{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T05:54:18Z","timestamp":1768974858377,"version":"3.49.0"},"reference-count":46,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T00:00:00Z","timestamp":1693267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["DK099257"],"award-info":[{"award-number":["DK099257"]}]},{"name":"NIH","award":["TR003289"],"award-info":[{"award-number":["TR003289"]}]},{"name":"NIH","award":["DK096990"],"award-info":[{"award-number":["DK096990"]}]},{"name":"NIH","award":["DK117881"],"award-info":[{"award-number":["DK117881"]}]},{"name":"NIH","award":["DK119973"],"award-info":[{"award-number":["DK119973"]}]},{"name":"NIH","award":["TR002383"],"award-info":[{"award-number":["TR002383"]}]},{"name":"NIH","award":["1P30DK120531-01"],"award-info":[{"award-number":["1P30DK120531-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic-dysfunction-associated steatotic liver disease (MASLD), which affects 30 million people in the US and is anticipated to reach over 100 million by 2030, places a significant financial strain on the healthcare system. There is presently no FDA-approved treatment for MASLD despite its public health significance and financial burden. Understanding the connection between point mutations, liver enzymes, and MASLD is important for comprehending drug toxicity in healthy or diseased individuals. Multiple genetic variations have been linked to MASLD susceptibility through genome-wide association studies (GWAS), either increasing MASLD risk or protecting against it, such as PNPLA3 rs738409, MBOAT7 rs641738, GCKR rs780094, HSD17B13 rs72613567, and MTARC1 rs2642438. As the impact of genetic variants on the levels of drug-metabolizing cytochrome P450 (CYP) enzymes in human hepatocytes has not been thoroughly investigated, this study aims to describe the analysis of metabolic functions for selected phase I and phase II liver enzymes in human hepatocytes. For this purpose, fresh isolated primary hepatocytes were obtained from healthy liver donors (n = 126), and liquid chromatography\u2013mass spectrometry (LC\u2013MS) was performed. For the cohorts, participants were classified into minor homozygotes and nonminor homozygotes (major homozygotes + heterozygotes) for five gene polymorphisms. For phase I liver enzymes, we found a significant difference in the activity of CYP1A2 in human hepatocytes carrying MBOAT7 (p = 0.011) and of CYP2C8 in human hepatocytes carrying PNPLA3 (p = 0.004). It was also observed that the activity of CYP2C9 was significantly lower in human hepatocytes carrying HSD17B13 (p = 0.001) minor homozygous compared to nonminor homozygous. No significant difference in activity of CYP2E1, CYP2C8, CYP2D6, CYP2E1, CYP3A4, ECOD, FMO, MAO, AO, and CES2 and in any of the phase II liver enzymes between human hepatocytes carrying genetic variants for PNPLA3 rs738409, MBOAT7 rs641738, GCKR rs780094, HSD17B13 rs72613567, and MTARC1 rs2642438 were observed. These findings offer a preliminary assessment of the influence of genetic variations on drug-metabolizing cytochrome P450 (CYP) enzymes in healthy human hepatocytes, which may be useful for future drug discovery investigations.<\/jats:p>","DOI":"10.3390\/ijms241713406","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T08:51:14Z","timestamp":1693299074000},"page":"13406","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants"],"prefix":"10.3390","volume":"24","author":[{"given":"Lanuza A. P.","family":"Faccioli","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5379-4735","authenticated-orcid":false,"given":"Zeliha","family":"Cetin","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4156-7647","authenticated-orcid":false,"given":"Zehra N.","family":"Kocas-Kilicarslan","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiyue","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiping","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Kurihara","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3050-515X","authenticated-orcid":false,"given":"Edgar N.","family":"Tafaleng","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodrigo M.","family":"Florentino","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Liver Research Center, Human Synthetic Liver Biology Core, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengying","family":"Xia","sequence":"additional","affiliation":[{"name":"Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark T.","family":"Miedel","sequence":"additional","affiliation":[{"name":"Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. Lansing","family":"Taylor","sequence":"additional","affiliation":[{"name":"Pittsburgh Liver Research Center, Human Synthetic Liver Biology Core, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Statistics, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaideep","family":"Behari","sequence":"additional","affiliation":[{"name":"Pittsburgh Liver Research Center, Human Synthetic Liver Biology Core, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alina","family":"Ostrowska","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Liver Research Center, Human Synthetic Liver Biology Core, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Constantine","sequence":"additional","affiliation":[{"name":"Discovery Life Sciences, Huntsville, AL 35806, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"Li","sequence":"additional","affiliation":[{"name":"Discovery Life Sciences, Huntsville, AL 