{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:11:36Z","timestamp":1784887896140,"version":"3.55.0"},"reference-count":132,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T00:00:00Z","timestamp":1656288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Faculty of Medicine, University of Debrecen"},{"name":"Ministry for Innovation and Technology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Familial hypercholesterolemia (FH) is the most common monogenic metabolic disorder characterized by considerably elevated low-density lipoprotein cholesterol (LDL-C) levels leading to enhanced atherogenesis, early cardiovascular disease (CVD), and premature death. However, the wide phenotypic heterogeneity in FH makes the cardiovascular risk prediction challenging in clinical practice to determine optimal therapeutic strategy. Beyond the lifetime LDL-C vascular accumulation, other genetic and non-genetic risk factors might exacerbate CVD development. Besides the most frequent variants of three genes (LDL-R, APOB, and PCSK9) in some proband variants of other genes implicated in lipid metabolism and atherogenesis are responsible for FH phenotype. Furthermore, non-genetic factors, including traditional cardiovascular risk factors, metabolic and endocrine disorders might also worsen risk profile. Although some were extensively studied previously, others, such as common endocrine disorders including thyroid disorders or polycystic ovary syndrome are not widely evaluated in FH. In this review, we summarize the most important genetic and non-genetic factors that might affect the risk prediction and therapeutic strategy in FH through the eyes of clinicians focusing on disorders that might not be in the center of FH research. The review highlights the complexity of FH care and the need of an interdisciplinary attitude to find the best therapeutic approach in FH patients.<\/jats:p>","DOI":"10.3390\/genes13071158","type":"journal-article","created":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T22:31:14Z","timestamp":1656369074000},"page":"1158","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Clinical Aspects of Genetic and Non-Genetic Cardiovascular Risk Factors in Familial Hypercholesterolemia"],"prefix":"10.3390","volume":"13","author":[{"given":"Eszter","family":"Berta","sequence":"first","affiliation":[{"name":"Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"No\u00e9mi","family":"Zs\u00edros","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikl\u00f3s","family":"Bodor","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3397-2829","authenticated-orcid":false,"given":"Istv\u00e1n","family":"Balogh","sequence":"additional","affiliation":[{"name":"Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajnalka","family":"L\u0151rincz","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gy\u00f6rgy","family":"Paragh","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9761-9595","authenticated-orcid":false,"given":"Mariann","family":"Harangi","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.atherosclerosis.2018.05.039","article-title":"Identifying patients with familial hypercholesterolemia using data mining methods in the Northern Great Plain region of Hungary","volume":"277","author":"Paragh","year":"2018","journal-title":"Atherosclerosis"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.atherosclerosis.2011.09.052","article-title":"Accelerated subclinical coronary atherosclerosis in patients with familial hypercholesterolemia","volume":"219","author":"Neefjes","year":"2011","journal-title":"Atherosclerosis"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1136\/bmj.322.7293.1019","article-title":"Mortality over two centuries in large pedigree with familial hypercholesterolaemia: Family tree mortality study","volume":"322","author":"Sijbrands","year":"2001","journal-title":"BMJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.atherosclerosis.2007.12.024","article-title":"Cardiovascular disease in familial hypercholesterolaemia: Influence of low-density lipoprotein receptor mutation type and classic risk factors","volume":"200","author":"Alonso","year":"2008","journal-title":"Atherosclerosis"},{"key":"ref_5","first-page":"49","article-title":"Familial hypercholesterolaemia","volume":"25","author":"Marais","year":"2004","journal-title":"Clin. Biochem. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Madar, L., Juh\u00e1sz, L., Sz\u0171cs, Z., Kerkovits, L., Harangi, M., and Balogh, I. (2022). Establishing the Mutational Spectrum of Hungarian Patients with Familial Hypercholesterolemia. Genes, 13.","DOI":"10.3390\/genes13010153"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.jacc.2018.05.044","article-title":"Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel","volume":"72","author":"Sturm","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"574474","DOI":"10.3389\/fgene.2020.574474","article-title":"Genetics of Familial Hypercholesterolemia: New Insights","volume":"11","author":"Vrablik","year":"2020","journal-title":"Front. