POLYMORPHISM IN GENES INVOLVED IN LIPID METABOLISM IN MODY PATIENTS
Abstract
We have analyzed the lipid profile and polymorphism in the genes involved in lipid metabolism in patients with maturity onset diabetes of the young (MODY) in West Siberia, Russia. MODY is a heterogeneous group of disorders caused by mutations in different autosomal dominant genes with high penetration. MODY is characterized by a slow onset of symptoms, the absence of obesity, no ketosis, and no evidence of beta cell autoimmunity. Materials and methods: In the Clinical-Diagnostic Department of the Institute of Internal and Preventive Medicine, the eligible patients underwent a clinical examination, biochemical blood analysis, quantification of HbA1c, C-peptide, thyroid status, microalbuminuria testing, ultrasonography of the abdomen and kidneys, and blood glucose monitoring (MiniMed Paradigm, MMT-754). MODY2 diabetes was confirmed in 5 patients; MODY3, in 2 patients; MODY6, in 1 patient; MODY8, in 2 patients; MODY12, in 1 patient by sequencing. The plasma lipid levels were determined by standard enzymatic assays. The lipid metabolism genes ( APOA1, APOA2, APOA4, APOA5, APOB, APOC3, APOD, LDLR, LDLRAP1, LPL, PCSK9, SCARB1 and SREBF2 ) were analyzed. Results: Hyperlipidemia was detected in patients with MODY (MODY1, MODY2, MODY3 subtypes). We found the Pro434Gln polymorphism the SREBF2 gene exon 7 and the Gly2Ser polymorphism in the SCARB1 gene exon 1. We detected the Ser474Ter nonsense-mutation the LPL gene exon 9 in 2 patients. Conclusion: Polymorphism in the genes involved in lipid metabolism can cause the lipid disorder in MODY patients. Sequencing of the genes improved our understanding of the molecular basis of MODY phenotype and may help to provide the future personalized therapy.
About the Authors
M. I. Voevoda
Institute of Internal and Preventive Medicine; Institute Cytology and Genetics, RAS
Russian Federation
Russian Federation
E. V. Shakhtshneider
Institute of Internal and Preventive Medicine
Russian Federation
Russian Federation
A. K. Ovsyannikova
Institute of Internal and Preventive Medicine
Russian Federation
Russian Federation
O. D. Rymar
Institute of Internal and Preventive Medicine
Russian Federation
Russian Federation
D. E. Ivanoshchuk
Institute of Internal and Preventive Medicine; Institute Cytology and Genetics, RAS
Russian Federation
Russian Federation
A. M. Kurilshikov
Institute of Chemical Biology and Fundamental Medicine, RAS
Russian Federation
Russian Federation
Yu. I. Ragino
Institute of Internal and Preventive Medicine
Russian Federation
Russian Federation
References
1. Steele A. M., Shields B. M., Wensley K. J., Colclough K., Ellard S., Hattersley A. T. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA. 2014; 311 (3): 279-86. doi:10.1001/jama. 2013.283980;
2. Murphy R., Ellard S., Hattersley A. T. Clinical implication of a molecular genetic classification of monogenic β - cell diabetes. Nature Clinical Practice. 2008; 4 (4): 200-213. doi: 10.1038/ncpendmet0778.
3. Bonnefond A. et al. Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PloS one. - 2012. - Т. 7. - №. 6. - С. e37423;
4. Edghill E. L. et al. Sequencing of candidate genes selected by beta cell experts in monogenic diabetes of unknown aetiology. Jop. - 2010. - Т. 11. - С. 14-17.
5. Осипов А. Г., Силкина С. Б., Правдина Е. А. и др. Факторы риска и относительный коронарный риск у лиц молодого возраста. Кардиоваск. тер. и проф. - 2012; 1: 41-2.
6. Овсянникова А. К, Рымар О. Д., Воевода М. И. Показатели липидного профиля у лиц молодого возраста с сахарным диабетом. Атеросклероз - 2014; Т. 10, № 3, С. 37-40.
7. Feng Gao, Hao Luo, Zhiyao Fu, ChunTing Zhang, Ren Zhang Exome sequencing identifies novel ApoB loss-of-function mutations causing hypobetalipoproteinemia in type 1 diabetes. Acta Diabetol (2015) 52:531-537. DOI 10.1007/s00592-014-0687-7
8. Goldberg I. J. Clinical review 124: diabetic dyslipidemia: causes and consequences. J Clin Endocrinol Metab (2001) 86 (3):965-971.
9. Mooradian A. D. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab (2009) 5 (3):150-159.
10. Adiels M., Boren J., Caslake M. J., Stewart P., Soro A., Westerbacka J., Wennberg B., Olofsson S. O., Packard C., Taskinen M. R. Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia. Arterioscler Thromb Vasc Biol (2005) 25 (8):1697-1703.
11. Haffner S. M. Management of dyslipidemia in adults with diabetes. Diabetes Care (2003) 26 (Suppl 1):S83 - S86.
12. World Health Organization (2006) Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia: Report of a WHO/IDF Consultation. World Health Organization, Geneva.
