Abstract
To evaluate the association of melanocortin 1 receptor gene (MC1R) variants with melanoma risk in a Latvian population, the MC1R gene was sequenced in 200 melanoma patients and 200 control persons. A functional study of previously uncharacterized, rare MC1R variants was also performed. In total, 26 different MC1R variants, including two novel variants Val165Ile and Val188Ile, were detected. The highest risk of melanoma was associated with the Arg151Cys variant (odds ratio (OR) 4.47, 95% confidence interval (CI) 2.19-9.14, P<0.001). A gene dosage effect was observed, with melanoma risk for carriers of two variants being twice (OR 3.98, 95% CI 2.15-7.38, P<0.001) that of carriers of one variant (OR 1.98, 95% CI 1.26-3.11, P=0.003). After stratification according to the pigmentation phenotype, the risk of melanoma remained in groups with otherwise protective phenotypes. Functional analyses of eight previously uncharacterized MC1R variants revealed that a subset of them is functionally relevant. Our results support the contribution of MC1R variants to a genetic predisposition to melanoma in Latvia.
Highlights
To evaluate the association of melanocortin 1 receptor gene (MC1R) variants with melanoma risk in a Latvian population, the MC1R gene was sequenced in 200 melanoma patients and 200 control persons
The frequency of MC1R variants in the control population (58%) was intermediate compared with the frequencies reported in North European and Mediterranean populations, which were highest in Britain/Ireland and lowest in Greece [29]
The influence of MC1R variants on genetic predisposition to melanoma has been investigated in many association studies (10,13,16,30e35)
Summary
To evaluate the association of melanocortin 1 receptor gene (MC1R) variants with melanoma risk in a Latvian population, the MC1R gene was sequenced in 200 melanoma patients and 200 control persons. Most common MC1R variants have been investigated in relation to their effects on receptor functional activity. Results from these studies demonstrated that MC1R with RHC variants have, to different extents, reduced receptor functional activity in a cyclic adenosine monophosphate (cAMP) assay (17e20) and/or reduced cell surface expression [17,21]. Little is known about the functional activity of other less common MC1R variants This is the first study that investigates the prevalence and type of MC1R variants among melanoma patients and control persons in a Latvian population and, to our knowledge, in the Eastern European region. We performed functional analyses of previously uncharacterized rare MC1R variants that were detected in our study population
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