Pharmacogenetics of statin therapy and the endothelial function parameters in patients with type 2 diabetes mellitus

Aim. To investigate the association of variation in lipid-lowering response and endothelial function (EF) parameters after atorvastatin therapy in patients with type 2 diabetes mellitus (T2DM) with genetic markers of atherosclerosis.

Methods. We included 97 patients with T2DM who were prescribed atorvastatin. Fasting lipid profiles and EF parameters were assessed before and after 12 months of statin therapy. For EF evaluation, we performed pulse-wave analysis during reactive hyperaemia. The genotypes for polymorphic markers were identified by real-time polymerase chain reaction with TaqMan probes. The statistical analysis included Wilcoxon, Mann–Whitney and Kruskal–Wallis tests. P-values <0.05 were considered statistically significant.

Results. With statin therapy, PPARG2Pro/Pro patients had significantly lower TC and LDL-C levels than PPARG2 Pro/Ala and PPARG2 Ala/Ala patients (TC: 20.74% vs. 4.6% and 5.61%; p = 0.04 and LDL-C: 26.00% vs. 6.11% and 7.32%; p = 0.029). Patients with АРОЕЕ4/Е4 had significantly lower TC and TG levels than other АРОЕ patients (TC: -46.25% for Е4/Е4 vs. +33.33% for Е4/Е2, +5.73% for Е3/Е2, +11.80% for Е3/Е4, -10.92% for Е3/Е3, р = 0,01; TG: -56.52% for Е4/Е4 vs. +24.43% for Е4/Е2, +19.63% for Е3/Е2, +8.05% for Е3/Е4, -20.00% for Е3/Е3, р = 0.04). The patients with GG for TNFα G(238)A and GA for TNFα G(308)A had significantly greater amplitude of post-occlusive wave increase (Apw) than patients with GA for TNFα G(238)A and GG for TNFα G(308)A (+8.16 % vs. -0.93%, р = 0,04; +44% vs. -4.4%, p = 0.004, respectively).

Conclusion. PPARG2Pro12Ala and АРОЕE2/Е3/Е4 polymorphism contributed to the between-patient variability in the response to statin therapy in patients with T2DM. Significant associations of the TNFαgene polymorphism with EF in patients with T2DM suggest an important role of inflammation in the pathogenesis of MVD.

1. Baskova I, Pavlova I and Parfenov A. Analysis of the effects of medicinal leech on arterial function in elderly volunteers by means of photoplethysmography with Angioscan-01. Human Physiology. 2014;40(2):214-219. doi: 10.1134/S0362119714020029

2. Викулова О.К., Ярек-Мартынова И.Я., Трубицина Н.П., и др. Показатели вазомоторной функции эндотелия и эластичности артериальной стенки при терапии ингибиторомангиотензинпревращающего фермента рамиприлом у больных сахарным диабетом ٢-го типа. // Кардиология. — 2008. – №11 - С.47-52. [Vikulova OK, Yarek-Martynova IY, Trubitsina NP, et al. Parameters of Vasomotor Function of Endothelium and Elasticity of Arterial Wall During Therapy With Angiotensin Converting Enzyme Inhibitor Ramiprilin Patients With Type 2 Diabetes Mellitus.Kardiologiia. 2008;(11):47-52. (In Russ).]

3. Доборджгинидзе Л.М., Грацианский Н.А. Роль статинов в коррекции диабетической дислипидемии // Сахарный диабет. — 2001. — Т.4. — №2. — С.41-47. [Dobordzhginidze LM, Gratsianskiy NA. Rol’ statinov v korrektsii diabeticheskoy dislipidemii. Diabetes mellitus. 2001;4(2):41-47. (In Russ).] doi: 10.14341/2072-0351-5662

4. Valanti E, Tsompanidis A, Sanoudou D. Pharmacogenomics in the development and characterization of atheroprotective drugs. Methods Mol Biol. 2014;1175:259-300. doi: 10.1007/978-1-4939-0956-8_11.

5. Журавлева М.В., Кукес В.Г., Прокофьев А.Б., и др. Эффективность и безопасность применения лекарственных средств: значение и возможности клинической фармакологии. // Ведомости Научного центра экспертизы средств медицинского применения. - 2015;(2):20–24. [Zhuravleva MV, Kukes VG, Prokofiev AB, et al. Efficacy and safety of medicines: the value and opportunities of clinical pharmacology. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya. 2015;(2):20–24. (In Russ).].

