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NAFLD, metabolic syndrome, ultrasound steatometry, controlled attenuation parameter, rs 1801282 (Pro12Ala) polymorphism in gene PPAR-γ, pioglitazone

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Shypulin, V., Parunyan, L., Tishhenko, V., KolyadaО., Ponomarov, O., & Melnyk, N. (2019). EFFECTIVENESS OF TREATMENT WITH PІOGLITAZONE IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE AND CONCOMITANT METABOLIC SYNDROME DEPENDING ON PRESENCE RS 1801282 (PRO12ALA) POLYMORPHISM IN GENE PPAR-γ. Medical Science of Ukraine (MSU), 15(1-2), 25-33. https://doi.org/10.32345/2664-4738.1-2.2019.04


Relevance. Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease on the one hand, and on the other, remains an unnoticed significant risk factor for cardiovascular disease. The course of NAFLD is often exacerbated by concomitant metabolic syndrome (MS). Existing medication for NAFLD has shortcomings in its efficacy and focus on non-alcoholic steatohepatitis (NASH). Given the lack of effective medication registered for NASH, optimizing NAFLD treatment is an urgent task. Pioglitazone (PPAR-γ agonist) is an insulin sensitizer recommended for the treatment of NASH after liver biopsy. The lack of efficiency of pioglitazone is probably due to the pleiotropic effect of PPAR-γ gene. Among the mutations of PPAR-γ gene, the most common Pro12Ala polymorphism. The PPAR-γ gene is a nuclear transcriptional regulation protein that affects adipocyte differentiation, fatty acid metabolism, and insulin sensitivity. Studies in Ukraine regarding the efficacy of pioglitazone in the treatment of NAFLD in combination with MS, depending on presence rs 1801282 (Pro12Ala) polymorphism in PPAR-γ gene, have not been performed previously.

Objective - to study the effectiveness of treatment with pioglitazone in patients with NAFLD and MS, depending on presence rs 1801282 (Pro12Ala) polymorphism in gene PPAR-γ.

Materials that methods. 93 patients with NAFLD and concomitant MS participated in the clinical-genetic intervention study. The randomization method of patients was divided into two groups, comparable in age, sex, and body mass index. All patients were offered a comprehensive weight loss program consisting of a 12-week follow-up. The comprehensive weight loss program included lifestyle modification: a reduction in diet of 500 kcal from the physiological daily energy expenditure and its physical activity for 150-200 min per week, the problems of adherence to recommendations were additionally discussed during the visits. The patients of the first group adhered to the comprehensive weight loss program and received pioglitazone 15 mg / day. Patients in the second group adhered only to comprehensive weight loss program. Overall, the program consisted of 5 visits over a 12-week period. All patients underwent a molecular genetic study of detecting rs 1801282 (Pro12Ala) polymorphism in PPAR-γ gene, as well as anthropometric measurements, laboratory and instrumental examinations (Ultrasound steatometry) before and after 12 weeks of treatment.

Results. Comparative analysis revealed that patients with NAFLD and MS in group 1 who adhered to comprehensive weight loss program and received pioglitazone at a daily dose of 15 mg had a more significant decrease in controlled attenuation parameter (p <0.05) compared with patients in group 2, which only the comprehensive weight loss program complied. In group 1, liver steatosis rates had a direct correlation with BMI (r = 0.33), visceral fat (r = 0.475), ALT (r = 0.42), TG (r = 0.48), fasting insulin (r = 0.38). The prevalence of minor allele 12Ala rs 1801282 of the PPAR-γ gene polymorphism in patients with NAFLD in combination with MS is 15%. Group 1 patients showed an association (p = 0.03) of the presence of 12Ala rs 1801282 allele in PPAR-γ gene polymorphism with a decrease of controlled attenuation parameter score, OR = 8.6 (95% CI 1.0–78.7). Patients in Group 2 found no association (p = 0.59) in the reduction of steatosis score with the presence of  12Ala allele, HS = 1.6 (95% CI 0.3–8.0).

Conclusions. In patients with NAFLD and concomitant MS, additional prescribing to the comprehensive weight loss program of pioglitazone (15 mg / day for 12 weeks) is likely to reduce steatosis. In patients with NAFLD in combination with MS, there is an association of the presence of 12Ala allele in PPAR-γ gene polymorphism and the effectiveness of pioglitazone 15 mg, OR = 8.6 (95% CI 1,0-78.7) compared to 12Pro allele.

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