MRPS30 区域的遗传变异与绝经后乳腺癌风险。
Genetic variants in the MRPS30 region and postmenopausal breast cancer risk.
机构信息
Fred Hutchinson Cancer Research Center, Divisions of Public Health Sciences, and Vaccine and Infectious Diseases, 1100 Fairview Avenue North, Seattle, WA 98109-1024, USA.
出版信息
Genome Med. 2011 Jun 24;3(6):42. doi: 10.1186/gm258.
BACKGROUND
Genome-wide association studies have identified several genomic regions that are associated with breast cancer risk, but these provide an explanation for only a small fraction of familial breast cancer aggregation. Genotype by environment interactions may contribute further to such explanation, and may help to refine the genomic regions of interest.
METHODS
We examined genotypes for 4,988 SNPs, selected from recent genome-wide studies, and four randomized hormonal and dietary interventions among 2,166 women who developed invasive breast cancer during the intervention phase of the Women's Health Initiative (WHI) clinical trial (1993 to 2005), and one-to-one matched controls. These SNPs derive from 3,224 genomic regions having pairwise squared correlation (r2) between adjacent regions less than 0.2. Breast cancer and SNP associations were identified using a test statistic that combined evidence of overall association with evidence for SNPs by intervention interaction.
RESULTS
The combined 'main effect' and interaction test led to a focus on two genomic regions, the fibroblast growth factor receptor two (FGFR2) and the mitochondrial ribosomal protein S30 (MRPS30) regions. The ranking of SNPs by significance level, based on this combined test, was rather different from that based on the main effect alone, and drew attention to the vicinities of rs3750817 in FGFR2 and rs7705343 in MRPS30. Specifically, rs7705343 was included with several FGFR2 SNPs in a group of SNPs having an estimated false discovery rate < 0.05. In further analyses, there were suggestions (nominal P < 0.05) that hormonal and dietary intervention hazard ratios varied with the number of minor alleles of rs7705343.
CONCLUSIONS
Genotype by environment interaction information may help to define genomic regions relevant to disease risk. Combined main effect and intervention interaction analyses raise novel hypotheses concerning the MRPS30 genomic region and the effects of hormonal and dietary exposures on postmenopausal breast cancer risk.
背景
全基因组关联研究已经确定了几个与乳腺癌风险相关的基因组区域，但这些只能解释家族性乳腺癌聚集的一小部分。基因型与环境的相互作用可能会进一步解释这种情况，并有助于精化相关的基因组区域。
方法
我们在 Women's Health Initiative（WHI）临床试验的干预阶段（1993 年至 2005 年），对 2166 名患有浸润性乳腺癌的妇女和一对一匹配的对照中，检查了从最近的全基因组研究中选择的 4988 个单核苷酸多态性（SNP）的基因型，以及四项随机的激素和饮食干预措施。这些 SNP 来自于 3224 个基因组区域，这些区域之间的相邻区域的平方相关系数（r2）小于 0.2。乳腺癌和 SNP 的关联是通过一种统计检验来确定的，该检验综合了总体关联的证据和 SNP 与干预相互作用的证据。
结果
综合的“主要效应”和相互作用检验导致了对两个基因组区域的关注，即成纤维细胞生长因子受体 2（FGFR2）和线粒体核糖体蛋白 S30（MRPS30）区域。基于这种综合检验的 SNP 显著性水平的排序，与仅基于主要效应的排序有很大的不同，并且引起了人们对 FGFR2 中的 rs3750817 和 MRPS30 中的 rs7705343 附近区域的关注。具体来说，rs7705343 与 FGFR2 中的几个 SNP 一起，被包括在一个估计错误发现率<0.05 的 SNP 组中。在进一步的分析中，有一些迹象表明（名义 P<0.05），激素和饮食干预的危险比随着 rs7705343 的少数等位基因数量的变化而变化。
结论
基因型与环境的相互作用信息可能有助于确定与疾病风险相关的基因组区域。综合的主要效应和干预相互作用分析提出了关于 MRPS30 基因组区域和激素和饮食暴露对绝经后乳腺癌风险的影响的新假设。
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