Genes Potentially Associated with Familial Hypercholesterolemia
Abstract
1. Introduction
2. STAP1
3. CYP7A1
4. LIPA
5. ABCG5 and ABCG8
6. PNPLA5
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
List of Abbreviations
aa | amino acid residues |
FH | familial hypercholesterolemia |
HDL-C | high-density lipoprotein cholesterol |
IHD | ischemic heart disease |
LDL-C | low-density lipoprotein cholesterol |
NGS | next-generation sequencing |
TC | total cholesterol |
TG | triglycerides |
References
- Ezhov, M.V.; Bazhan, S.S.; Ershova, A.I. Clinical guidelines for familial hypercholesterolemia. J. Atheroscler. Dyslipidemias 2019, 1, 5–43. [Google Scholar] [CrossRef]
- Goldberg, A.C.; Hopkins, P.N.; Toth, P.P.; Ballantyne, C.M.; Rader, D.J.; Robinson, J.G.; Daniels, S.R.; Gidding, S.S.; de Ferranti, S.D.; Ito, M.K.; et al. Executive Summary Familial Hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients Clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J. Clin. Lipidol. 2011, 5, S1–S8. [Google Scholar] [CrossRef] [PubMed]
- Vella, A.; Pineda, A.A.; O’Brien, T. Low-density lipoprotein apheresis for the treatment of refractory hyperlipidemia. Mayo Clin. Proc. 2001, 76, 1039–1046. [Google Scholar] [CrossRef] [PubMed]
- Thompsen, J.; Thompson, P.D. A systematic review of LDL apheresis in the treatment of cardiovascular disease. Atherosclerosis 2006, 189, 31–38. [Google Scholar] [CrossRef] [PubMed]
- Marks, D.; Thorogood, M.; Neil, H.A.W.; Humphries, S.E. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 2003, 168, 1–14. [Google Scholar] [CrossRef]
- Rodenburg, J.; Vissers, M.N.; Wiegman, A.; Trip, M.D.; Bakker, H.D.; Kastelein, J.J. Familial hypercholesterolemia in children. Curr. Opin. Lipidol. 2004, 15, 405–411. [Google Scholar] [CrossRef]
- Gidding, S.S.; Ann Champagne, M.; de Ferranti, S.D.; Defesche, J.; Ito, M.K.; Knowles, J.W.; McCrindle, B.; Raal, F.; Rader, D.; Santos, R.D.; et al. The agenda for familial hypercholesterolemia: A scientific statement from the American heart association. Circulation 2015, 132, 2167–2192. [Google Scholar] [CrossRef]
- Leren, T.P. Cascade genetic screening for familial hypercholesterolemia. Clin. Genet. 2004, 66, 483–487. [Google Scholar] [CrossRef]
- Watts, G.F.; Gidding, S.; Wierzbicki, A.S.; Toth, P.P.; Alonso, R.; Brown, W.V.; Bruckert, E.; Defesche, J.; Lin, K.K.; Livingston, M.; et al. International FH Foundation. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation: Executive summary. Int J. Cardiol. 2014, 171, 309–325. [Google Scholar] [CrossRef]
- Familial Hypercholesterolaemia: Identification and Management. NICE Guideline. 2008. Available online: https://www.nice.org.uk/guidance/cg71/resources/familial-hypercholesterolaemia-identification-and-management-pdf-975623384005 (accessed on 27 August 2008).
- Wiegman, A.; Gidding, S.S.; Watts, G.F.; Chapman, M.J.; Ginsberg, H.N.; Cuchel, M.; Ose, L.; Averna, M.; Boileau, C.; Borén, J.; et al. European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: Gaining decades of life by optimizing detection and treatment. Eur. Heart J. 2015, 36, 2425–2437. [Google Scholar] [CrossRef]
- Cuchel, M.; Bruckert, E.; Ginsberg, H.N.; Raal, F.J.; Santos, R.D.; Hegele, R.A.; Kuivenhoven, J.A.; Nordestgaard, B.G.; Descamps, O.S.; Steinhagen-Thiessen, E.; et al. European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. Homozygous familial hypercholesterolaemia: New insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur. Heart J. 2014, 35, 2146–2157. [Google Scholar] [CrossRef] [PubMed]
- Leren, T.P.; Finborud, T.H.; Manshaus, T.E.; Ose, L.; Berge, K.E. Diagnosis of Familial Hypercholesterolemia in General Practice Using Clinical Diagnostic Criteria or Genetic Testing as Part of Cascade Genetic Screening. Public Health Genom. 2008, 11, 26–35. [Google Scholar] [CrossRef] [PubMed]
- Kanehisa, M.; Sato, Y.; Furumichi, M.; Morishima, K.; Tanabe, M. New approach for understanding genome variations in KEGG. Nucleic Acids Res. 2019, 47, D590–D595. [Google Scholar] [CrossRef] [PubMed]
- Humphries, S.E.; Whittall, R.A.; Hubbart, C.S.; Maplebeck, S.; Cooper, J.A.; Soutar, A.K.; Naoumova, R.; Thompson, G.R.; Seed, M.; Durrington, P.N.; et al. Genetic causes of familial hypercholesterolaemia in patients in the UK: Relation to plasma lipid levels and coronary heart disease risk. J. Med. Genet. 2006, 43, 943–949. [Google Scholar] [CrossRef] [PubMed]
