In this prospective analysis, we found an approximately twofold increase in risk of PD among individuals who reported a family history of melanoma in a first-degree relative, as compared with those without such a family history. The significant association was independent of several known risk factors for PD, including smoking and caffeine intake. In contrast, we did not observe significant associations between a family history of 4 other common cancers and PD risk.
Our findings do not support the notion that melanoma in patients with PD is due to adverse effects of levodopa treatment. These are consistent with results from 2 recent epidemiologic studies. In a case-control study of 314 patients with PD (45 of them had melanoma), no effect of levodopa on the risk of melanoma was reported; the OR for each 1,000 g cumulative intake of the drug was 1.0 (95% CI: 0.8, 1.3).19
In the DATATOP (deprenyl and tocopherol antioxidative therapy of parkinsonism) trials, incidence of melanoma was significantly higher than expected in the general population, with a standardized event ratio (SER) of 3.3 (95% CI: 1.1, 7.8), but the incidence rates of melanoma before and after initiation of levodopa were similar (SER 3.2 vs 3.4).20
Our finding that a family history of melanoma was associated with a higher risk of PD is unlikely to be explained by smoking or socioeconomic variations, which were thought to confound the association between melanoma and PD observed in previous studies.1,8
Several observational studies reported that individuals who smoked or had a lower socioeconomic status had a lower risk of PD21,22
However, in the current study, adjustment for smoking status did not materially change our results. In a subgroup analysis, we also observed a similar association between family history of melanoma and PD among nonsmokers. Our populations are rather homogenous in respect to their educational level and socioeconomic status. Further, exclusion of non-Caucasian participants generated similar significant results.
Family history represents a combination of an increased genetic susceptibility and environmental factors, such as lifestyle and dietary factors. In the present analysis, however, the excess risk of PD associated with a family history of melanoma did not change materially after controlling for smoking, intake of caffeine and lactose, ethnicity, and other known or suspected environmental risk factors for PD. Although we cannot completely rule out a possibility that other unknown environmental factors may partially contribute the observed associations between a family history and melanoma and PD risk, our results suggest the existence of important genetic contributions.
The metabolism of pigments, and genes that encode the proteins in this process, may, at least in part, explain the observed association between a family history of melanoma and PD risk.7,9
One clinical characteristic of PD is an abnormal loss of neuromelanin-containing cells within the substantia nigra. We previously reported that light hair color, an important phenotype of human pigmentation and a well-established risk factor for melanoma,27
is significantly associated with PD risk in the HPFS and the NHS.7
In a case-control study including 509 newly diagnosed patients with PD in Northern California, individuals with darker skin color were found to have a lower PD risk, both among Caucasians (OR = 0.46; 95% CI: 0.28, 0.78) and among African Americans (OR = 0.60; 95% CI: 0.38, 0.94).28
In addition, we found that carriers of the MC1R Arg151Cys polymorphism, a key genetic determinant for human pigmentation and red hair color, had a higher PD risk than noncarriers in a case-control study nested in the HPFS and the NHS.7
MC1R Arg151Cys variants are associated with an increased melanoma risk, independent of skin type and hair color.27
Other genes, such as cyclins and cyclin dependent kinases (CDKs), could also have a role in the observed association between a family history of melanoma and PD risk. CDKs are often overexpressed in melanoma cells as compared to benign nevi.29
It has been suggested recently that an increased expression of proteins involved in the cell cycle (e.g., CDKs) may have a critical role in neuronal cell death in patients with PD.30,31
Animal studies have shown that 1-methyl-4-phenylpyridinium (MPP+
) induces neuronal apoptosis and could be attenuated by flavopiridol, a broad-spectrum CDK inhibitor.30
Because of the prospective design, our results are unlikely to be significantly affected by recall or selection bias. We also carried out several sensitivity analyses that generated similar significant results. Although known PD risk factors were adjusted in our analysis, we cannot exclude the possibility of residual confounding by unknown risk factors. However, the magnitude of the observed association was rather large and might not be totally explained by these unknown confounders. Data on family history were self-reported by study participants, and no formal validation study was conducted to assess accuracy. Because the participants were all health care professionals, the accuracy of the reports is likely to be high. This was supported by the significant associations of a self-reported family history of melanoma with red natural hair color and a history of painful sunburn. In the NHS and the HPFS cohorts, a family history of melanoma was associated with an increased risk of melanoma.32
Further, prior studies showed that self-reported family history of several common cancers, including colorectal, breast, and prostate cancer, is reliable.33,34
Nevertheless, some degree of nondifferential misclassification in reported family history of cancers cannot be excluded, which could attenuate rather than exaggerate risk estimates.