Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-05-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/10/2376 |
| _version_ | 1797501043502743552 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | José Manuel Sánchez-Maldonado |
| collection | DOAJ |
| description | 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 <i>Staphylococcus Aureus</i>. The meta-analysis of our data with those from six large cohorts confirmed that each copy of the <i>FTO</i><sub>rs9939609A</sub>, <i>HNF1B</i><sub>rs7501939T</sub>, <i>HNF1B</i><sub>rs757210T</sub>, <i>HNF1B</i><sub>rs4430796G</sub>, and <i>JAZF1</i><sub>rs10486567A</sub> alleles significantly decreased risk of developing PCa (<i>p</i> = 3.70 × 10<sup>−5</sup>, <i>p</i> = 9.39 × 10<sup>−54</sup>, <i>p</i> = 5.04 × 10<sup>−54</sup>, <i>p</i> = 1.19 × 10<sup>−71</sup>, and <i>p</i> = 1.66 × 10<sup>−18</sup>, respectively). Although it was not statistically significant after correction for multiple testing, we also found that the <i>NOTCH2</i><sub>rs10923931T</sub> and <i>RBMS1</i><sub>rs7593730</sub> SNPs associated with the risk of developing PCa (<i>p</i> = 8.49 × 10<sup>−4</sup> and 0.004). Interestingly, we found that the protective effect attributed to the <i>HFN1B</i> locus could be mediated by the SULT1A1 protein (<i>p</i> = 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 <i>HNF1B</i><sub>rs7501939</sub>, <i>HNF1B</i><sub>rs757210</sub>, <i>HNF1B</i><sub>rs4430796</sub>, <i>NOTCH2</i><sub>rs10923931</sub>, and <i>RBMS1</i><sub>rs7593730</sub> 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. |
| first_indexed | 2024-03-10T03:12:39Z |
| format | Article |
| id | doaj.art-6c9c365f7f9247e7bb5f9d9a7f337daf |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T03:12:39Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6c9c365f7f9247e7bb5f9d9a7f337daf2023-11-23T10:22:17ZengMDPI AGCancers2072-66942022-05-011410237610.3390/cancers14102376Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-AnalysisJosé Manuel Sánchez-Maldonado0Ricardo Collado1Antonio José Cabrera-Serrano2Rob Ter Horst3Fernando Gálvez-Montosa4Inmaculada Robles-Fernández5Verónica Arenas-Rodríguez6Blanca Cano-Gutiérrez7Olivier Bakker8María Inmaculada Bravo-Fernández9Francisco José García-Verdejo10José Antonio López López11Jesús Olivares-Ruiz12Miguel Ángel López-Nevot13Laura Fernández-Puerta14José Manuel Cózar-Olmo15Yang Li16Mihai G. Netea17Manuel Jurado18Jose Antonio Lorente19Pedro Sánchez-Rovira20María Jesús Álvarez-Cubero21Juan Sainz22Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, SpainMedical Oncology Department, Hospital de San Pedro Alcántara, 10003 Cáceres, SpainGenomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, SpainDepartment of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, SpainGenomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, SpainGenomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, SpainDepartment of Biochemistry and Molecular Biology III, Faculty of Medicine, University of Granada, 18016 Granada, SpainDepartment of Genetics, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The NetherlandsMedical Oncology Department, Hospital de San Pedro Alcántara, 10003 Cáceres, SpainDepartment of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, SpainDepartment of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, SpainMedical Oncology Department, Hospital de San Pedro Alcántara, 10003 Cáceres, SpainImmunology Department, Virgen de las Nieves University Hospital, 18012 Granada, SpainHematology Department, Virgen de las Nieves University Hospital, 18012 Granada, SpainUrology Department, Virgen de las Nieves University Hospital, 18012 Granada, SpainDepartment of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The NetherlandsGenomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, SpainGenomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, SpainDepartment of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, SpainGenomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, SpainGenomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, SpainIn 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 <i>Staphylococcus Aureus</i>. The meta-analysis of our data with those from six large cohorts confirmed that each copy of the <i>FTO</i><sub>rs9939609A</sub>, <i>HNF1B</i><sub>rs7501939T</sub>, <i>HNF1B</i><sub>rs757210T</sub>, <i>HNF1B</i><sub>rs4430796G</sub>, and <i>JAZF1</i><sub>rs10486567A</sub> alleles significantly decreased risk of developing PCa (<i>p</i> = 3.70 × 10<sup>−5</sup>, <i>p</i> = 9.39 × 10<sup>−54</sup>, <i>p</i> = 5.04 × 10<sup>−54</sup>, <i>p</i> = 1.19 × 10<sup>−71</sup>, and <i>p</i> = 1.66 × 10<sup>−18</sup>, respectively). Although it was not statistically significant after correction for multiple testing, we also found that the <i>NOTCH2</i><sub>rs10923931T</sub> and <i>RBMS1</i><sub>rs7593730</sub> SNPs associated with the risk of developing PCa (<i>p</i> = 8.49 × 10<sup>−4</sup> and 0.004). Interestingly, we found that the protective effect attributed to the <i>HFN1B</i> locus could be mediated by the SULT1A1 protein (<i>p</i> = 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 <i>HNF1B</i><sub>rs7501939</sub>, <i>HNF1B</i><sub>rs757210</sub>, <i>HNF1B</i><sub>rs4430796</sub>, <i>NOTCH2</i><sub>rs10923931</sub>, and <i>RBMS1</i><sub>rs7593730</sub> 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.https://www.mdpi.com/2072-6694/14/10/2376prostate cancergenetic susceptibilitytype 2 diabetes-related variants |
| spellingShingle | 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 Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis Cancers prostate cancer genetic susceptibility type 2 diabetes-related variants |
| title | Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis |
| title_full | Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis |
| title_fullStr | Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis |
| title_full_unstemmed | Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis |
| title_short | Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis |
| title_sort | type 2 diabetes related variants influence the risk of developing prostate cancer a population based case control study and meta analysis |
| topic | prostate cancer genetic susceptibility type 2 diabetes-related variants |
| url | https://www.mdpi.com/2072-6694/14/10/2376 |
| work_keys_str_mv | AT josemanuelsanchezmaldonado type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT ricardocollado type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT antoniojosecabreraserrano type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT robterhorst type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT fernandogalvezmontosa type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT inmaculadaroblesfernandez type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT veronicaarenasrodriguez type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT blancacanogutierrez type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT olivierbakker type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT mariainmaculadabravofernandez type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT franciscojosegarciaverdejo type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT joseantoniolopezlopez type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT jesusolivaresruiz type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT miguelangellopeznevot type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT laurafernandezpuerta type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT josemanuelcozarolmo type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT yangli type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT mihaignetea type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT manueljurado type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT joseantoniolorente type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT pedrosanchezrovira type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT mariajesusalvarezcubero type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis AT juansainz type2diabetesrelatedvariantsinfluencetheriskofdevelopingprostatecancerapopulationbasedcasecontrolstudyandmetaanalysis |