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"103831","DOI":"10.1016\/j.ejmg.2019.103831","article-title":"Familial hypercholesterolemia: A complex genetic disease with variable phenotypes","volume":"63","author":"Giacobbe","year":"2020","journal-title":"Eur. J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"718","DOI":"10.4161\/epi.27981","article-title":"Epipolymorphisms within lipoprotein genes contribute independently to plasma lipid levels in familial hypercholesterolemia","volume":"9","author":"Guay","year":"2014","journal-title":"Epigenetics"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Vaseghi, G., Javanmard, S.H., Heshmat-Ghahdarijani, K., Sarrafzadegan, N., and Amerizadeh, A. (2022). Comorbidities with Familial Hypercholesterolemia (FH): A Systematic Review. Curr. Probl. Cardiol., 101109.","DOI":"10.1016\/j.cpcardiol.2022.101109"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"641","DOI":"10.7326\/0003-4819-121-9-199411010-00002","article-title":"Cholesterol and coronary heart disease: Predicting risks by levels and ratios","volume":"121","author":"Kinosian","year":"1994","journal-title":"Ann. Intern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/S0002-9149(01)01843-4","article-title":"Efficacy of cholesterol levels and ratios in predicting future coronary heart disease in a Chinese population","volume":"88","author":"Wang","year":"2001","journal-title":"Am. J. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1111\/j.1365-2796.2004.01405.x","article-title":"The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: Data in 2400 patients","volume":"256","author":"Jansen","year":"2004","journal-title":"J. Intern. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1038\/sj.ejhg.5201467","article-title":"Genetic determinants of plasma HDL-cholesterol levels in familial hypercholesterolemia","volume":"13","author":"Jansen","year":"2005","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1053\/euhj.2000.2408","article-title":"Importance of HDL cholesterol levels and the total\/HDL cholesterol ratio as a risk factor for coronary heart disease in molecularly defined heterozygous familial hypercholesterolaemia","volume":"22","author":"Real","year":"2001","journal-title":"Eur. Heart J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.plipres.2017.05.001","article-title":"HDL abnormalities in familial hypercholesterolemia: Focus on biological functions","volume":"67","author":"Ganjali","year":"2017","journal-title":"Prog. Lipid Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Pedro-Botet, J., Climent, E., and Benaiges, D. (2021). Familial Hypercholesterolemia: Do HDL Play a Role?. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070810"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.1093\/eurheartj\/ehq386","article-title":"Lipoprotein(a) as a cardiovascular risk factor: Current status","volume":"31","author":"Nordestgaard","year":"2010","journal-title":"Eur. Heart J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/eurheartj\/ehz455","article-title":"2019 ESC\/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk","volume":"41","author":"Mach","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e148","DOI":"10.5114\/amsad.2020.97105","article-title":"Risk of cardiovascular disease with lipoprotein(a) in familial hypercholesterolemia: A review","volume":"5","author":"Watanabe","year":"2020","journal-title":"Arch. Med. Sci. Atheroscler. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/gepi.1370120203","article-title":"Segregation analysis of plasma lipoprotein(a) levels in pedigrees with molecularly defined familial hypercholesterolemia","volume":"12","author":"Friedlander","year":"1995","journal-title":"Genet. Epidemiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1161\/01.ATV.20.2.522","article-title":"Lipoprotein(a) in homozygous familial hypercholesterolemia","volume":"20","author":"Kraft","year":"2000","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"849197","DOI":"10.3389\/fgene.2022.849197","article-title":"Assessment of Associations Between Serum Lipoprotein (a) Levels and Atherosclerotic Vascular Diseases in Hungarian Patients with Familial Hypercholesterolemia Using Data Mining and Machine Learning","volume":"13","author":"Harangi","year":"2022","journal-title":"Front. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1172\/JCI115329","article-title":"Relationship between apolipoprotein(a) phenotype, lipoprotein(a) concentration in plasma, and low density lipoprotein receptor function in a large kindred with familial hypercholesterolemia due to the pro664----leu mutation in the LDL receptor gene","volume":"88","author":"Soutar","year":"1991","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1399-0004.1992.tb03255.x","article-title":"Detection of the Pro664-Leu mutation in the low-density lipoprotein receptor and its relation to lipoprotein(a) levels in patients with familial hypercholesterolemia of Dutch ancestry from The Netherlands and Canada","volume":"42","author":"Defesche","year":"1992","journal-title":"Clin. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.pathol.2018.11.003","article-title":"Lipoprotein(a) catabolism: A case of multiple receptors","volume":"51","author":"McCormick","year":"2019","journal-title":"Pathology"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Greco, M.F., Sirtori, C.R., Corsini, A., Ezhov, M., Sampietro, T., and Ruscica, M. (2020). Lipoprotein(a) Lowering-From Lipoprotein Apheresis to Antisense Oligonucleotide Approach. J. Clin. Med., 9.","DOI":"10.3390\/jcm9072103"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.atherosclerosis.2018.08.012","article-title":"What have we learned from Turkish familial hypercholesterolemia registries (A-HIT1 and A-HIT2)?","volume":"277","author":"Kayikcioglu","year":"2018","journal-title":"Atherosclerosis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1194\/jlr.R056549","article-title":"Lipoprotein apheresis to treat elevated lipoprotein (a)","volume":"57","author":"Waldmann","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1016\/S0140-6736(16)31009-1","article-title":"Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): Two randomised, double-blind, placebo-controlled, dose-ranging trials","volume":"388","author":"Viney","year":"2016","journal-title":"Lancet"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1161\/CIRCRESAHA.115.306249","article-title":"Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease: New Insights from Epidemiology, Genetics, and Biology","volume":"118","author":"Nordestgaard","year":"2016","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"171","DOI":"10.2147\/VHRM.S104369","article-title":"Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease","volume":"12","author":"Toth","year":"2016","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1194\/jlr.M600140-JLR200","article-title":"Upregulation of liver VLDL receptor and FAT\/CD36 expression in LDLR-\/- apoB100\/100 mice fed trans-10, cis-12 conjugated linoleic acid","volume":"47","author":"Degrace","year":"2006","journal-title":"J. Lipid Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1194\/jlr.M300448-JLR200","article-title":"Increased production of VLDL apoB-100 in subjects with familial hypercholesterolemia carrying the same null LDL receptor gene mutation","volume":"45","author":"Tremblay","year":"2004","journal-title":"J. Lipid Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1046\/j.1365-2796.1998.00367.x","article-title":"Delayed chylomicron remnant clearance in subjects with heterozygous familial hypercholesterolaemia","volume":"244","author":"Cabezas","year":"1998","journal-title":"J. Intern. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1111\/j.1742-1241.2004.00223.x","article-title":"Heterozygote men with familial hypercholesterolaemia may have an abnormal triglyceride response post-prandially. Evidence for another predictor of vascular risk in familial hypercholesterolaemia","volume":"59","author":"Kolovou","year":"2005","journal-title":"Int. J. Clin. Pract."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1515\/CCLM.2002.082","article-title":"Apolipoprotein E2\/E2 genotype in combination with mutations in the LDL receptor gene causes type III hyperlipoproteinemia","volume":"40","author":"Geisel","year":"2002","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.jacl.2016.12.005","article-title":"Heterozygous familial hypercholesterolemia presenting as chylomicronemia syndrome","volume":"11","author":"Rosenson","year":"2017","journal-title":"J. Clin. Lipidol."},{"key":"ref_40","first-page":"29","article-title":"Secondary hypertriglyceridemia","volume":"33","author":"Yago","year":"2021","journal-title":"Clin. Investig. Arterioscler."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.ijcard.2015.08.146","article-title":"Elevated lipoprotein(a), hypertension and renal insufficiency as predictors of coronary artery disease in patients with genetically confirmed heterozygous familial hypercholesterolemia","volume":"201","author":"Chan","year":"2015","journal-title":"Int. J. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.atherosclerosis.2019.06.899","article-title":"The prevalence and management of familial hypercholesterolemia in patients with acute coronary syndrome in the Polish tertiary centre: Results from the TERCET registry with 19,781 individuals","volume":"288","author":"Desperak","year":"2019","journal-title":"Atherosclerosis"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.atherosclerosissup.2019.08.029","article-title":"Efficiency and problems of statin therapy in patients with heterozygous familial hypercholesterolemia","volume":"40","author":"Korneva","year":"2019","journal-title":"Atheroscler. Suppl."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12944-020-01428-y","article-title":"Evaluation of cardiovascular risk factors in patients with familial hypercholesterolemia from the North-Eastern area of Romania","volume":"20","author":"Vlad","year":"2021","journal-title":"Lipids Health Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"113","DOI":"10.2174\/1573402115666190118142818","article-title":"Prevalence of HTN in Iran: Meta-analysis of Published Studies in 2004\u20132018","volume":"15","author":"Oori","year":"2019","journal-title":"Curr. Hypertens. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.atherosclerosis.2013.01.007","article-title":"Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy","volume":"227","author":"Bertolini","year":"2013","journal-title":"Atherosclerosis"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.jacl.2020.12.001","article-title":"Familial hypercholesterolemia in Mexico: Initial insights from the national registry","volume":"15","author":"Mehta","year":"2021","journal-title":"J. Clin. Lipidol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.atherosclerosis.2013.12.020","article-title":"Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: A study of a cohort of 14,000 mutation carriers","volume":"233","author":"Besseling","year":"2014","journal-title":"Atherosclerosis"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1161\/01.HYP.36.5.808","article-title":"Renin-angiotensin system polymorphisms and coronary events in familial hypercholesterolemia","volume":"36","author":"Wierzbicki","year":"2000","journal-title":"Hypertension"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Polfus, L.M., Smith, J.A., Shimmin, L.C., Bielak, L.F., Morrison, A.C., Kardia, S.L., Peyser, P.A., and Hixson, J.E. (2013). Genome-wide association study of gene by smoking interactions in coronary artery calcification. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074642"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1038\/s41588-019-0378-y","article-title":"Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids","volume":"51","author":"Bentley","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s12944-020-01287-7","article-title":"Association of common gene-smoking interactions with elevated plasma apolipoprotein B concentration","volume":"19","author":"Roy","year":"2020","journal-title":"Lipids Health Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"707","DOI":"10.3389\/fphar.2018.00707","article-title":"Familial Hypercholesterolemia: New Horizons for Diagnosis and Effective Management","volume":"9","author":"Mytilinaiou","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"511","DOI":"10.3389\/fendo.2018.00511","article-title":"A Renewed Focus on the Association Between Thyroid Hormones and Lipid Metabolism","volume":"9","author":"Duntas","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1089\/10507250252949405","article-title":"Thyroid disease and lipids","volume":"12","author":"Duntas","year":"2002","journal-title":"Thyroid"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1210\/er.2018-00163","article-title":"Thyroid Dysfunction and Diabetes Mellitus: Two Closely Associated Disorders","volume":"40","author":"Biondi","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"76","DOI":"10.2174\/1874192401105010076","article-title":"Effects of thyroid dysfunction on lipid profile","volume":"5","author":"Rizos","year":"2011","journal-title":"Open Cardiovasc. Med. J."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Damiano, F., Rochira, A., Gnoni, A., and Siculella, L. (2017). Action of Thyroid Hormones, T3 and T2, on Hepatic Fatty Acids: Differences in Metabolic Effects and Molecular Mechanisms. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040744"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1365-2362.1981.tb01758.x","article-title":"Serum lipoprotein and apolipoprotein concentrations and tissue lipoprotein-lipase activity in overt and subclinical hypothyroidism: The effect of substitution therapy","volume":"11","author":"Lithell","year":"1981","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"500","DOI":"10.14310\/horm.2002.1707","article-title":"Thyroid hormones: A potential ally to LDL-cholesterol-lowering agents","volume":"15","author":"Duntas","year":"2016","journal-title":"Hormones"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1001\/archinte.160.4.526","article-title":"The Colorado thyroid disease prevalence study","volume":"160","author":"Canaris","year":"2000","journal-title":"Arch. Intern. Med."