- Marduel, M.; Carrié, A.; Sassolas, A.; Devillers, M.; Carreau, V.; Di Filippo, M.; Erlich, D.; Abifadel, M.; Marques-Pinheiro, A.; Munnich, A.; et al. Molecular Spectrum of Autosomal Dominant Hypercholesterolemia in France. Hum. Mutat. 2010, 31, E1811–E1824. [Google Scholar] [CrossRef] [PubMed]
- Iacocca, M.A.; Hegele, R.A. Recent advances in genetic testing for familial hypercholesterolemia. Expert Rev. Mol. Diagn. 2017, 17, e641–e651. [Google Scholar] [CrossRef]
- Hooper, A.J.; Nguyen, L.T.; Burnett, J.R.; Bates, T.R.; Bell, D.A.; Redgrave, T.G.; Watts, G.F.; Van Bockxmeer, F.M. Genetic analysis of familial hypercholesterolaemia in Western Australia. Atherosclerosis 2012, 224, e430–e434. [Google Scholar] [CrossRef]
- Talmud, P.J.; Shah, S.; Whittall, R.; Futema, M.; Howard, P.; Cooper, J.A.; Harrison, S.C.; Li, K.; Drenos, F.; Karpe, F.; et al. Use of low density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: A case-control study. Lancet 2013, 381, e1293–e1301. [Google Scholar] [CrossRef]
- Day, I.N.M. FH4=STAP1. Another Gene for Familial Hypercholesterolemia? Relevance to Cascade Testing and Drug Development? Circ. Res. 2014, 115, 534–536. [Google Scholar] [CrossRef]
- Ohya, K.I.; Kajigaya, S.; Kitanaka, A.; Yoshida, K.; Miyazato, A.; Yamashita, Y.; Yamanaka, T.; Ikeda, U.; Shimada, K.; Ozawa, K.; et al. Molecular cloning of a docking protein, BRDG1, that acts downstream of the Tec tyrosine kinase. Proc. Natl. Acad. Sci. USA 1999, 96, 11976–11981. [Google Scholar] [CrossRef]
- Masuhara, M.; Nagao, K.; Nishikawa, M.; Sasaki, M.; Yoshimura, A.; Osawa, M. Molecular cloning of murine STAP-1, the stem-cell-specific adaptor protein containing PH and SH2 domains. Biochem. Biophys. Res. Commun. 2000, 268, 697–703. [Google Scholar] [CrossRef] [PubMed]
- Yokohari, K.; Yamashita, Y.; Okada, S.; Ohya, K.I.; Oda, S.; Hatano, M.; Mano, H.; Hirasawa, H.; Tokuhisa, T. Isoform-dependent interaction of BRDG1 with Tec kinase. Biochem. Biophys. Res. Commun. 2001, 289, 414–420. [Google Scholar] [CrossRef] [PubMed]
- Kaneko, T.; Huang, H.; Zhao, B.; Li, L.; Liu, H.; Voss, C.K.; Wu, C.; Schiller, M.R.; Li, S.S. Loops govern SH2 domain specificity by controlling access to binding pockets. Sci. Signal. 2010, 3, ra34. [Google Scholar] [CrossRef] [PubMed]
- Kim, T.D.; Rea, D. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia 2013, 27, 1316–1321. [Google Scholar] [CrossRef] [PubMed]
- Rea, D.; Mirault, T.; Cluzeau, T.; Gautier, J.F.; Guilhot, F.; Dombret, H.; Messas, E. Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia. Haematologica 2014, 99, 1197–1203. [Google Scholar] [CrossRef]
- Stoecker, K.; Weigelt, K. Induction of STAP-1 promotes neurotoxic activation of microglia. Biochem. Biophys. Res. Commun. 2009, 379, 121–126. [Google Scholar] [CrossRef]
- Ma, J.; Dempsey, A.A.; Stamatiou, D.; Marshall, K.W.; Liew, C.C. Identifying leukocyte gene expression patterns associated with plasma lipid levels in human subjects. Atherosclerosis 2007, 191, 63–72. [Google Scholar] [CrossRef]
- Fouchier, S.W.; Dallinga-Thie, G.M.; Meijers, J.C.; Zelcer, N.; Kastelein, J.J.; Defesche, J.C.; Hovingh, G.K. Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. Circ. Res. 2014, 115, 552–555. [Google Scholar] [CrossRef]
- Brænne, I.; Kleinecke, M.; Reiz, B.; Graf, E.; Strom, T.; Wieland, T.; Fischer, M.; Kessler, T.; Hengstenberg, C.; Meitinger, T.; et al. Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. Eur. J. Hum. Genet. 2016, 24, 191–197. [Google Scholar] [CrossRef]
- Amor-Salamanca, A.; Castillo, S.; Gonzalez-Vioque, E.; Dominguez, F.; Quintana, L.; Lluís-Ganella, C.; Escudier, J.M.; Ortega, J.; Lara-Pezzi, E.; Alonso-Pulpon, L.; et al. Genetically Confirmed Familial Hypercholesterolemia in Patients With Acute Coronary Syndrome. J. Am. Coll. Cardiol. 2017, 70, 1732–1740. [Google Scholar] [CrossRef]
- Blanco-Vaca, F.; Martín-Campos, J.M.; Pérez, A.; Fuentes-Prior, P. Rare STAP1 mutation incompletely associated with familial hypercholesterolemia. Clin. Chim. Acta 2018, 487, 270–274. [Google Scholar] [CrossRef] [PubMed]
- Cao, Y.X.; Wu, N.Q.; Sun, D.; Liu, H.H.; Jin, J.L.; Li, S.; Guo, Y.L.; Zhu, C.G.; Gao, Y.; Dong, Q.T.; et al. Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease. J. Transl. Med. 2018, 16, 345. [Google Scholar] [CrossRef] [PubMed]
- Hartgers, M.; Reeskamp, R.; Winkelmeijer, M.; Volta, A.; Hovingh, K.; Grehorst, A. Grehorst Variants in signal transducing adaptor family member 1 (STAP1) do not affect LDL-cholesterol. Atherosclerosis 2019, 287, e79. [Google Scholar] [CrossRef]
