Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis

José Manuel Sánchez-Maldonado; Ricardo Collado; Antonio José Cabrera-Serrano; Rob Ter Horst; Fernando Gálvez-Montosa; Inmaculada Robles-Fernández; Verónica Arenas-Rodríguez; Blanca Cano-Gutiérrez; Olivier Bakker; María Inmaculada Bravo-Fernández; Francisco José García-Verdejo; José Antonio López López; Jesús Olivares-Ruiz; Miguel Ángel López-Nevot; Laura Fernández-Puerta; José Manuel Cózar-Olmo; Yang Li; Mihai G Netea; Manuel Jurado; Jose Antonio Lorente; Pedro Sánchez-Rovira; María Jesús Álvarez-Cubero; Juan Sainz

doi:10.3390/cancers14102376

Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis

Cancers (Basel). 2022 May 12;14(10):2376. doi: 10.3390/cancers14102376.

Authors

José Manuel Sánchez-Maldonado^{1

2

3}, Ricardo Collado⁴, Antonio José Cabrera-Serrano^{1

2

3}, Rob Ter Horst⁵, Fernando Gálvez-Montosa⁶, Inmaculada Robles-Fernández¹, Verónica Arenas-Rodríguez^{1

7}, Blanca Cano-Gutiérrez⁷, Olivier Bakker⁸, María Inmaculada Bravo-Fernández⁴, Francisco José García-Verdejo⁶, José Antonio López López⁶, Jesús Olivares-Ruiz⁴, Miguel Ángel López-Nevot⁹, Laura Fernández-Puerta², José Manuel Cózar-Olmo¹⁰, Yang Li^{5

11}, Mihai G Netea^{5

12}, Manuel Jurado^{1

2

3

13}, Jose Antonio Lorente^{1

14}, Pedro Sánchez-Rovira⁶, María Jesús Álvarez-Cubero^{1

7}, Juan Sainz^{1

2

3

15}

Affiliations

¹ Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain.
² Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain.
³ Instituto de Investigación Biosanataria IBs. Granada, 18012 Granada, Spain.
⁴ Medical Oncology Department, Hospital de San Pedro Alcántara, 10003 Cáceres, Spain.
⁵ Department of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands.
⁶ Department of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, Spain.
⁷ Department of Biochemistry and Molecular Biology III, Faculty of Medicine, University of Granada, 18016 Granada, Spain.
⁸ Department of Genetics, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
⁹ Immunology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain.
¹⁰ Urology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain.
¹¹ Centre for Individualised Infection Medicine (CiiM) & TWINCORE, Joint Ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), 30625 Hannover, Germany.
¹² Department for Immunology & Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany.
¹³ Department of Medicine, Faculty of Medicine, University of Granada, 18016 Granada, Spain.
¹⁴ Department of Legal Medicine, Faculty of Medicine, University of Granada, 18016 Granada, Spain.
¹⁵ Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18071 Granada, Spain.

Abstract

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 Staphylococcus Aureus. The meta-analysis of our data with those from six large cohorts confirmed that each copy of the FTO_rs9939609A, HNF1B_rs7501939T, HNF1B_rs757210T, HNF1B_rs4430796G, and JAZF1_rs10486567A alleles significantly decreased risk of developing PCa (p = 3.70 × 10^-5, p = 9.39 × 10^-54, p = 5.04 × 10^-54, p = 1.19 × 10^-71, and p = 1.66 × 10^-18, respectively). Although it was not statistically significant after correction for multiple testing, we also found that the NOTCH2_rs10923931T and RBMS1_rs7593730 SNPs associated with the risk of developing PCa (p = 8.49 × 10^-4 and 0.004). Interestingly, we found that the protective effect attributed to the HFN1B locus could be mediated by the SULT1A1 protein (p = 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 HNF1B_rs7501939, HNF1B_rs757210, HNF1B_rs4430796, NOTCH2_rs10923931, and RBMS1_rs7593730 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.

Keywords: genetic susceptibility; prostate cancer; type 2 diabetes-related variants.

Abstract

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