CYP2D6 gene polymorphic markers role in determining the optimal treatment tactics for portal hypertension in patients with liver cirrhosis

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Abstract

Aim. To study the polymorphic markers CYP2D6*4 (G1846A, rs3892097), CYP2D6*6 (T1707del, rs5030655), CYP2D6*10 (C100T, rs1065852), CYP2D6*41 (G2988A, rs28371725) and CYP2D6*3 (A2549del, rs4986774) role in treatment optimization of portal hypertension with propranolol in patients with liver cirrhosis (LC).

Materials and methods. The study included 60 patients with LC who received propranolol therapy at a daily dose of 30 mg for 14 days. The efficacy of treatment was assessed by ultrasonography measuring the linear blood flow velocity of portal vein. Genotyping of CYP2D6*4, CYP2D6*6, CYP2D6*10, CYP2D6*41 and CYP2D6*3 was carried out by real-time polymerase chain reaction. Evaluation of the CYP2D6 activity was carried out by determining the ratio of pinoline and its metabolite concentration in morning urine using high performance liquid chromatography with mass spectrometry.

Results. Positive hemodynamics in the form of any increase in the mean linear blood flow velocity of the portal vein compared to baseline was observed in 41 patients. Portal vein mean linear blood flow rate increased from 10.4±3.9 to 14.7±4.3 cm/s (p<0.001). Of these, 29 patients showed an increase in this indicator by ≥20% from the initial one with a dynamic of 5.5 cm/s (p<0.001). The regression analysis constructed by us revealed the presence of a statistically significant effect of the CYP2D6 gene polymorphic marker G1846A carriage on the propranolol therapeutic effect (p<0.05). There was no statistically significant effect of polymorphic markers T1707del, C100T, G2988A, and A2549del of the CYP2D6 gene (p>0.05). No convincing reliable dependence of CYP2D6 activity on the severity of LC was revealed (p>0.05).

Conclusion. An association was found between CYP2D6 gene polymorphic marker G1846A carriage and the hemodynamic effect of propranolol in patients with LC of the Russian population. There is a more significant positive dynamics of manifestations of portal hypertension on the background of propranolol therapy in carriers of the homozygous GG CYP2D6*4 genotype, in contrast to patients with the heterozygous GA genotype. Based on the results of the study, an algorithm has been developed for personalizing the treatment of patients with LC with nonselective b-adrenergic blockers using the method of CYP2D6 genotyping. Carriage of polymorphic markers T1707del, C100T, G2988A and A2549del gene CYP2D6 does not affect the effectiveness of propranolol therapy in patients with LC.

About the authors

Dmitry A. Sychev

Russian Medical Academy of Continuous Professional Education

Email: andre_webster@mail.ru
ORCID iD: 0000-0002-4496-3680

чл.-кор. РАН, д-р мед. наук, проф., зав. каф. клинической фармакологии и терапии

Russian Federation, Moscow

Andrei I. Parusov

Russian Medical Academy of Continuous Professional Education

Author for correspondence.
Email: andre_webster@mail.ru
ORCID iD: 0000-0002-2379-0960

ассистент каф. гастроэнтерологии

Russian Federation, Moscow

Irina D. Loranskaya

Russian Medical Academy of Continuous Professional Education

Email: andre_webster@mail.ru
ORCID iD: 0000-0002-3681-4132

д-р мед. наук, проф., зав. каф. гастроэнтерологии

Russian Federation, Moscow

Natalia P. Denisenko

Russian Medical Academy of Continuous Professional Education

Email: andre_webster@mail.ru
ORCID iD: 0000-0003-3278-5941

канд. мед. наук, зав. отд. персонализированной медицины

Russian Federation, Moscow

Kristina A. Akmalova

Russian Medical Academy of Continuous Professional Education

Email: andre_webster@mail.ru
ORCID iD: 0000-0003-3505-8520

науч. сотр. отд. молекулярной медицины

Russian Federation, Moscow

Zhannet A. Sozaeva

Russian Medical Academy of Continuous Professional Education

Email: andre_webster@mail.ru
ORCID iD: 0000-0001-5166-7903

мл. науч. сотр. отд. молекулярной медицины

Russian Federation, Moscow

Olga L. Turkina

Bakhrushin Brothers City Clinical Hospital

Email: andre_webster@mail.ru

врач ультразвуковой диагностики

Russian Federation, Moscow

Michael S. Zastrozhin

Russian Medical Academy of Continuous Professional Education

Email: andre_webster@mail.ru
ORCID iD: 0000-0003-0607-4812

д-р мед. наук, доц. каф. наркологии

Russian Federation, Moscow

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2. Fig. 1. Distribution of genotypes for the studied polymorphic markers in patients with LC.

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3. Fig. 2. Algorithm for personalizing treatment of patients with LC with nonselective β-blockers.

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