- Danyel, M.; Ott, C.E.; Grenkowitz, T.; Salewsky, B.; Hicks, A.A.; Fuchsberger, C.; Steinhagen-Thiessen, E.; Bobbert, T.; Kassner, U.; Demuth, I. Evaluation of the role of STAP1 in Familial Hypercholesterolemia. Sci. Rep. 2019, 9, 11995. [Google Scholar] [CrossRef] [PubMed]
- Nakamoto, K.; Wang, S. Linkage disequilibrium blocks, haplotype structure, and htSNPs of human CYP7AI gene. BMC Genet. 2006, 7, 29. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Kim, I.; Ahn, S.H.; Inagaki, T.; Choi, M.; Ito, S.; Guo, G.L.; Kliewer, S.A.; Gonzalez, F.J. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J. Lipid Res. 2007, 48, 2664–2672. [Google Scholar] [CrossRef] [PubMed]
- Li, T.; Chanda, D.; Zhang, Y.; Choi, H.S.; Chiang, J.Y. Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes. J. Lipid Res. 2010, 51, 832–842. [Google Scholar] [CrossRef]
- Gong, R.; Lv, X.; Liu, F. MiRNA-17 encoded by the miR-17-92 cluster increases the potential for steatosis in hepatoma cells by targeting CYP7A1. Cell. Mol. Biol. Lett. 2018, 23, 16. [Google Scholar] [CrossRef]
- Liao, Y.C.; Lin, H.F.; Rundek, T.; Cheng, R.; Hsi, E.; Sacco, R.L.; Juo, S.H. Multiple genetic determinants of plasma lipid levels in Caribbean Hispanics. Clin. Biochem. 2008, 41, 306–312. [Google Scholar] [CrossRef]
- Iwanicki, T.; Balcerzyk, A.; Niemiec, P.; Nowak, T.; Ochalska-Tyka, A.; Krauze, J.; Kosiorz-Gorczynska, S.; Grzeszczak, W.; Zak, I. CYP7A1 Gene Polymorphism Located in the 5′ Upstream Region Modifies the Risk of Coronary Artery Disease. Dis. Markers 2015, 2015, 6. [Google Scholar] [CrossRef]
- Qayyum, F.; Lauridsen, B.K.; Frikke-Schmidt, R.; Kofoed, K.F.; Nordestgaard, B.G.; Tybjærg-Hansen, A. Genetic variants in CYP7A1 and risk of myocardial infarction and symptomatic gallstone disease. Eur. Heart J. 2018, 39, 2106–2116. [Google Scholar] [CrossRef]
- Vlachová, M.; Blahová, T.; Lánská, V.; Leníček, M.; Piťha, J.; Vítek, L.; Kovář, J. Diurnal variation in cholesterol 7α-hydroxylase activity is determined by the -203A>C polymorphism of the CYP7A1 gene. Croat. Med. J. 2016, 57, 111–117. [Google Scholar] [CrossRef] [PubMed]
- Wang, D.; Hartmann, K.; Seweryn, M.; Sadee, W. Interactions Between Regulatory Variants in CYP7A1 (Cholesterol 7α-Hydroxylase) Promoter and Enhancer Regions Regulate CYP7A1 Expression. Circ. Genom. Precis. Med. 2018, 11, e002082. [Google Scholar] [CrossRef] [PubMed]
- Ameis, D.; Merkel, M.; Eckerskorn, C.; Greten, H. Purification, characterization and molecular cloning of human hepaticlysosomal acid lipase. Eur. J. Biochem. 1994, 219, 905–914. [Google Scholar] [CrossRef] [PubMed]
- Klima, H.; Ullrich, K.; Aslanidis, C.; Fehringer, P.; Lackner, K.J.; Schmitz, G. A splice junction mutation causes deletion of a 72-base exon from the mRNA for lysosomal acid lipase in a patient with cholesteryl ester storage disease. J. Clin. Investig. 1993, 92, 2713–2718. [Google Scholar] [CrossRef] [PubMed]
- Aslanidis, C.; Ries, S.; Fehringer, P.; Büchler, C.; Klima, H.; Schmitz, G. Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity. Genomics 1996, 33, 85–93. [Google Scholar] [CrossRef]
- Anderson, R.A.; Bryson, G.M.; Parks, J.S. Lysosomal acid lipase mutations that determine phenotype in Wolman and cholesterol ester storage disease. Mol. Genet. Metab. 1999, 68, 333–345. [Google Scholar] [CrossRef]
- Fouchier, S.W.; Defesche, J.C. Lysosomal acid lipase A and the hypercholesterolaemic phenotype. Curr. Opin. Lipidol. 2013, 24, 332–338. [Google Scholar] [CrossRef]
- Guénard, F.; Houde, A.; Bouchard, L.; Tchernof, A.; Deshaies, Y.; Biron, S.; Lescelleur, O.; Biertho, L.; Marceau, S.; Pérusse, L.; et al. Association of LIPA gene polymorphisms with obesity-related metabolic complications among severely obese patients. Obesity 2012, 20, 2075–2082. [Google Scholar] [CrossRef]
- Pisciotta, L.; Tozzi, G.; Travaglini, L.; Taurisano, R.; Lucchi, T.; Indolfi, G.; Papadia, F.; Di Rocco, M.; D’Antiga, L.; Crock, P.; et al. Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants. Atherosclerosis 2017, 265, 124–132. [Google Scholar] [CrossRef]
- Vargas-Alarcón, G.; Posadas-Romero, C.; Villarreal-Molina, T.; Alvarez-León, E.; Angeles, J.; Vallejo, M.; Posadas-Sánchez, R.; Cardoso, G.; Medina-Urrutia, A.; Kimura-Hayama, E. Single nucleotide polymorphisms within LIPA (Lysosomal Acid Lipase A) gene are associated with susceptibility to premature coronary artery disease. a replication in the genetic of atherosclerotic disease (GEA) Mexican study. PLoS ONE 2013, 8, e74703. [Google Scholar] [CrossRef] [PubMed]
