Translational Sciences Section, Jonsson Comprehensive Cancer Center, School of Nursing, University of California, Los Angeles, Los Angeles, California.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Cancer Prev Res (Phila). 2019 Jan;12(1):31-42. doi: 10.1158/1940-6207.CAPR-18-0180. Epub 2018 Oct 16.
Insulin resistance (IR)-related genetic variants are possibly associated with breast cancer, and the gene-phenotype-cancer association could be modified by lifestyle factors including obesity, physical inactivity, and high-fat diet. Using data from postmenopausal women, a population highly susceptible to obesity, IR, and increased risk of breast cancer, we implemented a genome-wide association study (GWAS) in two steps: (1) GWAS meta-analysis of gene-environmental (i.e., behavioral) interaction (GE) for IR phenotypes (hyperglycemia, hyperinsulinemia, and homeostatic model assessment-insulin resistance) and (2) after the GE GWAS meta-analysis, the identified SNPs were tested for their associations with breast cancer risk in overall or subgroup population, where the SNPs were identified at genome-wide significance. We found 58 loci (55 novel SNPs; 5 index SNPs and 6 SNPs, independent of each other) that are associated with IR phenotypes in women overall or women stratified by obesity, physical activity, and high-fat diet; among those 58 loci, 29 (26 new loci; 2 index SNPs and 2 SNPs, independently) were associated with postmenopausal breast cancer. Our study suggests that a number of newly identified SNPs may have their effects on glucose intolerance by interplaying with obesity and other lifestyle factors, and a substantial proportion of these SNPs' susceptibility can also interact with the lifestyle factors to ultimately influence breast cancer risk. These findings may contribute to improved prediction accuracy for cancer and suggest potential intervention strategies for those women carrying genetic risk that will reduce their breast cancer risk.
胰岛素抵抗（IR）相关的遗传变异可能与乳腺癌有关，基因-表型-癌症的关联可能受到生活方式因素的影响，包括肥胖、身体活动不足和高脂肪饮食。利用绝经后妇女的数据，这些女性易发生肥胖、IR 和乳腺癌风险增加，我们实施了一项两步的全基因组关联研究（GWAS）：（1）对 IR 表型（高血糖、高胰岛素血症和稳态模型评估胰岛素抵抗）的基因-环境（即行为）相互作用（GE）进行 GWAS 荟萃分析；（2）在 GE GWAS 荟萃分析后，对与乳腺癌风险相关的 SNPs 进行总体或亚组人群的检测，这些 SNPs 在全基因组范围内具有显著意义。我们发现了 58 个与女性整体或根据肥胖、身体活动和高脂肪饮食分层的女性的 IR 表型相关的位点（55 个新的 SNPs；5 个索引 SNPs 和 6 个彼此独立的 SNPs）；在这 58 个位点中，有 29 个（26 个新的位点；2 个索引 SNPs 和 2 个彼此独立的 SNPs）与绝经后乳腺癌相关。我们的研究表明，许多新鉴定的 SNPs 可能通过与肥胖和其他生活方式因素相互作用对葡萄糖不耐受产生影响，而这些 SNPs 易感性的很大一部分也可以与生活方式因素相互作用，最终影响乳腺癌风险。这些发现可能有助于提高对癌症的预测准确性，并为携带遗传风险的女性提供潜在的干预策略，从而降低她们的乳腺癌风险。
