A Customized Pigmentation SNP Array Identifies a Novel SNP Associated with Melanoma Predisposition in the SLC45A2 Gene
A Customized Pigmentation SNP Array Identifies a Novel SNP Associated with Melanoma Predisposition in the SLC45A2 Gene
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DOI：
10.1371/journal.pone.0019271
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发表时间：
2011-04-29
期刊：
影响因子：
3.7
通讯作者：
Ribas, Gloria
中科院分区：
文献类型：
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作者：
Ibarrola-Villava, Maider;Fernandez, Lara P.;Ribas, Gloria
由于恶性黑色素瘤（MM）的发病率反映了皮肤颜色和紫外线暴露之间的相互作用，涉及色素沉着和晒黑对紫外线的反应的基因变异可能与MM的易感性有关。在这项研究中，属于色素沉着途径的65个基因区域中的363个SNP已成功地使用SNP阵列进行基因分型。在发现阶段I中分析了590例MM病例和507例对照。基于0.01的p值阈值，鉴定了10个候选SNP。其中两个，rs35414（SLC 45 A2）和rs 2069398（SILV/CKD 2），在保守Bonferroni校正后具有统计学显著性。在一个独立的西班牙系列（624例MM病例和789例对照）中进一步测试了最佳的六个SNP。发现位于SLC 45 A2基因上的新SNP（rs35414）与I期和II期黑素瘤显著相关（P < 0.0001）。在研究的第二阶段，其他五个SNP都没有重复。然而，当考虑整个DNA收集（1214例MM病例和1296例对照）时，TYR、SILV/CDK 2和ADAMTS 20基因中的三个SNP（分别为rs 17793678、rs 2069398和rs 1510521）具有总体p值< 0.05。SLC 45 A2和SILV/CDK 2变体都表现为保护性等位基因，而TYR和ADAMTS 20变体似乎起着风险等位基因的作用。当这四种变体一起考虑时，检测到累积效应。此外，在MC 1 R（一种众所周知的低转移率黑色素瘤易感基因）中携带两个或更多突变的个体，如果同时携带SLC 45 A2保护性变体，MM风险降低。据我们所知，这是迄今为止对西班牙散发性MM病例进行的最大规模的研究。
As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P < 0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value < 0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date.