- Vinje, T.; Wierød, L.; Leren, T.P.; Strøm, T.B. Prevalence of cholesteryl ester storage disease among hypercholesterolemic subjects and functional characterization of mutations in the lysosomal acid lipase gene. Mol. Genet. Metab. 2018, 123, 169–176. [Google Scholar] [CrossRef] [PubMed]
- Holmes, R.S.; VandeBerg, J.L.; Cox, L.A. Genomics and proteomics of vertebrate cholesterol ester lipase (LIPA) and cholesterol 25-hydroxylase (CH25H). Biotech 2011, 1, 99–109. [Google Scholar] [CrossRef] [PubMed]
- Morris, G.E.; Braund, P.S.; Moore, J.S.; Samani, N.J.; Codd, V.; Webb, T.R. Coronary artery disease-associated LIPA coding variant rs1051338 reduces lysosomal acid lipase levels and activity in lysosomes. Arterioscler. Thromb. Vasc. Biol. 2017, 37, 1050–1057. [Google Scholar] [CrossRef] [PubMed]
- Scott, S.A.; Liu, B.; Nazarenko, I.; Martis, S.; Kozlitina, J.; Yang, Y.; Ramirez, C.; Kasai, Y.; Hyatt, T.; Peter, I.; et al. Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups. Hepatology 2013, 58, 958–965. [Google Scholar] [CrossRef] [PubMed]
- Bernstein, D.L.; Hülkova, H.; Bialer, M.G.; Desnick, R.J. Cholesteryl ester storage disease: Review of the findings in 135 reported patients with an underdiagnosed disease. J. Hepatol. 2013, 58, 1230–1243. [Google Scholar] [CrossRef] [PubMed]
- Pullinger, C.R.; Stock, E.O.; Movsesyan, I.; Malloy, M.J.; Frost, P.H.; Tripuraneni, R.; Quinn, A.G.; Ishida, B.Y.; Schaefer, E.J.; Asztalos, B.F.; et al. Identification and metabolic profiling of patients with lysosomal acid lipase deficiency. J. Clin. Lipidol. 2015, 9, 716–726. [Google Scholar] [CrossRef]
- Muntoni, S.; Wiebusch, H.; Jansen-Rust, M.; Rust, S.; Schulte, H.; Berger, K.; Pisciotta, L.; Bertolini, S.; Funke, H.; Seedorf, U.; et al. Heterozygosity for lysosomal acid lipase E8SJM mutation and serum lipid concentrations. Nutr. Metab. Cardiovasc. Dis. 2013, 23, 732–736. [Google Scholar] [CrossRef]
- Lee, T.M.; Welsh, M.; Benhamed, S.; Chung, W.K. Intragenic deletion as a novel type of mutation in Wolman disease. Mol. Genet. Metab. 2011, 104, 703–705. [Google Scholar] [CrossRef][Green Version]
- Ameis, D.; Brockmann, G.; Knoblich, R.; Merkel, M.; Ostlund, R.E.; Yang, J.W.; Coates, P.M.; Cortner, J.A.; Feinman, S.V.; Greten, H. A 5’splice-region mutation and a dinucleotide deletion in the lysosomal acid lipase gene in two patients with cholesteryl ester storage disease. J. Lipid Res. 1995, 36, 241–250. [Google Scholar]
- Santillán-Hernández, Y.; Almanza-Miranda, E.; Xin, W.W.; Goss, K.; Vera-Loaiza, A.; Gorráez-De La Mora, M.T.; Piña-Aguilar, R.E. Novel LIPA mutations in Mexican siblings with lysosomal acid lipase deficiency. World J. Gastroenterol. 2015, 21, 1001–1008. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Rajamohan, F.; Reyes, A.R.; Ruangsiriluk, W.; Hoth, L.R.; Han, S.; Caspers, N.; Tu, M.; Ward, J.; Kurumbail, R.G. Expression and functional characterization of human lysosomal acid lipase gene (LIPA) mutation responsible for cholesteryl ester storage disease (CESD) phenotype. Protein Expr. Purif. 2015, 110, 22–29. [Google Scholar] [CrossRef] [PubMed]
- Sjouke, B.; Defesche, J.C.; de Randamie, J.S.; Wiegman, A.; Fouchier, S.W.; Hovingh, G.K. Sequencing for LIPA mutations in patients with a clinical diagnosis of familial hypercholesterolemia. Atherosclerosis 2016, 251, 263–265. [Google Scholar] [CrossRef] [PubMed]
- Chora, J.R.; Alves, A.C.; Medeiros, A.M.; Mariano, C.; Lobarinhas, G.; Guerra, A.; Mansilha, H.; Cortez-Pinto, H.; Bourbon, M. Lysosomal acid lipase deficiency: A hidden disease among cohorts of familial hypercholesterolemia? J. Clin. Lipidol. 2017, 11, 477–484. [Google Scholar] [CrossRef] [PubMed]
- Reiner, Ž.; Guardamagna, O.; Nair, D.; Soran, H.; Hovingh, K.; Bertolini, S.; Jones, S.; Ćorić, M.; Calandra, S.; Hamilton, J.; et al. Lysosomal acid lipase deficiency—an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis 2014, 235, 21–30. [Google Scholar] [CrossRef] [PubMed]
- Cebolla, J.J.; Irun, P.; Mozas, P.; Giraldo, P. Evaluation of two approaches to lysosomal acid lipase deficiency patient identification: An observational retrospective study. Atherosclerosis 2019, 285, 49–54. [Google Scholar] [CrossRef]
