{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:43:36Z","timestamp":1760150616955,"version":"build-2065373602"},"reference-count":31,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:00:00Z","timestamp":1702857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Familial hypercholesterolemia (FH) is an inherited metabolic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-c) from birth. About 85% of all FH cases are caused by pathogenic variants in the LDLR gene. Individuals with FH have increased cardiovascular risk, including a high risk of premature myocardial infarction (PMI). Methods: We conducted an opportunistic exome screening to identify variants in the LDLR gene among Vietnamese patients with PMI treated at a general hospital in southern Vietnam. A cascade testing for LDLR variants was conducted in their relatives within three generations, and the effects of the LDLR variant on the response to rosuvastatin treatment were also studied using a comparative before-and-after study design on those who were eligible. Results: A total of 99 participants from the three generations of four PMI patients were recruited, mean age 37.3 \u00b1 18.5 years, 56.6% males. Sanger sequencing revealed two variants in the LDLR gene: variant rs577934998 (c.664T&gt;C), detected in 17 individuals within one family, and variant rs12710260 (c.1060+10G&gt;C), found in 32 individuals (49.5%) in the other three families tested. Individuals harboring the variant c.664T&gt;C had significantly higher baseline LDL-c and total cholesterol levels compared to those with variant c.1060+10G&gt;C (classified as benign) or those without LDLR variants, and among the 47 patients subjected to a 3-month course of rosuvastatin therapy, those with variant c.664T&gt;C had a significantly higher risk of not achieving the LDL-c target after the course of treatment compared to the c.1060+10G&gt;C carriers. Conclusions: These findings provide evidence supporting the existence of pathogenic LDLR variants in Vietnamese patients with PMI and their relatives and may indicate the need for personalizing lipid-lowering therapies. Further studies are needed to delineate the extent and severity of the problem.<\/jats:p>","DOI":"10.3390\/jpm13121725","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T05:41:35Z","timestamp":1702878095000},"page":"1725","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Prevalent Variants in the LDLR Gene Impair Responsiveness to Rosuvastatin among Family Members of Patients with Premature Myocardial Infarction"],"prefix":"10.3390","volume":"13","author":[{"given":"Nguyen Trung","family":"Kien","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho 900000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1485-2813","authenticated-orcid":false,"given":"Tran Tin","family":"Nghia","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho 900000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nguyen Minh","family":"Hoang","sequence":"additional","affiliation":[{"name":"Tra Vinh General Hospital, Tra Vinh 940000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tran Nguyen Trong","family":"Phu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho 900000, Vietnam"},{"name":"Faculty of Medicine, Chulalongkorn University, 1873, Rama 4 Road, Pathumwan, Bangkok 10330, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9321-132X","authenticated-orcid":false,"given":"Pham Thi Ngoc","family":"Nga","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho 900000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9962-2165","authenticated-orcid":false,"given":"Ha Thi Thao","family":"Mai","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho 900000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1794-6666","authenticated-orcid":false,"given":"J. Luis","family":"Espinoza","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Kanazawa University, Kanazawa 920-0942, Ishikawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"83","DOI":"10.4274\/balkanmedj.galenos.2022-2-19","article-title":"Premature Myocardial Infarction: A Rising Threat","volume":"39","author":"Kayikcioglu","year":"2022","journal-title":"Balk. Med. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.mayocpiqo.2021.03.009","article-title":"Risk Factors for Premature Myocardial Infarction: A Systematic Review and Meta-analysis of 77 Studies","volume":"5","author":"Dugani","year":"2021","journal-title":"Mayo Clin. Proc. Innov. Qual. Outcomes"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1007\/s11883-008-0030-2","article-title":"Genetics of premature myocardial infarction","volume":"10","author":"Roberts","year":"2008","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Henderson, R., O\u2019kane, M., McGilligan, V., and Watterson, S. (2016). The genetics and screening of familial hypercholesterolaemia. J. Biomed. Sci., 23.","DOI":"10.1186\/s12929-016-0256-1"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12967-018-1737-7","article-title":"Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease","volume":"16","author":"Cao","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1093\/eurheartj\/ehn422","article-title":"Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: A prospective registry study","volume":"29","author":"Neil","year":"2008","journal-title":"Eur. Heart J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1097\/00125817-200207000-00005","article-title":"High \u201cpopulation attributable fraction\u201d for coronary heart disease mortality among relatives in monogenic familial hypercholesterolemia","volume":"4","author":"Austin","year":"2002","journal-title":"Genet Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s12687-018-0383-3","article-title":"Barriers to the identification of familial hypercholesterolemia among primary care providers","volume":"10","author":"Zimmerman","year":"2019","journal-title":"J. Community Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3478","DOI":"10.1093\/eurheartj\/eht273","article-title":"Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society","volume":"34","author":"Nordestgaard","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"413","DOI":"10.29090\/psa.2021.05.20.144","article-title":"Efficacy of Rosuvastatin and Atorvastatin in Vietnamese Patients with Acute Coronary Syndrome: A randomized trial","volume":"48","author":"Tran","year":"2021","journal-title":"Pharm Sci Asia."