Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
PLoS One. 2022 Apr 7;17(4):e0266481. doi: 10.1371/journal.pone.0266481. eCollection 2022.
Platelet Endothelial Aggregation Receptor 1 (PEAR1) modulates angiogenesis and platelet contact-induced activation, which play a role in the pathogenesis of colorectal cancer. We therefore tested the association of incident colorectal cancer and genetic and epigenetic variability in PEAR1 among 2532 randomly recruited participants enrolled in the family-based Flemish Study on Environment, Genes and Health Outcomes (51.2% women; mean age 44.8 years). All underwent genotyping of rs12566888 located in intron 1 of the PEAR1 gene; in 926 participants, methylation at 16 CpG sites in the PEAR1 promoter was also assessed. Over 18.1 years (median), 49 colorectal cancers occurred, all in different pedigrees. While accounting for clustering of risk factors within families and adjusting for sex, age, body mass index, the total-to-HDL cholesterol ratio, serum creatinine, plasma glucose, smoking and drinking, use of antiplatelet and nonsteroidal anti-inflammatory drug, the hazard ratio of colorectal cancer contrasting minor-allele (T) carriers vs. major-allele (GG) homozygotes was 2.17 (95% confidence interval, 1.18-3.99; P = 0.013). Bootstrapped analyses, from which we randomly excluded from two to nine cancer cases, provided confirmatory results. In participants with methylation data, we applied partial least square discriminant analysis (PLS-DA) and identified two methylation sites associated with higher colorectal cancer risk and two with lower risk. In-silico analysis suggested that methylation of the PEAR1 promoter at these four sites might affect binding of transcription factors p53, PAX5, and E2F-1, thereby modulating gene expression. In conclusion, our findings suggest that genetic and epigenetic variation in PEAR1 modulates the risk of colorectal cancer in white Flemish. To what extent, environmental factors as exemplified by our methylation data, interact with genetic predisposition and modulate penetrance of colorectal cancer risk is unknown.
血小板内皮聚集受体 1（PEAR1）调节血管生成和血小板接触诱导的激活，这在结直肠癌的发病机制中发挥作用。因此，我们在 2532 名随机招募的、参加基于家庭的佛兰芒环境、基因和健康结果研究（51.2%为女性；平均年龄 44.8 岁）的参与者中，检测了 PEAR1 中与结直肠癌发病相关的遗传和表观遗传变异性。所有参与者均接受了位于 PEAR1 基因内含子 1 中的 rs12566888 基因分型；在 926 名参与者中，还评估了 PEAR1 启动子中 16 个 CpG 位点的甲基化。在 18.1 年（中位数）的随访中，发生了 49 例结直肠癌，均发生在不同的家系中。在考虑到家族内危险因素的聚集并调整了性别、年龄、体重指数、总胆固醇与高密度脂蛋白胆固醇比值、血清肌酐、血浆葡萄糖、吸烟和饮酒、使用抗血小板和非甾体抗炎药后，与 minor-allele（T）携带者相比，major-allele（GG）纯合子的结直肠癌风险的风险比为 2.17（95%置信区间，1.18-3.99；P=0.013）。bootstrap 分析（我们从中随机排除了 2 到 9 个癌症病例）提供了证实性结果。在有甲基化数据的参与者中，我们应用偏最小二乘判别分析（PLS-DA），并鉴定出与更高的结直肠癌风险相关的两个甲基化位点和与更低的风险相关的两个甲基化位点。在计算机模拟分析中，提示这些四个位点的 PEAR1 启动子的甲基化可能影响转录因子 p53、PAX5 和 E2F-1 的结合，从而调节基因表达。总之，我们的研究结果表明，PEAR1 的遗传和表观遗传变异可调节佛兰芒白人结直肠癌的发病风险。在多大程度上，我们的甲基化数据所代表的环境因素与遗传易感性相互作用，并调节结直肠癌风险的外显率尚不清楚。