35806, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"Soto-Gutierrez","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Liver Research Center, Human Synthetic Liver Biology Core, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/hep.29466","article-title":"Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease","volume":"67","author":"Estes","year":"2018","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1055\/s-0035-1562943","article-title":"Epidemiology and Natural History of Nonalcoholic Fatty Liver Disease","volume":"35","author":"Satapathy","year":"2015","journal-title":"Semin. Liver Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"28","DOI":"10.12703\/P7-28","article-title":"Recent advances in understanding\/management of non-alcoholic steatohepatitis","volume":"7","author":"Pacana","year":"2015","journal-title":"F1000Prime Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e00136","DOI":"10.1002\/prp2.136","article-title":"Saroglitazar, a novel PPARalpha\/gamma agonist with predominant PPARalpha activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models","volume":"3","author":"Jain","year":"2015","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Speliotes, E.K., Yerges-Armstrong, L.M., Wu, J., Hernaez, R., Kim, L.J., Palmer, C.D., Gudnason, V., Eiriksdottir, G., Garcia, M.E., and Launer, L.J. (2011). Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.1001324"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/ng.3252","article-title":"Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets","volume":"47","author":"Schulze","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.bbalip.2013.12.006","article-title":"Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function","volume":"1841","author":"Pingitore","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1136\/gutjnl-2020-320853","article-title":"Loss of hepatic Mboat7 leads to liver fibrosis","volume":"70","author":"Thangapandi","year":"2021","journal-title":"Gut"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10240","DOI":"10.1038\/s41598-019-46750-3","article-title":"An intronic variant in the GCKR gene is associated with multiple lipids","volume":"9","author":"Vangipurapu","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1056\/NEJMoa1712191","article-title":"A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease","volume":"378","author":"Cheng","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Emdin, C.A., Haas, M.E., Khera, A.V., Aragam, K., Chaffin, M., Klarin, D., Hindy, G., Jiang, L., Wei, W.Q., and Feng, Q. (2020). A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease. PLoS Genet., 16.","DOI":"10.1371\/journal.pgen.1009503"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1002\/hep4.1955","article-title":"Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17-beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms","volume":"6","author":"Hudert","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1002\/hep.30350","article-title":"17-Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated with Histological Features of Nonalcoholic Fatty Liver Disease","volume":"69","author":"Ma","year":"2019","journal-title":"Hepatology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Motomura, T., Amirneni, S., Diaz-Aragon, R., Faccioli, L.A., Malizio, M.R., Coard, M.C., Kocas-Kilicarslan, Z.N., Frau, C., Haep, N., and Ostrowska, A. (2021). Is HSD17B13 Genetic Variant a Protector for Liver Dysfunction? Future Perspective as a Potential Therapeutic Target. J. Pers. Med., 11.","DOI":"10.3390\/jpm11070619"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.jhep.2020.02.020","article-title":"Update on NAFLD genetics: From new variants to the clinic","volume":"72","author":"Trepo","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1002\/hep.23759","article-title":"The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease","volume":"52","author":"Rotman","year":"2010","journal-title":"Hepatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1038\/ng.3417","article-title":"A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis","volume":"47","author":"Buch","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1002\/hep4.1353","article-title":"Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes","volume":"3","author":"Barata","year":"2019","journal-title":"Hepatol. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/ng.2901","article-title":"Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease","volume":"46","author":"Kozlitina","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4309","DOI":"10.1038\/ncomms5309","article-title":"TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease","volume":"5","author":"Liu","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1038\/ng.257","article-title":"Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease","volume":"40","author":"Romeo","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1038\/s41588-022-01199-5","article-title":"Multiomics study of nonalcoholic fatty liver disease","volume":"54","author":"Sveinbjornsson","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1074\/mcp.M112.021352","article-title":"Enhanced phase II detoxification contributes to beneficial effects of dietary restriction as revealed by multi-platform metabolomics studies","volume":"12","author":"Wen","year":"2013","journal-title":"Mol. Cell. Proteom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/hep.30623","article-title":"A 17-Beta-Hydroxysteroid Dehydrogenase 13 Variant Protects from