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.atherosclerosis.2018.06.013","article-title":"Homozygous familial hypercholesterolaemia in Vietnam: Case series, genetics and cascade testing of families","volume":"277","author":"Truong","year":"2018","journal-title":"Atherosclerosis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"914","DOI":"10.3389\/fgene.2020.00914","article-title":"Genetics, Screening, and Treatment of Familial Hypercholesterolemia: Experience Gained from the Implementation of the Vietnam Familial Hypercholesterolemia Registry","volume":"11","author":"Truong","year":"2020","journal-title":"Front. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1161\/01.ATV.18.6.1007","article-title":"Association of Specific LDL Receptor Gene Mutations With Differential Plasma Lipoprotein Response to Simvastatin in Young French Canadians With Heterozygous Familial Hypercholesterolemia","volume":"18","author":"Couture","year":"1998","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.cjca.2021.10.013","article-title":"Influence of the LDL-Receptor Genotype on Statin Response in Heterozygous Familial Hypercholesterolemia: Insights from the Canadian FH Registry","volume":"38","author":"Roy","year":"2022","journal-title":"Can. J. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1097\/01213011-200504000-00005","article-title":"Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia","volume":"15","author":"Miltiadous","year":"2005","journal-title":"Pharmacogenet. Genom."},{"key":"ref_16","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":"2020","journal-title":"Eur. Heart J."},{"key":"ref_17","first-page":"293","article-title":"The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel Consensus Guidelines for LDLR Variant Classification","volume":"24","author":"Chora","year":"2021","journal-title":"Genet. Genom. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"639","DOI":"10.5551\/jat.62773","article-title":"Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia","volume":"29","author":"Huang","year":"2022","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.atherosclerosis.2016.10.028","article-title":"Spectrum of mutations in homozygous familial hypercholesterolemia in India, with four novel mutations","volume":"255","author":"Setia","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.atherosclerosis.2016.08.037","article-title":"Clinical characterization and mutation spectrum of German patients with familial hypercholesterolemia","volume":"253","author":"Grenkowitz","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1034\/j.1399-0004.2000.580202.x","article-title":"Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia","volume":"58","author":"Khoo","year":"2000","journal-title":"Clin. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.jacl.2016.02.020","article-title":"Genetic causes of monogenic familial hypercholesterolemia in the Greek population: Lessons, mistakes, and the way forward","volume":"10","author":"Mollaki","year":"2016","journal-title":"J. Clin. Lipidol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"625959","DOI":"10.3389\/fgene.2021.625959","article-title":"Mutational Spectrum of LDLR and PCSK9 Genes Identified in Iranian Patients With Premature Coronary Artery Disease and Familial Hypercholesterolemia","volume":"12","author":"Moradi","year":"2021","journal-title":"Front. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13282","DOI":"10.1016\/S0021-9258(18)37702-0","article-title":"Mutational analysis of the ligand binding domain of the low density lipoprotein receptor","volume":"263","author":"Esser","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1093\/eurheartj\/ehp051","article-title":"Familial-combined hyperlipidaemia in very young myocardial infarction survivors (< or =40 years of age)","volume":"30","author":"Wiesbauer","year":"2009","journal-title":"Eur. Heart J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2147\/TACG.S202942","article-title":"High prevalence of genetic determined familial hypercholesterolemia in premature coronary artery disease","volume":"12","author":"Pirazzi","year":"2019","journal-title":"Appl. Clin. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/humu.9218","article-title":"Molecular characterization of familial hypercholesterolemia in German and Greek patients","volume":"23","author":"Dedoussis","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"gmr16039226","DOI":"10.4238\/gmr16039226","article-title":"Research Article Mutational screening in the LDLR gene among patients presenting familial hypercholesterolemia in the Southeast of Brazil","volume":"16","author":"Molfetta","year":"2017","journal-title":"Genet. Mol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s00439-002-0813-4","article-title":"Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia","volume":"111","author":"Amsellem","year":"2002","journal-title":"Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1136\/jmedgenet-2016-104054","article-title":"The UCL low-density lipoprotein receptor gene variant database: Pathogenicity update","volume":"54","author":"Leigh","year":"2017","journal-title":"J. Med. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.atherosclerosis.2013.12.028","article-title":"Presence and type of low density lipoprotein receptor (LDLR) mutation influences the lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia","volume":"233","author":"Santos","year":"2014","journal-title":"Atherosclerosis"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/12\/1725\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:40:47Z","timestamp":1760132447000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/12\/1725"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,18]]},"references-count":31,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["jpm13121725"],"URL":"https:\/\/doi.org\/10.3390\/jpm13121725","relation":{},"ISSN":["2075-4426"],"issn-type":[{"type":"electronic","value":"2075-4426"}],"subject":[],"published":{"date-parts":[[2023,12,18]]}}}