{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T09:10:24Z","timestamp":1783933824784,"version":"3.55.0"},"reference-count":29,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T00:00:00Z","timestamp":1783814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Organic anion-transporting polypeptides (OATPs) are crucial for hepatic uptake. However, the independent contribution of SLCO1B1\/1B3 germline variations to hepatocellular carcinoma (HCC) susceptibility remains controversial. This study investigated SLCO1B1\/1B3 polymorphisms and HCC risk in a Turkish cohort, accounting for clinical, viral, and metabolic confounders. In this retrospective case\u2013control study (81 HCC patients, 162 healthy controls), fully adjusted multivariable logistic regression models were constructed across multiple inheritance configurations (dominant, recessive, and additive) and adjusted for age, sex, and viral status (HBV\/HCV) to address demographic and etiological discrepancies. Genotyping for SLCO1B1 (c.388A&gt;G, c.521T&gt;C) and SLCO1B3 (c.334T&gt;G, c.699G&gt;A) was performed using PCR-RFLP, cross-verified via automated digital capillary electrophoresis. Exploratory univariate analysis showed the SLCO1B1 388A&gt;G variant was more prevalent in the HCC group. However, after strict adjustments for multiplicity and controlling for background viral etiology, age (OR: 1.10) and male sex (OR: 5.82, 95% CI: 2.74\u201312.41) remained the primary independent predictors, whereas the statistical significance of the genetic variant completely dissolved (p = 0.673). Notably, HCC patients exhibited profound hypocholesterolemia that significantly correlated with liver dysfunction severity; a significant inverse correlation was found between Child-Pugh scores and total cholesterol (r = \u22120.286, p = 0.031), validating that metabolic decline is a consequence of hepatic synthetic failure rather than an independent risk factor. Ultimately, age, male sex, and background etiological factors are the primary independent determinants characterizing HCC in this cohort, confirming that common germline SLCO variations do not exert a robust independent influence once major demographic and clinical confounders are considered.<\/jats:p>","DOI":"10.3390\/ijms27146214","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T08:53:58Z","timestamp":1783932838000},"page":"6214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical and Genetic Determinants of Hepatocellular Carcinoma in a Turkish Cohort: Impact of SLCO1B1 and SLCO1B3 Germline Variations and Demographic Risk Factors"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9805-6624","authenticated-orcid":false,"given":"Zuhal","family":"Altintas","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Mersin University, Mersin 33343, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,12]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Cancer Statistics GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/hep.31288","article-title":"Epidemiology of Hepatocellular Carcinoma","volume":"73","author":"McGlynn","year":"2021","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1007\/s40471-019-00188-3","article-title":"The changing epidemiology of primary liver cancer","volume":"6","author":"Petrick","year":"2019","journal-title":"Curr. Epidemiol. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1124\/mol.118.114314","article-title":"Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology","volume":"95","author":"Schulte","year":"2019","journal-title":"Mol. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chen, H. (2025). Roles of organic anion transporting polypeptides in hepatocellular carcinoma. Front Genet., 16.","DOI":"10.3389\/fgene.2025.1550723"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.mam.2012.10.009","article-title":"The SLCO (former SLC21) superfamily of transporters","volume":"34","author":"Hagenbuch","year":"2013","journal-title":"Mol. Asp. Med."},{"key":"ref_8","first-page":"1","article-title":"Uptake transporters of the human OATP family: Molecular characteristics, substrates, their role in drug-drug interactions, and functional consequences of polymorphisms","volume":"201","year":"2011","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"T\u00fcrkmen, D., Bowden, J., Masoli, J.A.H., Melzer, D., and Pilling, L.C. (2024). SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084426"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Pastras, P., Zazas, E., Kalafateli, M., Aggeletopoulou, I., Tsounis, E.P., Kanaloupitis, S., Zisimopoulos, K., Kottaridou, E.-E.-K., Antonopoulou, A., and Drakopoulos, D. (2024). Predictive Risk Factors and Scoring Systems Associated with the Development of Hepatocellular Carcinoma in Chronic Hepatitis B. Cancers, 16.","DOI":"10.3390\/cancers16142521"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Fassio, E., Colombato, L., Gualano, G., Perez, S., Puga-Tejada, M., and Landeira, G. (2025). Hepatocellular Carcinoma After HCV Eradication with Direct-Acting Antivirals: A Reappraisal Based on New Parameters to Assess the Persistence of Risk. Cancers, 17.","DOI":"10.3390\/cancers17061018"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kao, Y.-T., Liu, Y.-C., Cheng, Y.-T., Wen, Y.-W., Hsieh, Y.-C., Hsu, C.-E., Su, C.-W., Tai, J.C.-H., Chen, Y.-C., and Jeng, W.