Melanocortin 1 receptor variants and skin cancer risk

Han, Jiali; Kraft, Peter; Colditz, Graham A.; Wong, Jason; Hunter, David J.

doi:10.1002/ijc.22074

Cited by 124 publications

(164 citation statements)

References 45 publications

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“…At the level of individual variants, in contrast to earlier studies, in the present investigation the R151C variant was not associated with a statistically significant increased risk of BCC. 7,17 However, our data showed a significant association of the R163Q, a non-RHC variant along with the R160W, with increased risk of the disease as reported previously in a study on female nurses. 7 An estimate of haplotype frequency and relative linkage of different polymorphisms within the gene showed that the risk of BCC emanated from individual variants and not the haplotypes per se.…”

Section: Discussionsupporting

confidence: 87%

“…The genetic association studies are in general linked with poor reproducibility, however, our investigation was based on a prior hypothesis and results are in accord with an earlier study. 7 The proportion of BCC attributable to MC1R variants as per our data was fairly high when compared with population based contribution of disease-segregating germ-line mutations in high penetrance genes like BCRA1 and 2 in breast cancer, CDKN2A in melanoma and patched in Gorlin syndrome. 21,25 The MC1R variants within the gene reportedly alter the penetrance of the germ-line CDKN2A mutations and influence the frequency of somatic B-RAF mutations in melanoma.…”

Section: Discussionmentioning

confidence: 48%

“…This one case was homozygous for both polymorphisms.-2 Present in 1 case; 2 other cases and 1 control had no other variant.-3 Present in both cases and 1 control.- 4 Present only in the case.-5 Present in both controls.- 6 One control contained V92M and T314T and the other control had only T314T.- 7 Three polymorphisms in addition to one nucleotide-insertion.- 8 One case contained V60L; 1 case and 1 control had R160W polymorphism; remaining case and controls contained no other variants. increased risk of the BCC contained variants individually associated with risk, namely R160W (OR 1.78; 95% CI 1.11-2.86) and R163Q (OR: 2.08; 95% CI: 1.01-4.30).…”

Section: Resultsmentioning

confidence: 93%

“…[3][4][5] Many of the polymorphisms in the genes involved in these processes, as a corollary, modulate the risk and contribute to the inter-individual differences in susceptibility to the skin cancers including basal cell carcinoma of skin (BCC). [6][7][8][9] The G-protein coupled Melanocortin receptor 1 (MC1R) is a pivotal component in the pathway involved in the production of melanin in melanocytes. 10 Activation of MC1R by a-MSH (a-melanocyte-stimulating hormone) leads to increased cellular cAMP.…”

mentioning

confidence: 99%

“…[14][15][16] Several studies have reported association between variants in the MC1R gene and risk of BCC including genotype-host factor interactions. 7,17,18 None of the investigations so far has explored the interaction between MC1R variants and risk genotypes in DNA repair genes. In this report, based on 529 BCC cases and 533 controls, we have investigated the effect of variants in the entire MC1R gene and their interactions with host factors like skin complexion and skin response to sun-exposure.…”

mentioning

confidence: 99%

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MC1R variants associated susceptibility to basal cell carcinoma of skin: Interaction with host factors and XRCC3 polymorphism

Scherer

Bermejo

Rudnai

et al. 2007

Intl Journal of Cancer

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The variants within the human melanocortin 1 receptor (MC1R) gene are associated with an increased risk of different skin cancers. In this study, we genotyped by direct sequencing, 529 cases of basal cell carcinoma of the skin (BCC) and 533 healthy controls for polymorphisms in the entire MC1R gene. In addition to 10 common polymorphisms, we detected 23 rare variants in the gene. The presence of any nonsynonymous MC1R variant was associated with an increased risk in the carriers (odds ratio OR 1.66, 95% confidence interval CI 1.28-2.14) corresponding to a population attributable fraction of about 27%. The odds ratio for the risk in the carriers of 2 MC1R variants was 2.69 (95% CI 1.77-4.08). The risk of BCC in the carriers of MC1R variants with fair complexion was almost twice as much as in the corresponding noncarriers. The carriers of the R163Q variant with a medium skin complexion were at a 3-fold higher risk than the noncarrier counterparts. The interaction, of effect on the BCC risk, between the MC1R variants and types of skin response to sun exposure was greater than multiplicative. We also observed a multiplicative interaction of risk due to the MC1R variants and the common allele (high risk) of the T241M polymorphism in the XRCC3 gene. Our data confirmed the status of the nonsynonymous MC1R variants as independent genetic risk factors for BCC. However, the mechanism through which the variants influence the risk likely involves complex interactions with other genetic and host risk factors. ' 2007 Wiley-Liss, Inc.Key words: MC1R; polymorphisms; basal cell carcinoma; complexion; interactions Skin pigmentation and DNA repair constitute intrinsic mechanisms evolved to prevent skin carcinogenesis. 1,2 Skin pigmentation, which inhibits DNA damage, manifests a preventive and DNA repair a corrective mechanism. A number of genes involved both in DNA repair and pigmentation, contingent to environmental and other historical selection constraints, are highly polymorphic. [3][4][5] Many of the polymorphisms in the genes involved in these processes, as a corollary, modulate the risk and contribute to the inter-individual differences in susceptibility to the skin cancers including basal cell carcinoma of skin (BCC). [6][7][8][9] The G-protein coupled Melanocortin receptor 1 (MC1R) is a pivotal component in the pathway involved in the production of melanin in melanocytes. 10 Activation of MC1R by a-MSH (a-melanocyte-stimulating hormone) leads to increased cellular cAMP. The levels of cAMP, through tyrosinase, control the switch over of synthesis from pheomelanin to photo protective eumelanin. 11 The gene encoding MC1R is highly polymorphic and many variants are associated with an increased risk of skin cancers. 12,13 More than 60 nonconservative variants of the receptor are known and at least 3 frequent variants are strongly associated with high risk phenotypes of red hair and fair skin (RHC alleles; R151C, R160W and D294H) in Caucasians. [14][15][16] Several studies have reported association between variants in the MC1R...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 48%

