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. 2018 Sep;42(6):571-586.
doi: 10.1002/gepi.22137. Epub 2018 Jul 3.

Hierarchical modeling of melanocortin 1 receptor variants with skin cancer risk

Amit D Joshi  1   2   3 , Xin Li  4 , Peter Kraft  1   2 , Jiali Han  4   5
Affiliations

Hierarchical modeling of melanocortin 1 receptor variants with skin cancer risk

Amit D Joshi et al. Genet Epidemiol. 2018 Sep.

Abstract

The human MC1R gene is highly polymorphic among lightly pigmented populations, and several variants in the MC1R gene have been associated with increased risk of both melanoma and nonmelanoma skin cancers. The functional consequences of MC1R gene variants have been studied in vitro and in vivo in postulated causal pathways, such as G-protein-coupled signaling transduction, pigmentation, immune response, inflammatory response, cell proliferation, and extracellular matrix adhesion. In a case-control study nested within the Nurses' Health Study, we utilized hierarchical modeling approaches, incorporating quantitative information from these functional studies, to examine the association between particular MC1R alleles and the risk of skin cancers. Different prior matrices were constructed according to the phenotypic associations in controls, cell surface expression, and enzymatic kinetics. Our results showed the parameter variance estimates of each single nucleotide polymorphism (SNP) were smaller when using a hierarchical modeling approach compared to standard multivariable regression. Estimates of second-level parameters gave information about the relative importance of MC1R effects on different pathways, and odds ratio estimates changed depending on prior models (e.g., the change ranged from -21% to 7% for melanoma risk assessment). In addition, the estimates of prior model hyperparameters in the hierarchical modeling approach allow us to determine the relevance of individual pathways on the risk of each of the skin cancer types. In conclusion, hierarchical modeling provides a useful analytic approach in addition to the widely used conventional models in genetic association studies that can incorporate measures of allelic function.

Keywords: MC1R; functional variants; hierarchical modeling; pigmentation; skin cancer.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Beta estimates from the conventional, prior, and hierarchical models for association between MC1R variants and risk of melanoma.
Figure 2.
Figure 2.
Beta estimates from the conventional, prior, and hierarchical models for association between MC1R variants and risk of SCC.
Figure 3.
Figure 3.
Beta estimates from the conventional, prior, and hierarchical models for association between MC1R variants and risk of BCC.
Figure 4.
Figure 4.
Standard error (se) of the beta estimates from the conventional and hierarchical models for the association between MC1R variants and risk of melanoma.
Figure 5.
Figure 5.
Standard error (se) of the beta estimates from the conventional and hierarchical models for the association between MC1R variants and risk of SCC.
Figure 6.
Figure 6.
Standard error (se) of the beta estimates from the conventional and hierarchical models for the association between MC1R variants and risk of BCC.
See this image and copyright information in PMC

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References

    1. 2017. Cancer facts and figures, American Cancer Society; Atlanta.
    1. Aragaki CC, Greenland S, Probst-Hensch N, Haile RW. 1997. Hierarchical modeling of gene-environment interactions: estimating NAT2 genotype-specific dietary effects on adenomatous polyps. Cancer Epidemiol Biomarkers Prev 6(5):307–14. - PubMed
    1. Bastiaens MT, ter Huurne JA, Kielich C, Gruis NA, Westendorp RG, Vermeer BJ, Bavinck JN. 2001. Melanocortin-1 receptor gene variants determine the risk of nonmelanoma skin cancer independently of fair skin and red hair. Am J Hum Genet 68(4):884–94. - PMC - PubMed
    1. Beaumont KA, Newton RA, Smit DJ, Leonard JH, Stow JL, Sturm RA. 2005. Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk. Hum Mol Genet 14(15):2145–54. - PubMed
    1. Box NF, Duffy DL, Irving RE, Russell A, Chen W, Griffyths LR, Parsons PG, Green AC, Sturm RA. 2001. Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma. J Invest Dermatol 116(2):224–9. - PubMed

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