The majority of GEM participants in these analyses (2431 of 2893, 84%) carried at least one MC1R variant. Consistent with a previous report from GEM [7
], carriage of any R variant (R151C, R160W, D294H, D84E) relative to none (con/con or r in the absence of R) had ORs of 1.45 (95% CI 1.22–1.72), 1.43 (95% CI 1.20–1.71) for just one R variant and 1.53 (95% CI 1.14–2.07) for two or more; adjusted for age, sex, center, ancestry, age*sex (). With reference to the con/con genotype, the ORs were 1.02 (95% CI 0.78–1.34) for any r variant in the absence of R (con/r or r/r) and 1.47 (95% CI 1.14–1.89) for any R (p for trend <0.001) (not tabulated).
Association between genotype, phenotype and sun exposure variables and risk of MPM in 2,893 GEM participants (1875 SPM, 1018 MPM)
ORs for MPM by phenotype were lowest for poor tanning ability, tendency to burn and any childhood facial freckling, intermediate for red hair, relative to other colors, and highest for fair skin and for the most sun sensitive pigment score, Q4; all p values were <0.05 (). Relative to black hair, the OR for red hair was 2.05 (95% CI 1.26–3.34), that for blond or fair 1.58 (95% CI 1.02–2.45), for light brown hair 1.46 (95% CI 0.95–2.25) and that for dark brown 1.14 (0.74–1.78) (p for trend=0.001). Eye color had no apparent effect on MPM risk. All models for phenotype were adjusted for age, sex, center, ancestry, and age*sex interaction.
The strongest associations of sun exposure with MPM were for any beach and waterside activities and > median average annual lifetime ambient UV (). In a multivariable model, any beach and waterside activities (OR=1.58; 95% CI 1.25–1.99) and having any R genotype (OR=1.34; 95% CI 1.11–1.62) were both statistically significantly associated with MPM (p <0.05) with pigment score, age, sex, center, ancestry and age*sex interaction included as covariates. The p values were >0.05 for addition individually to this model of the variables for ambient lifetime and early life UV. The ORs changed very little when the R genotype included the 3 variants Y152X, 86insA, and 537insC in addition to R151C, R160W, D294H, D84E.
There was some evidence that MC1R genotype modified the effects of beach and water activities (). The OR for MPM was higher for any activities in the absence of R variants (OR=1.94) than in their presence (OR=1.39) (p for interaction 0.08) (). Adding the 3 variants Y152X, 86insA and 537insC to the 4 variants R151C, R160W, D294H, D84E changed the ORs only slightly. There was little evidence of any similar modification of the effects of lifetime or early life ambient UV ().
Association between MC1R genotype and sun exposure in 2,893 GEM participants
We further examined modification of the association of sun exposure with MPM by MC1R genotype in two body site categories. The ORs for ambient early life UV were higher in those with no R (OR=4.23) than in those with any R (OR=1.04) for melanomas on the head and neck (p=0.01 for 2 way interaction) and significantly different by body site (p=0.01 for 3 way interaction), with no evidence of a similar interaction for MPM at other body sites. Lifetime ambient UV had a similar pattern of ORs but all p values for interaction were high. The higher OR of MPM with beach and water activities in those with no R variants was mostly for MPM on body sites other than the head and neck but not significantly different by body site (p=0.89 for 3 way interaction) ().
Association between sun exposure and MC1R genotype in two categories of body site
Risk for MPM of the head and neck increased strongly with increasing lifetime ambient UV across 4 exposure categories, the OR for Q4 was 5.30 (95% CI 1.44–19.58; p for trend 0.01); for early life UV it was 4.19 (95% CI 1.83–9.63; p for trend <0.001). For other body sites, ORs for ambient UV rose only to 1.75 and showed no apparent trend. The increase in ORs for MPM on the head and neck with increasing lifetime ambient UV was evident only in the absence of MC1R R variants. In people with no R variants the ORs for Q4 were 14.61 for lifetime ambient UV, 7.8 for early life ambient UV and 2.75 for beach and water activities, compared with ORs <2.0 when R variants were present (see ). There was little evidence of these divergent patterns of increasing MPM risk with increasing ambient UV for melanomas of other body sites. For beach and water activities, MPM risk did not increase consistently beyond the second exposure quarter (OR ~2) and there was little evidence that the pattern of increase differed by body site or by MC1R genotype ().
Figure 1 Risk of MPM on head and neck and other body sites: ORs for quartiles of average annual lifetime ambient UV (a,b) and average early life UV (c,d), and ORs for beach and water activities (none, tertiles of hours of average annual lifetime activities) (e,f) (more ...)
Like MC1R genotype (), phenotype also appeared to modify the effects of sun exposure on risk of MPM of the head and neck (). This effect was most evident for beach and water activities: the OR was 3.74 in those with a pigment score less than or equal to the median and 0.87 in those with a greater than median score (p=0.04 for 3 way interaction) (). The OR estimates in changed little when MC1R genotype (no R, any R) was added to the model. The ORs in 4 quarters of beach and water activities for MPM of the head and neck rose with increasing exposure to Q3 in the less sun sensitive; ORs for the more sun sensitive were low (see ).
Association between sun exposure and phenotype in two categories of body site
There was no consistent pattern of modification of effects of phenotype by MC1R genotype: p for interaction >0.20 for each of skin color, hair color, freckling, ability to tan and pigment score (results not shown). It may be noteworthy, though, that the positive association of red hair with MPM was restricted to those with any R variants: OR=1.35 (95% CI 1.00–1.83) for red hair with reference to other hair colors in those with any R variants compared with OR=0.60 (95% CI 0.18–1.98) in those with no R variants (p for interaction=0.21). Similarly, when the associations of all hair colors with MPM were examined with reference to black hair, the ORs in those with any R were all appreciably greater than unity: ORs of 1.75 (95% CI 0.80–3.83) for dark brown hair, 1.66 (95% CI 0.78–3.57) for light brown, 1.97 (95% CI 0.91–4.25) for blonde or fair, 2.37 (95% CI 1.08–5.21) for red hair.The highest OR in those with no R was 1.32 (95% CI 0.78–2.23) for light brown hair (p for interaction 0.86).