- Berge, K.E.; Tian, H.; Graf, G.A.; Yu, L.; Grishin, N.V.; Schultz, J.; Kwiterovich, P.; Shan, B.; Barnes, R.; Hobbs, H.H. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000, 290, 1771–1775. [Google Scholar] [CrossRef]
- Lee, M.H.; Lu, K.; Hazard, S.; Yu, H.; Shulenin, S.; Hidaka, H.; Kojima, H.; Allikmets, R.; Sakuma, N.; Pegoraro, R.; et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat. Genet. 2001, 27, 79–83. [Google Scholar] [CrossRef]
- Back, S.S.; Kim, J.; Choi, D.; Lee, E.S.; Choi, S.Y.; Han, K. Cooperative transcriptional activation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 genes by nuclear receptors including Liver-X-Receptor. BMB Rep. 2013, 46, 322–327. [Google Scholar] [CrossRef]
- Patel, S.B.; Salen, G.; Hidaka, H.; Kwiterovich, P.O.; Stalenhoef, A.F.; Miettinen, T.A.; Grundy, S.M.; Lee, M.H.; Rubenstein, J.S.; Polymeropoulos, M.H.; et al. Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21. J. Clin. Investig. 1998, 102, 1041–1044. [Google Scholar] [CrossRef]
- Shulenin, S.; Schriml, L.M.; Remaley, A.T.; Fojo, S.; Brewer, B.; Allikmets, R.; Dean, M. An ATP-binding cassette gene (ABCG5) from the ABCG (White) gene subfamily maps to human chromosome 2p21 in the region of the Sitosterolemia locus. Cytogenet. Genome Res. 2001, 92, 204–208. [Google Scholar] [CrossRef] [PubMed]
- Xavier, B.M.; Jennings, W.J.; Zein, A.A.; Wang, J.; Lee, J.Y. Structural snapshot of the cholesterol-transport ATP-binding cassette proteins. Biochem. Cell Biol. 2019, 97, 224–233. [Google Scholar] [CrossRef] [PubMed]
- Patel, S.B.; Graf, G.A.; Temel, R.E. ABCG5 and ABCG8: More than a defense against xenosterols. J. Lipid Res. 2018, 59, 1103–1113. [Google Scholar] [CrossRef] [PubMed]
- Hazard, S.E.; Patel, S.B. Sterolins ABCG5 and ABCG8: Regulators of whole body dietary sterols. Pflügers Arch. Eur. J. Physiol. 2007, 453, 745–752. [Google Scholar] [CrossRef]
- Lee, J.Y.; Kinch, L.N.; Borek, D.M.; Wang, J.; Wang, J.; Urbatsch, I.L.; Xie, X.S.; Grishin, N.V.; Cohen, J.C.; Otwinowski, Z.; et al. Crystal structure of the human sterol transporter ABCG5/ABCG8. Nature 2016, 533, 561–564. [Google Scholar] [CrossRef]
- Jiang, Z.Y.; Cai, Q.; Chen, E.Z. Association of three common single nucleotide polymorphisms of ATP binding cassette G8 gene with gallstone disease: A meta-analysis. PLoS ONE 2014, 9, e87200. [Google Scholar] [CrossRef]
- Renner, O.; Lütjohann, D. Role of the ABCG8 19H risk allele in cholesterol absorption and gallstone disease. BMC Gastroenterol. 2013, 13, 30. [Google Scholar] [CrossRef]
- Stender, S.; Frikke-Schmidt, R.; Nordestgaard, B.G.; Tybjærg-Hansen, A. The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease. J. Am. Coll. Cardiol. 2014, 63, 2121–2128. [Google Scholar] [CrossRef]
- Sabeva, N.S.; Liu, J.; Graf, G.A. The ABCG5 ABCG8 sterol transporter and phytosterols: Implications for cardiometabolic disease. Curr. Opin. Endocrinol. Diabetes Obes. 2009, 16, 172–177. [Google Scholar] [CrossRef]
- Stender, S.; Frikke-Schmidt, R.; Nordestgaard, B.G.; Tybjaerg-Hansen, A. Sterol transporter adenosine triphosphate-binding cassette transporter G8, gallstones, and biliary cancer in 62,000 individuals from the general population. Hepatology 2011, 53, 640–648. [Google Scholar] [CrossRef]
- Berge, K.E.; Von Bergmann, K.; Lutjohann, D.; Guerra, R.; Grundy, S.M.; Hobbs, H.H.; Cohen, J.C. Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8. J. Lipid Res. 2002, 43, 486–494. [Google Scholar] [PubMed]
- Lam, C.W.; Cheng, A.W.; Tong, S.F.; Chan, Y.W. Novel donor splice site mutation of ABCG5 gene in sitosterolemia. Mol. Genet. Metab. 2002, 75, 178–180. [Google Scholar] [CrossRef] [PubMed]
- Togo, M.; Hashimoto, Y.; Iso-O, N.; Kurano, M.; Hara, M.; Kadowaki, T.; Koike, K.; Tsukamoto, K. Identification of a novel mutation for phytosterolemia. Genetic analyses of 2 cases. Clin. Chim. Acta 2009, 401, 165–169. [Google Scholar] [CrossRef] [PubMed]
- Kaya, Z.; Niu, D.M.; Yorulmaz, A.; Tekin, A.; Gürsel, T. A novel mutation of ABCG5 gene in a Turkish boy with phytosterolemia presenting with macrotrombocytopenia and stomatocytosis. Pediatr. Blood Cancer. 2014, 61, 1457–1459. [Google Scholar] [CrossRef]
- Fausto, A.G.; García, J.R.; Madero, L.E.; Torres, M.T. Two novel mutations in the ABCG5 gene, c.144-1G>A and c.1523 delC, in a Mexican family with sitosterolemia. J. Clin. Lipidol. 2016, 10, 204–208. [Google Scholar] [CrossRef]