},{"key":"ref_62","first-page":"108","article-title":"The magnitude of the hypercholesterolemia of hypothyroidism is associated with variation in the low density lipoprotein receptor gene","volume":"77","author":"Wiseman","year":"1993","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_63","first-page":"488","article-title":"Metabolic syndrome prevalence in subclinic and overt hypothyroid patients and the relation among metabolic syndrome parameters","volume":"34","author":"Erdogan","year":"2011","journal-title":"J. Endocrinol. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1210\/jc.2003-030398","article-title":"Hypothyroidism and atherosclerosis","volume":"88","author":"Cappola","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1111\/j.1524-6175.2006.05180.x","article-title":"Hyperthyroidism: A secondary cause of isolated systolic hypertension","volume":"8","author":"Prisant","year":"2006","journal-title":"J. Clin. Hypertens."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3389\/fendo.2019.00482","article-title":"Hypertension in Thyroid Disorders","volume":"10","author":"Berta","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"233","DOI":"10.2165\/00024677-200403040-00005","article-title":"Subclinical hypothyroidism and cardiovascular risk: A reason to treat?","volume":"3","author":"Palmieri","year":"2004","journal-title":"Treat. Endocrinol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1530\/eje.1.02093","article-title":"Vascular and renal function in experimental thyroid disorders","volume":"154","author":"Vargas","year":"2006","journal-title":"Eur. J. Endocrinol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1210\/jcem-43-3-591","article-title":"Reversal of decreased human adipose tissue lipoprotein lipase and hypertriglyceridemia after treatment of hypothyroidism","volume":"43","author":"Goldberg","year":"1976","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.jacl.2018.09.008","article-title":"Diabetes is associated with an increased risk of cardiovascular disease in patients with familial hypercholesterolemia","volume":"13","author":"Paquette","year":"2019","journal-title":"J. Clin. Lipidol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1177\/2047487319878371","article-title":"Diabetes as a cardiovascular risk factor: An overview of global trends of macro and micro vascular complications","volume":"26","author":"Ceriello","year":"2019","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"266","DOI":"10.2174\/1573403X15666191111123622","article-title":"Assessing Cardiovascular Risk in Patients with Diabetes: An Update","volume":"16","author":"Damaskos","year":"2020","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1016\/S0140-6736(10)60484-9","article-title":"Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies","volume":"375","author":"Sarwar","year":"2010","journal-title":"Lancet"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0026-0495(73)90024-3","article-title":"Plasma triglyceride transport kinetics in diabetes mellitus","volume":"22","author":"Kekki","year":"1973","journal-title":"Metabolism"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s11886-015-0589-5","article-title":"Role for combination therapy in diabetic dyslipidemia","volume":"17","author":"Warraich","year":"2015","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s001250051333","article-title":"Very low density lipoprotein subfractions in Type II diabetes mellitus: Alterations in composition and susceptibility to oxidation","volume":"43","author":"McEneny","year":"2000","journal-title":"Diabetologia"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1007\/s001250050700","article-title":"Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM","volume":"40","author":"Packard","year":"1997","journal-title":"Diabetologia"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.2337\/diab.44.9.1059","article-title":"Acute hyperinsulinemia decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in NIDDM","volume":"44","author":"Cummings","year":"1995","journal-title":"Diabetes"},{"key":"ref_79","first-page":"172","article-title":"Differences in postprandial lipemia between patients with normal glucose tolerance and noninsulin-dependent diabetes mellitus","volume":"76","author":"Chen","year":"1993","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s13300-016-0167-x","article-title":"Diabetes