Keywords
How to Cite
Abstract
Physicians often lack knowledge in the field of genetic mutations in genes of cholesterol (Ch) transporters, which influence the strategy of pharmacological treatment of many patients. With the aim of estimation modern points of view on the role of mutations in genes of Ch transporters, namely, Niemann — Pick protein (NPP) and ABCG5/G8, in the development of cardiovascular and hepatobiliary disorders we made a search in Pubmed database. It was revealed that almost a half of cases of ischemic heart disease (IHD) is characterized by genetic anomalies, firstly, in locuses of Ch transporters — NPC1L1, ABCG5/G8, and also PCSK9, APOB, KCNK5, LPL, HMGCR, CETP, TRIB1, ABO, PMAIP1-MC4R and LDLR, each of which has multiple nucleotid polymorphisms. The latter fact challenges its usage in practice. Genetically determined higher levels of liver Х-receptor and farnesoid Х-receptor in peripheral mononuclears together with decreased amount of duodenal NPP lead to liver steatosis, whereas other genetic changes of Ch transporters are associated with more significant viral injury of liver in case of hepatitis. Mutations of genes of both Ch transporters (NPC1L1 and ABCG8) are significantly associated with cholestasis and cholelithiasis. Conclusions. Disorders of heart (IHD, arterial hypertension, cardiomyopathies), liver (steatosis) and gallbladder (cholesterosis, polips, cholelithiasis) develop with a huge amount of genetically determined changes of Ch-transporting proteins, namely, activation/inhibition of NPP and ATP-binding transporters ABCG5/G8. Understanding of genetic background of diseases is important for prevention, prognosis and treatment of cardiovascular and hepatobiliary pathological conditions, which are tightly connected.
References
2. Yamanashi Y., Takada T., Suzuki H. Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol // Biol. Pharm. Bull. — 2018. — 41 (1). — P. 1-10. DOI: 10.1248/bpb.b17-00690.
3. Pirillo A., Catapano A.L., Norata G.D. Niemann-Pick C1-Like 1 (NPC1L1) Inhibition and Cardiovascular Diseases // Curr. Med. Chem. — 2016. — 23 (10). — P. 983-99. DOI: 10.2174/ 0929867323666160229114111.
4. Lauridsen B.K., Stender S., Frikke-Schmidt R., Nordestgaard B.G., Tybjærg-Hansen A. Genetic variation in the cholesterol transporter NPC1L1, ischaemic vascular disease, and gallstone disease // Eur. Heart. J. — 2015. — 36 (25). — P. 1601-8. DOI: 10.1093/eurheartj/ehv108.
5. Orho-Melander M. Genetics of coronary heart disease: towards causal mechanisms, novel drug targets and more personalized prevention // J. Intern. Med. — 2015. — 278 (5). — P. 433-46. DOI: 10.1111/joim.12407.
6. Joseph P.G., Pare G., Asma S., Engert J.C., Yusuf S., Anand S.S. Impact of a Genetic Risk Score on Myocardial Infarction Risk Across Different Ethnic Populations // Can. J. Cardiol. — 2016. — 32 (12). — P. 1440-1446. DOI: 10.1016/j.cjca.2016.05.014.
7. Van der Laan S.W., Harshfield E.L., Hemerich D., Stacey D., Wood A.M., Asselbergs F.W. From lipid locus to drug target through human genomics // Cardiovasc. Res. — 2018 Jul 15. — 114 (9). — P. 1258-1270. DOI: 10.1093/cvr/cvy120.
8. Muendlein A., Leiherer A., Saely C.H., Rein P., Zanolin D., Kinz E., Brandtner E.M., Fraunberger P., Drexel H. Common single nucleotide polymorphisms at the NPC1L1 gene locus significantly predict cardiovascular risk in coronary patients // Atherosclerosis. — 2015. — 242 (1). — P. 340-5. DOI: 10.1016/j.atherosclerosis.2015.07.011.
9. Polisecki E., Peter I., Simon J.S., Hegele R.A., Robertson M., Ford I., et al. Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly // Journal of lipid research. — 2010. — 51 (5). — P. 1201-7. DOI: 10.1194/jlr.P001172.
10. Wu J., Cui W., Cai Q., Fei J., Zhang S.D., Han T.Q., Hu H., Jiang Z.Y. The NPC1L1 Polymorphism 1679C>G Is Associated with Gallstone Disease in Chinese Patients // PLoS One. — 2016. — 11 (1). — P. e0147562. DOI: 10.1371/journal.pone.014756.
11. Nissinen M.J., Pitkänen N., Simonen P., Gylling H., Viikari J., Raitakari O., Lehtimäki T., Juonala M., Pakarinen M.P. Genetic polymorphism of sterol transporters in children with future gallstones // Dig. Liver. Dis. — 2018. — 50 (9). — P. 954-960. DOI: 10.1016/j.dld.2018.04.007.
12. Huynh M.T., Nguyen T.-T., Grison S., Lascols O., Fernandez E., Barbu V. Clinical characteristics and genetic profiles of young and adult patients with cholestatic liver disease // Revista Española De Enfermedades Digestivas. — 2019. — 111. PMID: 31538484.
13. Rodriguez S., Gaunt T.R., Guo Y. Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array // European journal of human genetics. — 2016. — 24 (1). — P. 106-12. DOI: 10.1038/ejhg.2015.63.
14. 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 (20). — P. 2121-2128. DOI: 10.1016/j.jacc.2013.12.055.
15. Ahn S.B., Jun D.W., Jang K., Lee B.H., Shin K.J. Duodenal Niemann-Pick C1-like 1 expression was negatively correlated with liver X receptor expression in nonalcoholic fatty liver disease // Korean J. Intern Med. — 2019. — 34 (4). — P. 777-784. DOI: 10.3904/kjim.2017.100.