Translational Sciences Section, Jonsson Comprehensive Cancer Center, School of Nursing, University of California, Los Angeles, CA.
Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA.
Menopause. 2019 Jul;26(7):771-780. doi: 10.1097/GME.0000000000001301.
Genetic variants in metabolic signaling pathways may interact with lifestyle factors, such as dietary fatty acids, influencing postmenopausal colorectal cancer (CRC) risk, but these interrelated pathways are not fully understood.
In this study, we examined 54 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I/insulin traits and their signaling pathways and lifestyle factors in relation to postmenopausal CRC, using data from 6,539 postmenopausal women in the Women's Health Initiative Harmonized and Imputed Genome-Wide Association Studies. By employing a two-stage random survival forest analysis, we evaluated the SNPs and lifestyle factors by ranking them according to their predictive value and accuracy for CRC.
We identified four SNPs (IRS1 rs1801123, IRS1 rs1801278, AKT2 rs3730256, and AKT2 rs7247515) and two lifestyle factors (age and percentage calories from saturated fatty acids) as the top six most influential predictors for CRC risk. We further examined interactive effects of those factors on cancer risk. In the individual SNP analysis, no significant association was observed, but the combination of the four SNPs, age, and percentage calories from saturated fatty acid (≥11% per day) significantly increased the risk of CRC in a gene and lifestyle dose-dependent manner.
Our findings provide insight into gene-lifestyle interactions and will enable researchers to focus on individuals with risk genotypes to promote intervention strategies. Our study suggests the careful use of data on potential genetic targets in clinical trials for cancer prevention to reduce the risk for CRC in postmenopausal women.
代谢信号通路中的遗传变异可能与生活方式因素（如膳食脂肪酸）相互作用，影响绝经后结直肠癌（CRC）的风险，但这些相互关联的途径尚未完全阐明。
在这项研究中，我们使用来自妇女健康倡议（Women's Health Initiative）的 6539 名绝经后妇女的综合和推断全基因组关联研究的数据，研究了与胰岛素样生长因子-I/胰岛素特征及其信号通路和生活方式因素相关的 54 个单核苷酸多态性（SNP）与绝经后 CRC 的关系。通过采用两阶段随机生存森林分析，我们根据 SNP 和生活方式因素对 CRC 的预测价值和准确性进行排序，对它们进行了评估。
我们确定了四个 SNP（IRS1 rs1801123、IRS1 rs1801278、AKT2 rs3730256 和 AKT2 rs7247515）和两个生活方式因素（年龄和饱和脂肪酸卡路里百分比）为 CRC 风险的前六个最具影响力的预测因素。我们进一步研究了这些因素对癌症风险的相互作用效应。在个体 SNP 分析中，未观察到显著相关性，但四个 SNP、年龄和饱和脂肪酸卡路里百分比（每天≥11%）的组合以基因和生活方式剂量依赖的方式显著增加了 CRC 的风险。
我们的研究结果提供了对基因-生活方式相互作用的深入了解，并将使研究人员能够关注具有风险基因型的个体，以促进干预策略的实施。我们的研究表明，在临床试验中预防癌症时，应谨慎使用潜在遗传靶标数据，以降低绝经后妇女患 CRC 的风险。