Dyslipidemia","volume":"7","author":"Schofield","year":"2016","journal-title":"Diabetes Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.dsx.2016.08.029","article-title":"Size, density and cholesterol load of HDL predict microangiopathy, coronary artery disease and \u03b2-cell function in men with T2DM","volume":"11","author":"Hermans","year":"2017","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1016\/j.amjcard.2016.08.044","article-title":"Diabetes-Invoked High-Density Lipoprotein and Its Association with Coronary Artery Disease in Patients with Type 2 Diabetes Mellitus","volume":"118","author":"Sun","year":"2016","journal-title":"Am. J. Cardiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.2337\/dc16-1246","article-title":"Plasma Triglycerides and HDL-C Levels Predict the Development of Diabetic Kidney Disease in Subjects with Type 2 Diabetes: The AMD Annals Initiative","volume":"39","author":"Russo","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_84","first-page":"188","article-title":"Poor glycemic control in type 2 diabetes enhances functional and compositional alterations of small, dense HDL3c","volume":"1862","author":"Lhomme","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Cell. Biol. Lipids"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1161\/CIRCGENETICS.116.001457","article-title":"Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program","volume":"9","author":"Varga","year":"2016","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"333","DOI":"10.2147\/DMSO.S115855","article-title":"Diabetes and dyslipidemia: Characterizing lipoprotein metabolism","volume":"10","author":"Tomkin","year":"2017","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1016\/0026-0495(93)90138-E","article-title":"Insulin sensitivity in familial hypercholesterolemia","volume":"42","author":"Galvan","year":"1993","journal-title":"Metabolism"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2556","DOI":"10.1001\/jama.2011.860","article-title":"Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: A meta-analysis","volume":"305","author":"Preiss","year":"2011","journal-title":"JAMA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1001\/jama.2015.1206","article-title":"Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus","volume":"313","author":"Besseling","year":"2015","journal-title":"JAMA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"5596","DOI":"10.1038\/s41598-017-06101-6","article-title":"Effect of LDL cholesterol, statins and presence of mutations on the prevalence of type 2 diabetes in heterozygous familial hypercholesterolemia","volume":"7","author":"Climent","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.atherosclerosis.2014.08.047","article-title":"Statin therapy and risk of diabetes in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia","volume":"237","author":"Skoumas","year":"2014","journal-title":"Atherosclerosis"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1016\/j.jacc.2016.03.520","article-title":"Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients with Severe Hypercholesterolemia","volume":"67","author":"Khera","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.2337\/db17-0173","article-title":"Familial Hypercholesterolemia and Type 2 Diabetes in the Old Order Amish","volume":"66","author":"Xu","year":"2017","journal-title":"Diabetes"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"107788","DOI":"10.1016\/j.diabres.2019.107788","article-title":"Decreasing incidence of pharmacologically treated Type 2 diabetes in Hungary from 2001 to 2016: A nationwide cohort study","volume":"155","author":"Jermendy","year":"2019","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.atherosclerosis.2018.06.857","article-title":"Treatment pattern of familial hypercholesterolemia in Slovakia: Targets, treatment and obstacles in common practice","volume":"277","author":"Vohnout","year":"2018","journal-title":"Atherosclerosis"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s13300-019-00748-2","article-title":"Familial Hypercholesterolaemia in a Bulgarian Population of Patients with Dyslipidaemia and Diabetes: An Observational Study","volume":"11","author":"Tankova","year":"2020","journal-title":"Diabetes Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev.med.56.082103.104751","article-title":"Metabolic syndrome: A clinical and molecular perspective","volume":"56","author":"Moller","year":"2005","journal-title":"Annu. Rev. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3407306","DOI":"10.1155\/2018\/3407306","article-title":"The Impact of Obesity on the Cardiovascular System","volume":"2018","author":"Csige","year":"2018","journal-title":"J. Diabetes Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"6184","DOI":"10.3390\/ijms15046184","article-title":"Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease","volume":"15","author":"Jung","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s40477-019-00368-3","article-title":"Epicardial fat thickness is significantly increased and related to LDL cholesterol level in patients with familial hypercholesterolemia","volume":"22","author":"Bulut","year":"2019","journal-title":"J. Ultrasound"},{"key":"ref_101","first-page":"s176","article-title":"Obesity: Definition, comorbidities, causes, and burden","volume":"22","author":"Apovian","year":"2016","journal-title":"Am. J. Manag. Care"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"101090","DOI":"10.1016\/j.molmet.2020.101090","article-title":"Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease","volume":"46","author":"Baggio","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.3945\/jn.114.191775","article-title":"Serum lipid responses to weight loss differ between overweight adults with familial hypercholesterolemia and those with familial combined hyperlipidemia","volume":"144","author":"Cenarro","year":"2014","journal-title":"J. Nutr."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s12020-014-0327-6","article-title":"GH and the cardiovascular system: An update on a topic at heart","volume":"48","author":"Isgaard","year":"2015","journal-title":"Endocrine"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"876","DOI":"10.4103\/2230-8210.117234","article-title":"Evaluation of left ventricular mass and function, lipid profile, and insulin resistance in Egyptian children with growth hormone deficiency: A single-center prospective case-control study","volume":"17","author":"Metwalley","year":"2013","journal-title":"Indian J. Endocrinol. Metab."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1210\/jcem.86.3.7268","article-title":"Cardiac mass and function, carotid artery intima-media thickness, and lipoprotein levels in growth hormone-deficient adolescents","volume":"86","author":"Lanes","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1159\/000444143","article-title":"Growth Hormone Deficiency in Prepubertal Children: Predictive Markers of Cardiovascular Disease","volume":"85","author":"Stevens","year":"2016","journal-title":"Horm. Res. Paediatr."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1161\/01.ATV.0000110657.67317.90","article-title":"Growth hormone induces low-density lipoprotein clearance but not bile acid synthesis in humans","volume":"24","author":"Lind","year":"2004","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"691490","DOI":"10.3389\/fendo.2021.691490","article-title":"Case Report: A Clinical and Genetic Analysis of Childhood Growth Hormone Deficiency with Familial Hypercholesterolemia","volume":"12","author":"Yang","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/MED.0b013e32834ec952","article-title":"Diagnosis of growth hormone deficiency in childhood","volume":"19","author":"Stanley","year":"2012","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.atherosclerosis.2015.05.034","article-title":"Gonadal steroids, gonadotropins and DHEAS in young adults with familial hypercholesterolemia who had initiated statin therapy in childhood","volume":"241","author":"Braamskamp","year":"2015","journal-title":"Atherosclerosis"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/0960-0760(91)90333-Z","article-title":"The HMG-CoA reductase inhibitor simvastatin suppresses human testicular testosterone synthesis in vitro by a selective inhibitory effect on 17-ketosteroid-oxidoreductase enzyme activity","volume":"38","author":"Smals","year":"1991","journal-title":"J. Steroid. Biochem. Mol. Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1159\/000499285","article-title":"The Association between Serum Testosterone and Risk Factors for Atherosclerosis","volume":"13","author":"Rezanezhad","year":"2019","journal-title":"Curr. Urol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1210\/jc.2011-2513","article-title":"Characteristics of androgen deficiency in late-onset hypogonadism: Results from the European Male Aging Study (EMAS)","volume":"97","author":"Tajar","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"828","DOI":"10.2337\/dc10-1233","article-title":"Testosterone replacement in hypogonadal men with type 2 diabetes and\/or metabolic syndrome (the TIMES2 study)","volume":"34","author":"Jones","year":"2011","journal-title":"Diabetes Care"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1159\/000485999","article-title":"Metabolic Syndrome in Male Hypogonadism","volume":"49","author":"Rastrelli","year":"2018","journal-title":"Front. Horm. Res."