13. Sambrook J, Russell DW. Purification of nucleic acids by extraction with phenol: chloroform.// CSH Protoc.-2006. № 1
14. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al. (2010) A method and server for predicting damaging missense mutations. Nat Methods 7: 248-249.
15. Xiong H. Y., Alipanahi B., Lee L. J., Bretschneider H., Merico D., Yuen R. K. C., Hua Y., Gueroussov S., Najafabadi H. S., Hughes T. R., Morris Q., Barash Y., A. R. Krainer, N. Jojic, S. W. Scherer, B. J. Blencowe, and B. J. Frey, “The human splicing code reveals new insights into the genetic determinants of disease,” Science (80-.)., vol. 347, no. 6218, p. 1254806 - , 2014.
16. Ovsyannikova A. K., Rymar O. D., Shakhtshneider E. V., Klimontov W., Koroleva E. A., Myakina N. E., Voevoda M. I. ABCC8-related maturity-onset diabetes of the young (MODY12): clinical features and treatment perspective. Diabetes Therapy. 2016. Т. 7. № 3. С. 591-600.
17. https://www.ncbi.nlm.nih.gov/gene/4023
18. M. M. Hoffmann, S. Jacob, D. Luft, R. M. Schmülling, K. Rett, W. März, H. U. Häring, S. Matthaei Type I hyperlipoproteinemia due to a novel loss of function mutation of lipoprotein lipase, Cys (239) -Trp, associated with recurrent severe pancreatitis. // Journal of Clinical Endocrinology and Metabolism. 2000. 85 (12). P. 4795-4798.
19. Jaap Rip, Melchior C. Nierman, Colin J. Ross, Jan Wouter Jukema, Michael R. Hayden, John J. P. Kastelein, Erik S. G. Stroes, Jan Albert Kuivenhoven Lipoprotein Lipase S447X a Naturally Occurring Gain-of-Function Mutation. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006. V. 26. P. 1236-1245.
20. Lopez-Miranda, J., Cruz, G., Gomez, P., Marin, C., Paz, E., Perez-Martinez, P., Fuentes, F. J., Ordovas, J. M., Perez-Jimenez, F. The influence of lipoprotein lipase gene variation on postprandial lipoprotein metabolism. // J. Clin. Endocr. Metab. 2004. V. 89. Р. 4721-4728.
21. Шахтшнейдер Е. В., Рагино Ю. И., Полонская Я. В., Каштанова Е. В., Воевода М. И. Ассоциация HindIII полиморфизма гена LPL с формированием липидного профиля сыворотки // Атеросклероз - 2014 - Том 10 - № 2, стр. 24-31
22. C. Caussy, S. Charri, A. Meirhaeghe, J. Dallongeville, E. Lefai, S. Rome, C. Cuerq, V. Euthine, M. Delay, O. Marmontel, M. Di Filippo, M. Lagarde, P. Moulin, C. Marçais Multiple microRNA regulation of lipoprotein lipase gene abolished by 30UTR polymorphisms in a triglyceride-lowering haplotype harboring p. Ser474Ter. Atherosclerosis 246 (2016) 280e286.
23. Alegret M., Silvestre J. S. Pleiotropic effects of statins and related pharmacological experimental approaches. // Methods Find Exp Clin Pharmacol. - 2006 Nov; 28 (9): 627-56.
24. Najafi-Shoushtari, S. H., Kristo, F., Li, Y., Shioda, T., Cohen, D. E., Gerszten, R. E., Naar, A. M. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 328: 1566- 1569, 2010.
25. Rayner, K. J., Suarez, Y., Davalos, A., Parathath, S., Fitzgerald, M. L., Tamehiro, N., Fisher, E. A., Moore, K. J., Fernandez-Hernando, C. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328: 1570-1573, 2010.
26. Niemsiri V, et al. Impact of genetic variants in human scavenger receptor class B type I (SCARB1) on plasma lipid traits. Circ Cardiovasc Genet, 2014 Dec. PMID 25245032.
27. Yang X, Sethi A, Yanek LR, Knapper C, Nordestgaard BG, Tybjærg-Hansen A, Becker DM, Mathias RA, Remaley AT, Becker LC SCARB1 Gene Variants Are Associated With the Phenotype of Combined High High-Density Lipoprotein Cholesterol and High Lipoprotein (a). Circ Cardiovasc Genet. 2016 Oct;9 (5):408-418. Epub 2016 Sep 20.
Review
For citations:
Voevoda M.I., Shakhtshneider E.V., Ovsyannikova A.K., Rymar O.D., Ivanoshchuk D.E., Kurilshikov A.M., Ragino Yu.I. POLYMORPHISM IN GENES INVOLVED IN LIPID METABOLISM IN MODY PATIENTS. Ateroscleroz. 2016;12(4):5-11. (In Russ.)
Views:
266
Email this article 