-J. (2024). Hepatocellular Carcinoma Incidences and Risk Factors in Hepatitis C Patients: Interferon versus Direct-Acting Agents. Viruses, 16.","DOI":"10.3390\/v16091485"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Milo\u0161evi\u0107, I., Nikoli\u0107, N., Stankovi\u0107, S., Filipovi\u0107, A., Ranin, J., Paunovi\u0107, I., Simi\u0107, J., and Beronja, B. (2025). Pilot Study of PIVKA-II in the Prognostic Assessment of Hepatocellular Carcinoma in Chronic Viral Hepatitis: Comparative Findings from HBV and HCV Cohorts from a Single Center in Serbia. Biomedicines, 13.","DOI":"10.3390\/biomedicines13112653"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Androutsakos, T., Bakasis, A.D., Pouliakis, A., Gazouli, M., Vallilas, C., and Hatzis, G. (2022). Single Nucleotide Polymorphisms of Toll-like Receptor 4 in Hepatocellular Carcinoma-A Single-Center Study. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169430"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Esmail, A., Hamadneh, Y., Khasawneh, B., Al-Rawi, M., Al-Najjar, E., Dhillon, V., Alhaj, A., Rayyan, Y., and Abdelrahim, M. (2025). Atezolizumab Plus Bevacizumab Combination Therapy in Unresectable Hepatocellular Carcinoma: An Institutional Experience. Biomedicines, 13.","DOI":"10.3390\/biomedicines13122844"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41698-025-01198-9","article-title":"The regulatory roles and therapeutic strategies of the solute carrier transporters in cancer metabolism","volume":"10","author":"Zhang","year":"2026","journal-title":"npj Precis. Onc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.7150\/thno.82920","article-title":"The role of lipid metabolic reprogramming in tumor microenvironment","volume":"13","author":"Yang","year":"2023","journal-title":"Theranostics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"622","DOI":"10.3349\/ymj.2021.62.7.622","article-title":"Expression of Organic Anion Transporting Polypeptides in an H-Ras 12V Transgenic Mouse Model of Spontaneous Hepatocellular Carcinoma","volume":"62","author":"Kim","year":"2021","journal-title":"Yonsei Med. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s12957-020-01891-y","article-title":"Low expression of organic anion-transporting polypeptide 1B3 predicts a poor prognosis in hepatocellular carcinoma","volume":"18","author":"Chen","year":"2020","journal-title":"World J. Surg. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1148\/radiol.12112061","article-title":"Visualization of hepatic uptake transporter function in healthy subjects by using gadoxetic acid-enhanced MR imaging","volume":"264","author":"Nassif","year":"2012","journal-title":"Radiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.2147\/CMAR.S292197","article-title":"OATP1B3 Expression in Hepatocellular Carcinoma Correlates with Intralesional Gd-EOB-DTPA Uptake and Signal Intensity on Gd-EOB-DTPA-Enhanced MRI","volume":"13","author":"Zhou","year":"2021","journal-title":"Cancer Manag. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9711179","DOI":"10.1155\/2021\/9711179","article-title":"OATP1B1 Plays an Important Role in the Transport and Treatment Efficacy of Sorafenib in Hepatocellular Carcinoma","volume":"2021","author":"Wen","year":"2021","journal-title":"Dis. Markers"},{"key":"ref_23","first-page":"27","article-title":"Impact of genetic variants in the solute carrier (SLC) genes encoding drug uptake transporters on the response to anticancer chemotherapy","volume":"7","author":"Marin","year":"2024","journal-title":"Cancer Drug Resist."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1007\/s11033-025-11065-2","article-title":"Molecular mechanisms of sex hormones in Hepatocellular Carcinoma: A systematic review","volume":"52","author":"Zahra","year":"2025","journal-title":"Mol. Biol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/s41580-019-0190-7","article-title":"Mechanisms and regulation of cholesterol homeostasis","volume":"21","author":"Luo","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s12944-026-02946-x","article-title":"Association of LDLR and SCARB1 gene polymorphisms with hepatocellular carcinoma: A case-control study proposing a \u2018double-hit\u2019 model","volume":"25","author":"Altintas","year":"2026","journal-title":"Lipids Health Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"115681","DOI":"10.1016\/j.bcp.2023.115681","article-title":"Relevance of the organic anion transporting polypeptide 1B3 (OATP1B3) in the personalized pharmacological treatment of hepatocellular carcinoma","volume":"214","author":"Asensio","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhou, F., and Sun, X. (2021). Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.762828"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1186\/s40001-023-01547-z","article-title":"Dysregulated cholesterol regulatory genes in hepatocellular carcinoma","volume":"28","author":"Cao","year":"2023","journal-title":"Eur. J. Med. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6214\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T08:57:49Z","timestamp":1783933069000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6214"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,12]]},"references-count":29,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146214"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146214","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,12]]}}}