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Popovic, V., and Korbonits, M. (2018). Metabolic Syndrome Consequent to Endocrine Disorders, Karger.","DOI":"10.1159\/isbn.978-3-318-06335-6"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/dmrr.2354","article-title":"Androgen therapy in men with testosterone deficiency: Can testosterone reduce the risk of cardiovascular disease?","volume":"28","author":"Saad","year":"2012","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"3495","DOI":"10.1111\/j.1743-6109.2010.01931.x","article-title":"Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: Results from a 24-month, randomized, double-blind, placebo-controlled study","volume":"7","author":"Aversa","year":"2010","journal-title":"J. Sex. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1097\/MED.0b013e32814db856","article-title":"Androgen deficiency, diabetes, and the metabolic syndrome in men","volume":"14","author":"Kalyani","year":"2007","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"137","DOI":"10.5468\/ogs.2013.56.3.137","article-title":"Dyslipidemia in women with polycystic ovary syndrome","volume":"56","author":"Kim","year":"2013","journal-title":"Obstet. Gynecol. Sci."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"790454","DOI":"10.3389\/fcvm.2021.790454","article-title":"Prevalence, Pattern and Predictors for Dyslipidemia of Chinese Women with Polycystic Ovary Syndrome","volume":"8","author":"Luo","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.tjog.2019.05.003","article-title":"Dyslipidemia involvement in the development of polycystic ovary syndrome","volume":"58","author":"Liu","year":"2019","journal-title":"Taiwan. J. Obstet. Gynecol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.fertnstert.2017.10.018","article-title":"Metabolic syndrome, hypertension, and hyperlipidemia in mothers, fathers, sisters, and brothers of women with polycystic ovary syndrome: A systematic review and meta-analysis","volume":"109","author":"Yilmaz","year":"2018","journal-title":"Fertil. Steril."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1161\/CIRCULATIONAHA.110.990929","article-title":"Pregnancy outcomes in familial hypercholesterolemia: A registry-based study","volume":"124","author":"Toleikyte","year":"2011","journal-title":"Circulation"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"079","DOI":"10.29328\/journal.cjog.1001026","article-title":"Gestational hypercholesterolemia helps detect familial hypercholesterolemia and prevent late pregnancy complications","volume":"2","author":"Pehal","year":"2019","journal-title":"Clin. J. Obstet. Gynecol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1056\/NEJM200404083501524","article-title":"Central nervous system and limb anomalies in case reports of first-trimester statin exposure","volume":"350","author":"Edison","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.atherosclerosis.2021.09.003","article-title":"Loss of statin treatment years during pregnancy and breastfeeding periods in women with familial hypercholesterolemia","volume":"335","author":"Klevmoen","year":"2021","journal-title":"Atherosclerosis"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S0140-6736(04)15467-6","article-title":"Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia","volume":"363","author":"Wiegman","year":"2004","journal-title":"Lancet"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.atherosclerosis.2007.12.014","article-title":"No correlation and low agreement of imaging and inflammatory atherosclerosis\u2019 markers in familial hypercholesterolemia","volume":"200","author":"Martinez","year":"2008","journal-title":"Atherosclerosis"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1016\/j.jcmg.2018.09.019","article-title":"Coronary Artery Calcium and Cardiovascular Events in Patients with Familial Hypercholesterolemia Receiving Standard Lipid-Lowering Therapy","volume":"12","author":"Miname","year":"2019","journal-title":"JACC Cardiovasc. Imaging"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"634","DOI":"10.5551\/jat.42705","article-title":"Aortic Root Calcification Score as an Independent Factor for Predicting Major Adverse Cardiac Events in Familial Hypercholesterolemia","volume":"25","author":"Okada","year":"2018","journal-title":"J. Atheroscler. Thromb."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/7\/1158\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:05Z","timestamp":1760139545000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/7\/1158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,27]]},"references-count":132,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["genes13071158"],"URL":"https:\/\/doi.org\/10.3390\/genes13071158","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,27]]}}}