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Melanocortin 1 receptor genotype, past environmental sun exposure, and risk of multiple sclerosis

From Menzies Research Institute (T.D., I.v.d.M., A.-L.P., B.V.T., J.S., R.J.T., A.M.P., J.L.D.), University of Tasmania, Hobart, Tasmania, Australia; Murdoch Childrens Research Institute (T.D., A.-L.P.), Royal Children’s Hospital, Parkville, Victoria, Australia; The Walter and Eliza Hall Institute of Medical Research (J.S.), Parkville, Victoria, Australia; and International Agency for Cancer Research (J.D.M.), Lyon, France.

Address correspondence and reprint requests to Dr. Terry Dwyer, Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville Victoria 3052, Australia terry.dwyer{at}mcri.edu.au

Objective: Low past sun exposure, fair skin type, and polymorphisms of the MC1R gene have been associated with multiple sclerosis (MS) risk. We aimed to investigate the interplay between melanocortin 1 receptor gene variants, red hair/fair skin phenotype, and past environmental sun exposure in MS.

Methods: Population-based case–control study in Tasmania, Australia, involving 136 cases with MS and 272 controls randomly drawn from the community and matched on sex and year of birth. Measures included past sun exposure by calendar and questionnaire, spectrophotometric skin type, and MC1R genotype, with any MC1R Arg151Cys, Arg160Trp, or Asp294His alleles present denoted as red hair color (RHC) variant.

Results: The association between RHC variant genotype and MS was more evident for women (odds ratio 2.02 [1.15–3.54]) than for men (odds ratio 0.65 [0.27–1.57]) (difference in effect, p = 0.03). The RHC variant genotype was associated with behavioral sun avoidance. In addition, increasing summer sun exposure at ages 6 through 10 years was associated with reduced MS risk among those with no RHC variant (p = 0.03), but not among those with RHC variant genotype (p = 0.15; difference in effect, p = 0.02). Similar findings were evident for other past sun exposure measures and when the sample was restricted to women only.

Conclusion: The interplay between red hair color variant genotype, red hair/fair skin phenotype, and multiple sclerosis (MS) is complex. The modification of past sun exposure by MC1R genotype provides further support that ultraviolet radiation or derivatives such as vitamin D may be causally related to a reduced MS risk.

Abbreviations: AGRF = Australian Genome Research Facility; MSH = -melanocyte stimulating hormone; EBNA = Epstein–Barr virus nuclear antigen; EBV = Epstein–Barr virus; HLA = human leukocyte antigen; HWE = Hardy–Weinberg equilibrium; IgG = immunoglobulin G; MS = multiple sclerosis; OR = odds ratio; RHC = red hair color; SNP = single nucleotide polymorphism; UVR = ultraviolet radiation; VCA = Epstein–Barr virus capsid antigen.

Supported by the National Health and Research Council (NHMRC) of Australia, the Australian Rotary Health Research Fund, and MS Australia. I.v.d.M. is supported by an NHMRC Training Fellowship.

Disclosure: The authors report no disclosures.

Received January 7, 2008. Accepted in final form May 7, 2008.