- Buonuomo, P.S.; Iughetti, L.; Pisciotta, L.; Rabacchi, C.; Papadia, F.; Bruzzi, P.; Tummolo, A.; Bartuli, A.; Cortese, C.; Bertolini, S.; et al. Timely diagnosis of sitosterolemia by next generation sequencing in two children with severe hypercholesterolemia. Atherosclerosis 2017, 262, 71–77. [Google Scholar] [CrossRef]
- Bardawil, T.; Rebeiz, A.; Chaabouni, M.; El Halabi, J.; Kambris, Z.; Abbas, O.; Hassan, O.A.; Hamie, L.; Bitar, F.; Kibbi, A.G.; et al. Mutations in the ABCG8 gene are associated with sitosterolaemia in the homozygous form and xanthelasmas in the heterozygous form. Eur. J. Dermatol. 2017, 27, 519–523. [Google Scholar] [CrossRef]
- Horenstein, R.B.; Mitchell, B.D.; Post, W.S.; Lütjohann, D.; Von Bergmann, K.; Ryan, K.A.; Terrin, M.; Shuldiner, A.R.; Steinle, N.I. The ABCG8 G574R variant, serum plant sterol levels, and cardiovascular disease risk in the Old Order Amish. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 413–419. [Google Scholar] [CrossRef]
- Yu, X.H.; Qian, K.; Jiang, N.; Zheng, X.L.; Cayabyab, F.S.; Tang, C.K. ABCG5/ABCG8 in cholesterol excretion and atherosclerosis. ABCG5/ABCG8 in cholesterol excretion and atherosclerosis. Clin. Chim. Acta 2014, 428, 82–88. [Google Scholar] [CrossRef]
- Garcia-Rios, A.; Perez-Martinez, P.; Fuentes, F.; Mata, P.; Lopez-Miranda, J.; Alonso, R.; Rodriguez, F.; Garcia-Olid, A.; Ruano, J.; Ordovas, J.M.; et al. Genetic variations at ABCG5/G8 genes modulate plasma lipids concentrations in patients with familial hypercholesterolemia. Atherosclerosis 2010, 210, 486–492. [Google Scholar] [CrossRef]
- Lamiquiz-Moneo, I.; Baila-Rueda, L.; Bea, A.M.; Mateo-Gallego, R.; Pérez-Calahorra, S.; Marco-Benedí, V.; Martín-Navarro, A.; Ros, E.; Cofán, M.; Rodríguez-Rey, J.C.; et al. ABCG5/G8 gene is associated with hypercholesterolemias without mutation in candidate genes and noncholesterol sterols. J. Clin. Lipidol. 2017, 11, 1432–1440. [Google Scholar] [CrossRef] [PubMed]
- Koeijvoets, K.C.; van der Net, J.B.; Dallinga-Thie, G.M.; Steyerberg, E.W.; Mensink, R.P.; Kastelein, J.J.; Sijbrands, E.J.; Plat, J. ABCG8 gene polymorphisms, plasma cholesterol concentrations, and risk of cardiovascular disease in familial hypercholesterolemia. Atherosclerosis 2009, 204, 453–458. [Google Scholar] [CrossRef] [PubMed]
- Wu, G.; Li, G.B.; Yao, M.; Zhang, D.Q.; Dai, B.; Ju, C.J.; Han, M. ABCG5/8 variants are associated with susceptibility to coronary heart disease. Mol. Med. Rep. 2014, 9, 2512–2520. [Google Scholar] [CrossRef] [PubMed]
- Li, Q.; Wei, X.L.; Yin, R.X. Association of ATP binding cassette transporter G8 rs4148217 SNP and serum lipid levels in Mulao and Han nationalities. Lipids Health Dis. 2012, 11, 46. [Google Scholar] [CrossRef]
- Teupser, D.; Baber, R.; Ceglarek, U.; Scholz, M.; Illig, T.; Gieger, C.; Holdt, L.M.; Leichtle, A.; Greiser, K.H.; Huster, D.; et al. Genetic regulation of serum phytosterol levels and risk of coronary artery disease. Circ. Cardiovasc. Genet. 2010, 3, 331–339. [Google Scholar] [CrossRef]
- Szilvási, A.; Andrikovics, H.; Pongrácz, E.; Kalina, A.; Komlósi, Z.; Klein, I.; Tordai, A. Frequencies of four ATP-binding cassette transporter G8 polymorphisms in patients with ischemic vascular diseases. Genet. Test. Mol. Biomark. 2010, 14, 667–672. [Google Scholar] [CrossRef]
- Lake, A.C.; Sun, Y.; Li, J.L.; Kim, J.E.; Johnson, J.W.; Li, D.; Revett, T.; Shih, H.H.; Liu, W.; Paulsen, J.E.; et al. Expression, regulation, and triglyceride hydrolase activity of adiponutrin family members. J. Lipid Res. 2005, 46, 2477–2487. [Google Scholar] [CrossRef]
- Wilson, P.A.; Gardner, S.D.; Lambie, N.M.; Commans, S.A.; Crowther, D.J. Characterization of the human patatin-like phospholipase family. J. Lipid Res. 2006, 47, 1940–1949. [Google Scholar] [CrossRef]
- Rydel, T.J.; Williams, J.M.; Krieger, E.; Moshiri, F.; Stallings, W.C.; Brown, S.M.; Pershing, J.C.; Purcell, J.P.; Alibhai, M.F. The crystal structure, mutagenesis, and activity studies reveal that patatin is a lipid acyl hydrolase with a Ser-Asp catalytic dyad. Biochemistry 2003, 42, 6696–6708. [Google Scholar] [CrossRef]
- Murugesan, S.; Goldberg, E.B.; Dou, E.; Brown, W.J. Identification of diverse lipid droplet targeting motifs in the PNPLA family of triglyceride lipases. PLoS ONE 2013, 8, e64950. [Google Scholar] [CrossRef]
- Available online: https://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=150379 (accessed on 12 October 2019).
