Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk

Abstract

Genome-wide association studies (GWASs) have mainly focused on top significant single nucleotide polymorphisms (SNPs), most of which did not have clear biological functions but were just surrogates for unknown causal variants. Studying SNPs with modest association and putative functions in biologically plausible pathways has become one complementary approach to GWASs. To unravel the key roles of mitogen-activated protein kinase (MAPK) pathways in cutaneous melanoma (CM) risk, we re-evaluated the associations between 47 818 SNPs in 280 MAPK genes and CM risk using our published GWAS dataset with 1804 CM cases and 1026 controls. We initially found 105 SNPs with P ≤ 0.001, more than expected by chance, 26 of which were predicted to be putatively functional SNPs. The risk associations with 16 SNPs around DUSP14 (rs1051849) and a previous reported melanoma locus MAFF/PLA2G6 (proxy SNP rs4608623) were replicated in the GenoMEL dataset (P < 0.01) but failed in the Australian dataset. Meta-analysis showed that rs1051849 in the 3' untranslated regions of DUSP14 was associated with a reduced risk of melanoma (odds ratio = 0.89, 95% confidence interval: 0.82-0.96, P = 0.003, false discovery rate = 0.056). Further genotype-phenotype correlation analysis using the 90 HapMap lymphoblastoid cell lines from Caucasians showed significant correlations between two SNPs (rs1051849 and rs4608623) and messenger RNA expression levels of DUSP14 and MAFF (P = 0.025 and P = 0.010, respectively). Gene-based tests also revealed significant SNPs were over-represented in MAFF, PLA2G6, DUSP14 and other 16 genes. Our results suggest that functional SNPs in MAPK pathways may contribute to CM risk. Further studies are warranted to validate our findings.

Fig. 1.

Regional association plots in the 20kb neighborhood of DUSP14 (chr 17) and PLA2G6/MAFF (chr 22). The left-hand y-axis shows the association P value of individual SNPs in the discovery dataset, which is plotted as −log10 (P) against chromosomal basepair position. The right-hand y-axis shows the recombination rate estimated from the HapMap CEU population.

Fig. 2.

Analysis of DUSP14 and MAFF expression levels by genotypes of rs1051849 and rs4608623 in 90 HapMap lymphoblastoid cell lines from Caucasians (three with missing data). Consistent with their association results in Table III, genotypes AG + GG of rs1051849 were associated with low mRNA expression levels of DUSP14, compared with that of the AA genotype (P = 0.025); for SNP rs4608623, GG genotype carriers had lower MAFF expression levels than those with TT + TG genotypes (P = 0.010). The y-axis is the normalized gene expression levels. The box represents the central 50% of the data or the interquartile range. The lower edge of the box plot is the first quartile or 25th percentile. The upper edge of the box plot is the third quartile or 75th percentile. The line in the box is the median value. The ends of the vertical lines extend to minimum and maximum unless these values exceed 1.5 × interquartile range.