Hepatocellular Carcinoma Development in Alcoholic Liver Disease","volume":"70","author":"Yang","year":"2019","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2998","DOI":"10.1002\/hep.32063","article-title":"Modeling PNPLA3-Associated NAFLD Using Human-Induced Pluripotent Stem Cells","volume":"74","author":"Tilson","year":"2021","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102866","DOI":"10.1016\/j.ebiom.2020.102866","article-title":"MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD","volume":"57","author":"Meroni","year":"2020","journal-title":"EBioMedicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1016\/j.jhep.2021.08.012","article-title":"Epidemiology and risk-stratification of NAFLD-associated HCC","volume":"75","author":"Ioannou","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.medj.2021.04.011","article-title":"A genome-first approach to mortality and metabolic phenotypes in MTARC1 p.Ala165Thr (rs2642438) heterozygotes and homozygotes","volume":"2","author":"Schneider","year":"2021","journal-title":"Med"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1097\/FPC.0b013e32834c6efd","article-title":"PharmGKB summary: Very important pharmacogene information for CYP1A2","volume":"22","author":"Thorn","year":"2012","journal-title":"Pharmacogenet Genom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1097\/00008571-200110000-00006","article-title":"Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid","volume":"11","author":"Dai","year":"2001","journal-title":"Pharmacogenetics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"343","DOI":"10.2133\/dmpk.DMPK-10-RG-009","article-title":"Effects of CYP2C9*3 and CYP2C9*13 on Diclofenac Metabolism and Inhibition-based Drug-Drug Interactions","volume":"25","author":"Zi","year":"2010","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_32","unstructured":"(2023, August 03). Pharmgkb. Available online: https:\/\/www.pharmgkb.org\/clinicalAnnotation\/1450931522."},{"key":"ref_33","unstructured":"(2023, August 03). Pharmgkb. Available online: https:\/\/www.pharmgkb.org\/variantAnnotation\/982044657."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3708","DOI":"10.1016\/j.molcel.2021.08.027","article-title":"Lipid metabolism in sickness and in health: Emerging regulators of lipotoxicity","volume":"81","author":"Yoon","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0009-2797(99)00007-1","article-title":"Characterization of Phase I and Phase II hepatic drug metabolism activities in a panel of human liver preparations","volume":"118","author":"Iyer","year":"1999","journal-title":"Chem. Biol. Interact."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"103","DOI":"10.5507\/bp.2010.017","article-title":"Phase II drug metabolizing enzymes","volume":"154","author":"Jancova","year":"2010","journal-title":"Biomed. Pap. Med. Fac. Univ. Palacky. Olomouc Czech Repub."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1111\/apt.14952","article-title":"Review article: Drug-induced liver injury in the context of nonalcoholic fatty liver disease\u2014A physiopathological and clinical integrated view","volume":"48","author":"Bessone","year":"2018","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/0895-4356(93)90101-6","article-title":"Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries","volume":"46","author":"Danan","year":"1993","journal-title":"J. Clin. Epidemiol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Danan, G., and Teschke, R. (2015). RUCAM in Drug and Herb Induced Liver Injury: The Update. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17010014"},{"key":"ref_40","first-page":"1169","article-title":"Top-ranking drugs out of 3312 drug-induced liver injury cases evaluated by the Roussel Uclaf Causality Assessment Method","volume":"14","author":"Teschke","year":"2018","journal-title":"Expert. Opin. Drug Metab. Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/bs.apha.2019.01.003","article-title":"Drug-induced liver injury in obesity and nonalcoholic fatty liver disease","volume":"85","author":"Allard","year":"2019","journal-title":"Adv. Pharmacol."},{"key":"ref_42","first-page":"73","article-title":"Drug-induced Liver Injury","volume":"6","author":"David","year":"2010","journal-title":"US Gastroenterol. Hepatol. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1124\/dmd.109.027466","article-title":"Hepatic cytochrome P450 enzyme alterations in humans with progressive stages of nonalcoholic fatty liver disease","volume":"37","author":"Fisher","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/biostatistics\/kxt007","article-title":"An estimate of the science-wise false discovery rate and application to the top medical literature","volume":"15","author":"Jager","year":"2014","journal-title":"Biostatistics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1177\/1536867X0500500201","article-title":"Exploratory Analysis of Single Nucleotide Polymorphism (SNP) for Quantitative Traits","volume":"5","author":"Cleves","year":"2005","journal-title":"Stata J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13406\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:41:56Z","timestamp":1760128916000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13406"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,29]]},"references-count":46,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241713406"],"URL":"https:\/\/doi.org\/10.3390\/ijms241713406","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,29]]}}}