Table 3.

Association of individual melanocortin-1 receptor (MC1R) variants, number of MC1R variants, and types of MC1R variants with melanoma risk in cyclin-dependent kinase inhibitor 2A (CDKN2A) mutation carriers analyzed by continent and in all three continents^*

	Europe			North America			Australia			All continents
MC1R variants	No. of participants affected/unaffected†	OR (95% CI)‡	P§	No. of participants, affected/unaffected†	OR (95% CI)‡	P§	No. of participants, affected/unaffected†	OR (95% CI)‡	P§	No. of participants, affected/unaffected†	OR (95% CI)‡	P§	Phomogeneity║
Individual MC1R variants
V60L	109/120	2.50 (1.40 to 4.46)	.003	50/41	4.45 (1.36 to 14.56)	.09	32/13	6.91 (2.10 to 22.75)	.009	191/174	3.42 (2.10 to 5.58)	1.51 × 10−5	.38
V92M	91/117	2.03 (1.10 to 3.74)	.03	28/35	4.03 (1.08 to 14.98)	.03	24/17	2.51 (.85 to 7.41)	.12	143/169	2.43 (1.45 to 4.06)	.0007	.25
R151C	115/104	4.31 (1.81 to 10.23)	.0002	36/37	6.23 (2.25 to 17.28)	.02	57/20	5.58 (1.56 to 20.0)	.03	208/161	4.68 (2.52 to 8.68)	1.24 × 10−6	.73
R160W	94/105	3.32 (1.77 to 6.21)	.001	35/32	15.04 (3.20 to 70.67)	.05	23/14	2.52 (.97 to 6.57)	.13	152/151	4.13 (2.30 to 7.43)	9.42 × 10−5	.09
Any MC1R variant	270/227	2.59 (1.57 to 4.28)	.0006	116/77	5.67 (2.1 to 15.29)	.05	87/38	4.04 (1.53 to 10.65)	.02	472/342	3.05 (1.99 to 4.67)	2.39 × 10−5	.16
No. of MC1R variants	270/227			116/77			87/38			473/342			.23
1		1.85 (1.09 to 3.15)	.02		3.93 (1.36 to 11.32)	.06		3.73 (1.67 to 8.30)	.02		2.25 (1.44 to 3.52)	.0009
≥2		4.40 (2.56 to 7.57)	1.32 × 10−5		13.57 (4.94 to 37.29)	.02		5.09 (1.25 to 20.74)	.03		5.83 (3.60 to 9.46)	9.66 × 10−8
Ptrend¶			6.25 × 10−6			.01			.03			1.86 × 10−8
Types of MC1R variants	270/227			116/77			87/38			473/342			.07
1 NRHC#		1.75 (.99 to 3.10)	.05		3.54 (1.22 to 10.25)	.04		2.55 (.66 to 9.84)	.16		2.08 (1.28 to 3.40)	.003
1 RHC**		2.04 (1.08 to 3.85)	.03		4.36 (1.21 to 15.75)	.09		4.74 (1.41 to 15.99)	.02		2.59 (1.47 to 4.57)	.002
≥ 2 NRHC		2.74 (1.31 to 5.77)	.01		8.00 (2.33 to 27.41)	.03		1.86 (.55 to 6.28)	.33		3.62 (1.90 to 6.89)	.0002
1 RHC, 1 NRHC		4.43 (2.31 to 8.49)	4.9 × 10−5		11.13 (3.44 to 35.97)	.01		6.12 (1.03 to 36.28)	.04		6.24 (3.43 to 11.34)	9.97 × 10−8
≥2 RHC		7.73 (3.61 to 16.58)	7.6 × 10−5					7.72 (1.30 to 45.75)	.03		11.78 (5.34 to 26.02)	2.89 × 10−7

^*The association of each MC1R variable (individual MC1R variants, any MC1R variant, number of MC1R variants, types of MC1R variants) with melanoma risk was estimated by using homozygosity for the MC1R consensus sequence as the reference category. CI = confidence interval; OR = odds ratio; NRHC = nonred hair color; RHC = red hair color.

^†The number of GenoMEL participants contributing to the analysis of a given MC1R variable (individual MC1R variants, any MC1R variant, number of MC1R variants, types of MC1R variants) that were affected with melanoma and their unaffected relatives.

^‡The odds ratios and 95% confidence intervals are measures of association between melanoma risk and MC1R variants. These odds ratios were estimated by the generalized estimating equations method using a logit link function and an exchangeable correlation matrix to take into account the correlations among the family members’ melanoma affection status (affected, unaffected). The odds ratios shown in this table are adjusted for age, sex, and geographic locales.

^§P values for the two-sided generalized score test of association between melanoma risk and MC1R variants.

^║P values for the two-sided generalized score test of homogeneity of the association of MC1R variants with melanoma risk among different geographic locales.

^¶P values for the two-sided trend test which tests for a change in melanoma risk with a linear increase in the number of MC1R variants (0, 1, ≥2).

^#Nonsynonymous MC1R variants that were not RHC variants.

^**RHC variants included R151C, R160W, D294H, and D84E.