diseases.
We observed a stronger association between hair color and PD risk for relative younger onset of PD (<70 y, based on median value) than those with age of onset greater than 70 years. This observation suggests a possible important role of pigmentation genes in the etiology of PD. However, we were not able to examine whether hair color is associated with early-onset PD (<50 y), which has been shown to be strongly associated with genetic factors.50
A limitation of our study is reliance on self-reported hair color, which could introduce non-differential misclassification and attenuate the association between hair color and PD risk. Although known PD risk factors were adjusted in our analysis, we cannot exclude the possibility of confounding by unknown risk factors. Also, the clinical diagnosis of PD is not perfect, and some degree of diagnostic error is thus likely. In a large clinicopathological study, however, the positive predictive value of a clinical diagnosis of PD has been found to be 90% or higher,51
and bias from this source is thus likely to be modest. We observed a similar significant association between hair color and PD risk when we restricted to PD cases diagnosed by neurologists.
In summary, we found that individuals with light hair and those homozygous for the MC1R Arg151Cys allele of Cys have an increased risk of PD. Our findings suggest a potential important role of pigmentation or ethnicity in PD, and may in part explain the higher than expected co-occurrence of PD and melanoma.