Sánchez-Maldonado José Manuel, Collado Ricardo, Cabrera-Serrano Antonio José, Ter Horst Rob, Gálvez-Montosa Fernando, Robles-Fernández Inmaculada, Arenas-Rodríguez Verónica, Cano-Gutiérrez Blanca, Bakker Olivier, Bravo-Fernández María Inmaculada, García-Verdejo Francisco José, López José Antonio López, Olivares-Ruiz Jesús, López-Nevot Miguel Ángel, Fernández-Puerta Laura, Cózar-Olmo José Manuel, Li Yang, Netea Mihai G, Jurado Manuel, Lorente Jose Antonio, Sánchez-Rovira Pedro, Álvarez-Cubero María Jesús, Sainz Juan
Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain.
Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain.
Cancers (Basel). 2022 May 12;14(10):2376. doi: 10.3390/cancers14102376.
In this study, we have evaluated whether 57 genome-wide association studies (GWAS)-identified common variants for type 2 diabetes (T2D) influence the risk of developing prostate cancer (PCa) in a population of 304 Caucasian PCa patients and 686 controls. The association of selected single nucleotide polymorphisms (SNPs) with the risk of PCa was validated through meta-analysis of our data with those from the UKBiobank and FinnGen cohorts, but also previously published genetic studies. We also evaluated whether T2D SNPs associated with PCa risk could influence host immune responses by analysing their correlation with absolute numbers of 91 blood-derived cell populations and circulating levels of 103 immunological proteins and 7 steroid hormones. We also investigated the correlation of the most interesting SNPs with cytokine levels after in vitro stimulation of whole blood, peripheral mononuclear cells (PBMCs), and monocyte-derived macrophages with LPS, PHA, Pam3Cys, and . The meta-analysis of our data with those from six large cohorts confirmed that each copy of the , , , , and alleles significantly decreased risk of developing PCa ( = 3.70 × 10, = 9.39 × 10, = 5.04 × 10, = 1.19 × 10, and = 1.66 × 10, respectively). Although it was not statistically significant after correction for multiple testing, we also found that the and SNPs associated with the risk of developing PCa ( = 8.49 × 10 and 0.004). Interestingly, we found that the protective effect attributed to the locus could be mediated by the SULT1A1 protein ( = 0.00030), an arylsulfotransferase that catalyzes the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. In addition to these results, eQTL analysis revealed that the , , , , and SNPs influence the risk of PCa through the modulation of mRNA levels of their respective genes in whole blood and/or liver. These results confirm that functional TD2-related variants influence the risk of developing PCa, but also highlight the need of additional experiments to validate our functional results in a tumoral tissue context.
在本研究中,我们评估了57个全基因组关联研究(GWAS)鉴定出的2型糖尿病(T2D)常见变异是否会影响304名白种人前列腺癌(PCa)患者和686名对照人群患前列腺癌的风险。通过对我们的数据与英国生物银行(UKBiobank)和芬兰基因队列(FinnGen)的数据以及先前发表的基因研究进行荟萃分析,验证了所选单核苷酸多态性(SNP)与PCa风险的关联。我们还通过分析它们与91种血液来源细胞群体的绝对数量以及103种免疫蛋白和7种类固醇激素的循环水平的相关性,评估了与PCa风险相关的T2D SNP是否会影响宿主免疫反应。我们还研究了在全血、外周血单核细胞(PBMC)和单核细胞衍生的巨噬细胞用脂多糖(LPS)、植物血凝素(PHA)、Pam3Cys和 进行体外刺激后,最有趣的SNP与细胞因子水平的相关性。对我们的数据与来自六个大型队列的数据进行的荟萃分析证实, 、 、 、 和 等位基因的每个拷贝都显著降低了患PCa的风险(分别为 = 3.70 × 10, = 9.39 × 10, = 5.04 × 10, = 1.19 × 10,和 = 1.66 × 10)。尽管在多重检验校正后无统计学意义,但我们还发现 和 SNP与患PCa的风险相关( = 8.49 × 10和0.004)。有趣的是,我们发现 基因座的保护作用可能由SULT1A1蛋白介导( = 0.00030),SULT1A1是一种芳基硫酸转移酶,可催化许多激素、神经递质、药物和外源性化合物的硫酸结合。除了这些结果,表达数量性状基因座(eQTL)分析表明, 、 、 、 和 SNP通过调节其各自基因在全血和/或肝脏中的mRNA水平来影响PCa风险。这些结果证实了与T2D相关的功能性变异会影响患PCa的风险,但也突出了需要进行额外实验以在肿瘤组织背景下验证我们的功能结果。