Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Mol Carcinog. 2020 Aug;59(8):930-939. doi: 10.1002/mc.23208. Epub 2020 May 5.
Because the peroxisome proliferator-activated receptor (PPAR) signaling pathway is involved in development and progression of pancreatic cancer, we investigated associations between genetic variants of the PPAR pathway genes and pancreatic cancer risk by using three published genome-wide association study datasets including 8477 cases and 6946 controls of European ancestry. Expression quantitative trait loci (eQTL) analysis was also performed for correlations between genotypes of the identified genetic variants and messenger RNA (mRNA) expression levels of their genes by using available databases of the 1000 Genomes, TCGA, and GTEx projects. In the single-locus logistic regression analysis, we identified 1141 out of 17 532 significant single-nucleotide polymorphisms (SNPs) in 112 PPAR pathway genes. Further multivariate logistic regression analysis identified three independent, potentially functional loci (rs12947620 in MED1, rs11079651 in PRKCA, and rs34367566 in PRKCB) for pancreatic cancer risk (odds ratio [OR] = 1.11, 95% confidence interval [CI], [1.06-1.17], P = 5.46 × 10 ; OR = 1.10, 95% CI, [1.04-1.15], P = 1.99 × 10 ; and OR = 1.09, 95% CI, [1.04-1.14], P = 3.16 × 10 , respectively) among 65 SNPs that passed multiple comparison correction by false discovery rate (< 0.2). When risk genotypes of these three SNPs were combined, carriers with 2 to 3 unfavorable genotypes (NUGs) had a higher risk of pancreatic cancer than those with 0 to 1 NUGs. The eQTL analysis showed that rs34367566 A>AG was associated with decreased expression levels of PRKCB mRNA in 373 lymphoblastoid cell lines. Our findings indicate that genetic variants of the PPAR pathway genes, particularly MED1, PRKCA, and PRKCB, may contribute to susceptibility to pancreatic cancer.
由于过氧化物酶体增殖物激活受体 (PPAR) 信号通路参与胰腺癌的发生和发展，我们通过使用三个已发表的全基因组关联研究数据集（包括 8477 例病例和 6946 例对照），研究了 PPAR 通路基因的遗传变异与胰腺癌风险之间的关联。我们还进行了表达数量性状基因座 (eQTL) 分析，以确定鉴定出的遗传变异与它们基因的信使 RNA (mRNA) 表达水平之间的相关性，使用了 1000 基因组、TCGA 和 GTEx 项目的可用数据库。在单基因座逻辑回归分析中，我们在 112 个 PPAR 通路基因中确定了 17532 个显著单核苷酸多态性 (SNP) 中的 1141 个。进一步的多变量逻辑回归分析确定了三个独立的、潜在功能性的位点（MED1 中的 rs12947620、PRKCA 中的 rs11079651 和 PRKCB 中的 rs34367566）与胰腺癌风险相关（比值比 [OR] = 1.11，95%置信区间 [CI]，[1.06-1.17]，P = 5.46 × 10-5；OR = 1.10，95%CI，[1.04-1.15]，P = 1.99 × 10-5；OR = 1.09，95%CI，[1.04-1.14]，P = 3.16 × 10-4，分别）在 65 个通过错误发现率（<0.2）进行多重比较校正的 SNP 中。当这三个 SNP 的风险基因型合并时，携带 2 到 3 个不利基因型（NUGs）的携带者比携带 0 到 1 个 NUGs 的携带者患胰腺癌的风险更高。eQTL 分析显示，rs34367566A>AG 与 373 个淋巴母细胞系中 PRKCB mRNA 的表达水平降低有关。我们的研究结果表明，PPAR 通路基因的遗传变异，特别是 MED1、PRKCA 和 PRKCB，可能与胰腺癌易感性有关。