- Dupont, N.; Chauhan, S.; Arko-Mensah, J.; Castillo, E.F.; Masedunskas, A.; Weigert, R.; Robenek, H.; Proikas-Cezanne, T.; Deretic, V. Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis. Curr. Biol. 2014, 24, 609–620. [Google Scholar] [CrossRef]
- Lange, L.A.; Hu, Y.; Zhang, H.; Xue, C.; Schmidt, E.M.; Tang, Z.Z.; Bizon, C.; Lange, E.M.; Smith, J.D.; Turner, E.H.; et al. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. Am. J. Hum. Genet. 2014, 94, 233–245. [Google Scholar] [CrossRef] [PubMed]
- Pullinger, C.R.; Eng, C.; Salen, G.; Shefer, S.; Batta, A.K.; Erickson, S.K.; Verhagen, A.; Rivera, C.R.; Mulvihill, S.J.; Malloy, M.J.; et al. Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J. Clin. Investig. 2002, 110, 109–117. [Google Scholar] [CrossRef] [PubMed]
- Zakharova, E.; Kamenets, E.; Baydakova, G.; Mikhaylova, S.; Strokova, T.; Bagaeva, M.; Lavrova, A.; Amelina, M.; Pichkur, N. Lysosomal acid lipase deficiency diagnostics and mutation spectrum of LIPA gene in cohort of patients with hypercholesterolemia. Atherosclerosis 2017, 263, e60. [Google Scholar] [CrossRef]
- Nor, N.S.; Al-Khateeb, A.M.; Chua, Y.A.; Kasim, N.A.; Nawawi, H.M. Heterozygous familial hypercholesterolaemia in a pair of identical twins: A case report and updated review. BMC Pediatr. 2019, 19, 106. [Google Scholar] [CrossRef]
- Jakulj, L.; Vissers, M.N.; Tanck, M.W.; Hutten, B.A.; Stellaard, F.; Kastelein, J.J.; Dallinga-Thie, G.M. ABCG5/G8 polymorphisms and markers of cholesterol metabolism: Systematic review and meta-analysis. J. Lipid Res. 2010, 51, 3016–3023. [Google Scholar] [CrossRef]
- Sturm, A.C.; Knowles, J.W.; Gidding, S.S.; Ahmad, Z.S.; Ahmed, C.D.; Ballantyne, C.M.; Baum, S.J.; Bourbon, M.; Carrié, A.; Cuchel, M.; et al. Convened by the Familial Hypercholesterolemia Foundation. Clinical genetic testing for familial hypercholesterolemia: JACC Scientific Expert Panel. J. Am. Coll. Cardiol. 2018, 72, 662–680. [Google Scholar] [CrossRef]
- Khera, A.V.; Won, H.H.; Peloso, G.M.; Lawson, K.S.; Bartz, T.M.; Deng, X.; van Leeuwen, E.M.; Natarajan, P.; Emdin, C.A.; Bick, A.G.; et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J. Am. Coll. Cardiol. 2016, 67, 2578–2589. [Google Scholar] [CrossRef]
- Masana, L.; Ibarretxe, D.; Rodríguez-Borjabad, C.; Plana, N.; Valdivielso, P.; Pedro-Botet, J.; Civeira, F.; López-Miranda, J.; Guijarro, C.; Mostaza, J.; et al. Toward a new clinical classification of patients with familial hypercholesterolemia: One perspective from Spain. Atherosclerosis 2019, 287, 89–92. [Google Scholar] [CrossRef]
- Langsted, A.; Kamstrup, P.R.; Benn, M.; Tybjærg-Hansen, A.; Nordestgaard, B.G. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: A prospective cohort study. Lancet Diabetes Endocrinol. 2016, 4, 577–587. [Google Scholar] [CrossRef]
- Solanas-Barca, M.; de Castro-Orós, I.; Mateo-Gallego, R.; Cofán, M.; Plana, N.; Puzo, J.; Burillo, E.; Martín-Fuentes, P.; Ros, E.; Masana, L.; et al. Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia. Atherosclerosis 2012, 222, 449–455. [Google Scholar] [CrossRef] [PubMed]
- Marduel, M.; Ouguerram, K.; Serre, V.; Bonnefont-Rousselot, D.; Marques-Pinheiro, A.; Erik Berge, K.; Devillers, M.; Luc, G.; Lecerf, J.M.; Tosolini, L.; et al. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum. Mutat. 2013, 34, 83–87. [Google Scholar] [CrossRef] [PubMed]
- Awan, Z.; Choi, H.Y.; Stitziel, N.; Ruel, I.; Bamimore, M.A.; Husa, R.; Gagnon, M.H.; Wang, R.H.; Peloso, G.M.; Hegele, R.A.; et al. APOE p.Leu167del mutation in familial hypercholesterolemia. Atherosclerosis 2013, 231, 218–222. [Google Scholar] [CrossRef] [PubMed]
- Dron, J.S.; Hegele, R.A. Genetics of Lipid and Lipoprotein Disorders and Traits. Curr. Genet. Med. Rep. 2016, 4, 130–141. [Google Scholar] [CrossRef] [PubMed]
- Martín, B.; Solanas-Barca, M.; García-Otín, A.L.; Pampín, S.; Cofán, M.; Ros, E.; Rodríguez-Rey, J.C.; Pocoví, M.; Civeira, F. An NPC1L1 gene promoter variant is associated with autosomal dominant hypercholesterolemia. Nutr. Metab. Cardiovasc. Dis. 2010, 20, 236–242. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Tang, W.; Yang, P.; Shin, H.; Li, Q. Hepatic NPC1L1 promotes hyperlipidemia in LDL receptor deficient mice. Biochem. Biophys. Res. Commun. 2018, 499, 626–633. [Google Scholar] [CrossRef]
- Tveten, K.; Strøm, T.B.; Cameron, J.; Berge, K.E.; Leren, T.P. Mutations in the SORT1 gene are unlikely to cause autosomal dominant hypercholesterolemia. Atherosclerosis 2012, 225, 370–375. [Google Scholar] [CrossRef]
- Paththinige, C.S.; Sirisena, N.D.; Dissanayake, V. Genetic determinants of inherited susceptibility to hypercholesterolemia—a comprehensive literature review. Lipids Health Dis. 2017, 16, 103. [Google Scholar] [CrossRef]
- Chen, X.; Zhou, P.; De, L.; Li, B.; Su, S. The roles of transmembrane 6 superfamily member 2 rs58542926 polymorphism in chronic liver disease: A meta-analysis of 24,147 subjects. Mol. Genet. Genom. Med. 2019, 7, 824. [Google Scholar] [CrossRef]