6. Дедов И.И., Тюльпаков А.Н., Чехонин В.П., и др. Персонализированная медицина: современное состояние и перспективы. // Вестник РАМН. – 2012. – Т. 67. — №12. - С. 4-12. [Dedov II, Tyul’pakov AN, Chekhonin VP, et al. Personalized medicine: State-of-the-art and prospects. Annals of the Russian Academy of Medical Sciences. 2012;67(12):4-12. (InRuss).]. doi: 10.15690/vramn.v67i12.474

7. Железнякова А.В., Лебедева Н.О., Викулова О.К., и др. Риск развития хронической болезни почек у больных сахарным диабетом 2 типа детерминирован полиморфизмом генов NOS3, APOB, KCNJ11, TCF7L2 // Сахарный диабет. - 2014. - Т. 17. - №3. - C. 23-30. [Zheleznyakova AV, Lebedeva NO, Vikulova OK, Nosikov VV, Shamkhalova MS, Shestakova MV. Risk of chronic kidney disease in type 2 diabetes determined by polymorphisms in NOS3, APOB, KCNJ11, TCF7L2 genes as compound effect of risk genotypes combination. Diabetes mellitus. 2014;17(3):23-30. (In Russ).]. doi: 10.14341/DM2014323-30

8. Shestakova M, Vikulova O, Gorashko N, et al. The relationship between genetic and haemodynamic factors in diabetic nephropathy (DN): Case–control study in type 1 diabetes mellitus (T1DM). Diabetes Research and Clinical Practice. 2006;74(2):41-50.doi: 10.1016/j.diabres.2006.06.013

9. Викулова O.K. Клинико-лабораторные и генетические факторы развития и прогрессирования диабетической нефропатии у больных сахарным диабетом ١ типа. Дисс.… канд. мед. наук. -Москва; ٢٠٠٣. [Vikulova OK. Kliniko-laboratornye I geneticheskie faktory razvitiya I progressirovaniya diabeticheskoy nefropatii u bol’nykh sakharnym diabetom 1 tipa [dissertation] Moscow; 2003.(InRuss).]

10. Reiner Z. Resistance and intolerance to statins. Nutr Metab Cardiovasc Dis. 2014;24(10):1057-1066. doi: 10.1016/j.numecd.2014.05.009

11. Rodrigues AC, Sobrino B, Genvigir FD, et al. Genetic variants in genes related to lipid metabolism and atherosclerosis, dyslipidemia and atorvastatin response. Clin Chim Acta. 2013;417:8-11. doi: 10.1016/j.cca.2012.11.028.

12. Villeneuve S, Brisson D, Marchant NL, Gaudet D. The potential applications of Apolipoprotein E in personalized medicine. Front Aging Neurosci. 2014;6:154. doi: 10.3389/fnagi.2014.00154

13. Koopal C, van der Graaf Y, Asselbergs FW, et al. Influence of APOE-2 genotype on the relation between adiposity and plasma lipid levels in patients with vascular disease. Int J Obes (Lond).2015;39(2):265-269. doi: 10.1038/ijo.2014.105

14. AlBacha JdA, Khoury M, Mouawad C, et al. High Incidence of ACE/PAI-1 in Association to a Spectrum of Other Polymorphic Cardiovascular Genes Involving PBMCs Proinflammatory Cytokines in Hypertensive Hypercholesterolemic Patients: Reversibility with a Combination of ACE Inhibitor and Statin. PLoS ONE. 2015;10(5):e0127266. doi: 10.1371/journal.pone.0127266

15. Guney AI, Ergec D, Kirac D, et al. Effects of ACE polymorphisms and other risk factors on the severity of coronary artery disease. Genet Mol Res. 2013;12(4):6895-6906. doi: 10.4238/2013.December.19.8

16. Miramontes González JP, Cieza Borrella C, Mayoral R, et al. PPAR gamma pro12Ala polymorphism and type 2 diabetes: a study in a Spanish cohort. Journal of Genetics Study. 2014;2(1):1. doi: 10.7243/2054-1112-2-1