Section: Resultsmentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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MC1R variants associated susceptibility to basal cell carcinoma of skin: Interaction with host factors and XRCC3 polymorphism

Scherer

Bermejo

Rudnai

et al. 2007

Intl Journal of Cancer

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Genetic determinants of hair color and parkinson's disease risk

Gao

Simon

Han

et al. 2009

Annals of Neurology

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107

111

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A history of melanoma is associated with increased risks of Parkinson's disease (PD). We examined whether hair color, one of the most important phenotypes of pigmentation and a risk factor for melanoma, was associated with PD risk in the Health Professionals Follow-up Study (HPFS) (1986)(1987)(1988)(1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002) and the Nurses' Health Study (NHS) . We included 38,641 men and 93,661 women, free of PD at baseline. Information on natural hair color in early adulthood (age 18-21 years) was assessed via a questionnaire. We also conducted a case-control study (298 PD cases) nested in these two cohorts to examine the association between the melanocortin1-receptor (MC1R) Arg151Cys polymorphism and PD risk. Relative risks (RRs) were estimated using Cox proportional hazards models in the cohort analyses and conditional logistic regression in the nested case-control study. Log RRs from the two cohorts were pooled using a fixed-effects model. PD risk increased with decreasing darkness of hair color. Pooled RRs for PD were 1(ref.), 1.40, 1.61, and 1.93 (95% CI: 1.1, 3.4) for black, brown, blonde, and red hair, after adjusting for age, smoking, ethnicity and other covariates. The associations between hair color and PD were particularly strong for younger onset of PD (<70 y) (adjusted RR for red vs. black hair=3.83; 95% CI: 1.7, 8.7). In the case-control study, participants with Cys/Cys genotype, which was associated with red hair, had a higher PD risk, relative to the Arg/Arg genotype (adjusted RR=3.15; 95% CI: 1.1, 9.4). These findings suggest a potential role of pigmentation in PD.An increased risk of Parkinson's disease (PD) among individuals with melanoma has been reported in a few studies, 1 -4 but not all.5 Conversely, individuals with PD seem to have an increased risk of melanoma,6 and questions have been raised over whether the association was, at one point, attributed to an adverse effect of PD medicines.7 -9Hair color, one of the most important phenotypes of pigmentation, is largely determined by the quantity, quality, and distribution of the melanin and individuals with red hair have an approximately three-fold higher risk of melanoma than those with black hair. 10 , 11 We, therefore, examined the relationship between hair color and PD risk among 131,821 US men and women who participated in the two large ongoing prospective cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Study (NHS). In a secondary analysis, we examined the associations between the melanocortin 1 receptor (MC1R) Arg151Cys polymorphism, an important genetic determinant of hair color and risk factor for melanoma, 10 , 12 -18 and PD risk in a prospective case-control study nested within the HPFS and NHS cohorts. Ascertainment of PDWe identified new PD cases by biennial self-reported questionnaires.21 , 22 We then asked the treating neurologists to complete a questionnaire to confirm the diagnosis of PD or to send a copy of the medical record...

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Explicit Modeling of Ancestry Improves Polygenic Risk Scores and BLUP Prediction

Chen

Han

Hunter

et al. 2015

Genetic Epidemiology

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Polygenic prediction using genome-wide SNPs can provide high prediction accuracy for complex traits. Here, we investigate the question of how to account for genetic ancestry when conducting polygenic prediction. We show that the accuracy of polygenic prediction in structured populations may be partly due to genetic ancestry. However, we hypothesized that explicitly modeling ancestry could improve polygenic prediction accuracy. We analyzed three GWAS of hair color, tanning ability and basal cell carcinoma (BCC) in European Americans (sample size from 7,440 to 9,822) and considered two widely used polygenic prediction approaches: polygenic risk scores (PRS) and Best Linear Unbiased Prediction (BLUP). We compared polygenic prediction without correction for ancestry to polygenic prediction with ancestry as a separate component in the model. In 10-fold cross-validation using the PRS approach, the R2 for hair color increased by 66% (0.0456 to 0.0755; p<10−16), the R2 for tanning ability increased by 123% (0.0154 to 0.0344; p<10−16) and the liability-scale R2 for BCC increased by 68% (0.0138 to 0.0232; p<10−16) when explicitly modeling ancestry, which prevents ancestry effects from entering into each SNP effect and being over-weighted. Surprisingly, explicitly modeling ancestry produces a similar improvement when using the BLUP approach, which fits all SNPs simultaneously in a single variance component and causes ancestry to be underweighted. We validate our findings via simulations, which show that the differences in prediction accuracy will increase in magnitude as sample sizes increase. In summary, our results show that explicitly modeling ancestry can be important in both PRS and BLUP prediction.

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Melanocortin 1 receptor variants and skin cancer risk

Cited by 124 publications

References 45 publications

MC1R variants associated susceptibility to basal cell carcinoma of skin: Interaction with host factors and XRCC3 polymorphism

MC1R variants associated susceptibility to basal cell carcinoma of skin: Interaction with host factors and XRCC3 polymorphism

Genetic determinants of hair color and parkinson's disease risk

Explicit Modeling of Ancestry Improves Polygenic Risk Scores and BLUP Prediction

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