- Prill, S.; Caddeo, A.; Baselli, G.; Jamialahmadi, O.; Dongiovanni, P.; Rametta, R.; Kanebratt, K.P.; Pujia, A.; Pingitore, P.; Mancina, R.M.; et al. The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids. Sci. Rep. 2019, 12, 9. [Google Scholar] [CrossRef]
- Zhang, Y.Y.; Fu, Z.Y.; Wei, J.; Qi, W.; Baituola, G.; Luo, J.; Meng, Y.J.; Guo, S.Y.; Yin, H.; Jiang, S.Y.; et al. A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption. Science 2018, 360, 1087–1092. [Google Scholar] [CrossRef] [PubMed]
- Lim, G.B. LIMA1 variant influences cholesterol absorption. Nat. Rev. Cardiol. 2018, 15, 502. [Google Scholar] [CrossRef] [PubMed]
- Loaiza, N.; Oldoni, F.; Kuivenhoven, J. Novel regulators of plasma lipid levels. Curr. Opin. Lipidol. 2017, 28, 231–240. [Google Scholar] [CrossRef] [PubMed]
- Bartuzi, P.; Billadeau, D.D.; Favier, R.; Rong, S.; Dekker, D.; Fedoseienko, A.; Fieten, H.; Wijers, M.; Levels, J.H.; Huijkman, N.; et al. CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nat. Commun. 2016, 7, 10961. [Google Scholar] [CrossRef] [PubMed]
- Fedoseienko, A.; Wijers, M.; Wolters, J.C.; Dekker, D.; Smit, M.; Huijkman, N.; Kloosterhuis, N.; Klug, H.; Schepers, A.; Willems van Dijk, K.; et al. The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking. Circ. Res. 2018, 122, 1648–1660. [Google Scholar] [CrossRef] [PubMed]
- Rimbert, A.; Dalila, N.; Wolters, J.C.; Huijkman, N.; Smit, M.; Kloosterhuis, N.; Riemsma, M.; Van der Veen, Y.; Singla, A.; van Dijk, F.; et al. A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor. Eur. Heart J. 2019, ehz727. [Google Scholar] [CrossRef]
- Nordestgaard, B.G.; Chapman, M.J.; Humphries, S.E.; Ginsberg, H.N.; Masana, L.; Descamps, O.S.; Wiklund, O.; Hegele, R.A.; Raal, F.J.; Defesche, J.C.; et al. European Atherosclerosis Society Consensus Panel. 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. Eur. Heart J. 2013, 34, 3478–3490. [Google Scholar] [CrossRef]
Gene | Cohort | Method | Association with lipid metabolism or FH | References |
---|---|---|---|---|
STAP1 | Family with FH | Exome sequencing | Expression of STAP1 gene is associated with plasma concentration of lipids (total cholesterol, LDL-C, and triglycerides) | [29] |
Patients with FH and acute coronary syndrome | Targeted next-generation sequencing (NGS) of LDLR, APOB, PCSK9, APOE, STAP1, LDLRAP1, and LIPA | [31] | ||
Case report of FH | Exome sequencing | [32] | ||
Patients aged ≤ 35 years with LDL-C ≥ 3.4 mmol/L | Exome sequencing | [33] | ||
CYP7A1 | Case report of FH | Denaturing gradient gel electrophoresis | Variants of CYP7A1 are associated with total cholesterol and LDL-C levels as well as with changes in risk of IHD | [105] |
LIPA | Mutation-negative patients with FH | Sanger sequencing | Variants of LIPA are associated with high levels of total cholesterol, LDL-C, and triglycerides and low concentration of HDL-C. LIPA is also associated with IHD, metabolic complications of obesity, and FH | [65] |
Mutation-negative patients with FH | Sanger sequencing | [64] | ||
Patients with type II dyslipidemia | Sanger sequencing | [106] | ||
ABCG5/8 | Case report of FH | Targeted NGS | Variants of ABCG5/8 are associated with sitosterolemia and higher levels of total cholesterol and triglycerides as well as lower levels of HDL-C | [87] |
Mutation-negative patients with FH | Sanger sequencing | [92] | ||
Case report of FH | Targeted NGS | [107] | ||
Case/control study of patients with FH | TaqMan genotyping | [91,93,108] | ||
Case/control study of patients with FH | Meta-analysis | [108] | ||
PNPLA5 | Individuals with extremely high and extremely low LDL-C from population-based cohorts | Whole-exome sequencing | Variants of PNPLA5 are associated with extremely high LDL-C levels | [104] |
1. | Patients with clinically confirmed (definite) FH and a functional mutation in one copy of genes LDLR, ApoB100, and PCSK9 |
2. | Homozygous FH: both alleles are mutant |
3. | Polygenic FH: patients with clinically confirmed FH but without detectable mutations associated with FH (to be distinguished from nonfamilial multifactorial hypercholesterolemia) |
4. | FH combined with hypertriglyceridemia: a subgroup of patients with familial combined hyperlipidemia fulfilling the criteria of clinically definite FH with comorbid hypertriglyceridemia |
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Mikhailova, S.; Ivanoshchuk, D.; Timoshchenko, O.; Shakhtshneider, E. Genes Potentially Associated with Familial Hypercholesterolemia. Biomolecules 2019, 9, 807. https://doi.org/10.3390/biom9120807
Mikhailova S, Ivanoshchuk D, Timoshchenko O, Shakhtshneider E. Genes Potentially Associated with Familial Hypercholesterolemia. Biomolecules. 2019; 9(12):807. https://doi.org/10.3390/biom9120807
Chicago/Turabian StyleMikhailova, Svetlana, Dinara Ivanoshchuk, Olga Timoshchenko, and Elena Shakhtshneider. 2019. "Genes Potentially Associated with Familial Hypercholesterolemia" Biomolecules 9, no. 12: 807. https://doi.org/10.3390/biom9120807
APA StyleMikhailova, S., Ivanoshchuk, D., Timoshchenko, O., & Shakhtshneider, E. (2019). Genes Potentially Associated with Familial Hypercholesterolemia. Biomolecules, 9(12), 807. https://doi.org/10.3390/biom9120807