CYP2C19 Polymorphisms in Indonesia: Comparison among Ethnicities and the Association with Clinical Outcomes.

Alexander Michael Joseph Saudale,Taufan Bramantoro,Marselino Richardo,Yoshio Yamaoka,Titong Sugihartono,Willy Brodus Uwan,Ari Fahrial Syam,Dalla Doohan,Langgeng Agung Waskito,Tomohisa Uchida,Phawinee Subsomwong,Fardah Akil,Gontar Alamsyah Siregar ,Iswan Abbas Nusi,Kartika Afrida Fauzia,I Dewa Nyoman Wibawa,Muhammad Miftahussurur,Hasan Maulahela,Yudith Annisa Ayu Rezkitha,Alvi Chomariyati,Abdul Hamid Abdul Rahman

doi:10.3390/biology10040300

Abstract

Simple SummaryCYP2C19 is known as an enzyme primarily responsible for metabolizing various drugs, such as proton pump inhibitor, antiplatelet, anti-epileptic, and anticoagulant. CYP2C19 is known to be polymorphic and can result in the clinical efficacy of drugs. To examine the prevalence and the distribution of the CYP2C19 genetic polymorphisms in Indonesia, we performed polymerase chain reaction-restriction fragment length polymorphism to the genomic DNA of Indonesian participants. In addition, we also analyzed the distribution of CYP2C19 polymorphisms among ethnicities and clinical outcomes. We found that the prevalence of intermediate metabolizers were the highest in Indonesia, followed by rapid metabolizers and poor metabolizers, respectively. The distribution of metabolizer groups were different between ethnic groups in Indonesia. Therefore, dosage adjustment should be considered when administering drugs-affected by CYP2C19 in Indonesia. The results presented in this study showed the distribution of CYP2C19 variant alleles at the population level in Indonesia and might be used as a consideration for providing personalized treatment in clinical practice.CYP2C19 polymorphisms are important factors for proton pump inhibitor-based therapy. We examined the CYP2C19 genotypes and analyzed the distribution among ethnicities and clinical outcomes in Indonesia. We employed the polymerase chain reaction-restriction fragment length polymorphism method to determine the CYP2C19 genotypes and evaluated inflammation severity with the updated Sydney system. For CYP2C19*2, 46.4% were the homozygous wild-type allele, 14.5% were the homozygous mutated allele, and 39.2% were the heterozygous allele. For CYP2C19*3, 88.6% were the homozygous wild-type allele, 2.4% were the homozygous mutated allele, and 9.0% were the heterozygous allele. Overall, the prevalence of rapid, intermediate, and poor metabolizers in Indonesia was 38.5, 41.6, and 19.9%, respectively. In the poor metabolizer group, the frequency of allele *2 (78.8%) was higher than the frequency of allele *3 (21.2%). The Papuan had a significantly higher likelihood of possessing poor metabolizers than the Balinese (OR 11.0; P = 0.002). The prevalence of poor metabolizers was lower compared with the rapid and intermediate metabolizers among patients with gastritis and gastroesophageal reflux disease. Intermediate metabolizers had the highest prevalence, followed by rapid metabolizers and poor metabolizers. Dosage adjustment should therefore be considered when administering proton pump inhibitor-based therapy in Indonesia.

Highlights

Triple therapy consisting of two antibiotics, such as amoxicillin and clarithromycin, accompanied by a proton pump inhibitor (PPI) is widely employed for the eradication therapy of Helicobacter pylori infection [1,2,3,4], an eradication that can reduce gastric mucosal inflammation, and show improvement in chronic gastritis [4,5,6,7]
143 (143 out of 166; 86.1%) patients were endoscopically diagnosed with gastritis, 5 (5 out of 166; 3.0%) patients with gastric ulcers, 1 (1 out of 166; 0.6%) patient with duodenal ulcer, and 17 (17 out of 166; 10.2%) with gastroesophageal reflux disease (GERD)
In Indonesia, intermediate metabolizers had the highest prevalence, followed by rapid metabolizers and poor metabolizers

Summary

Introduction

Triple therapy consisting of two antibiotics, such as amoxicillin and clarithromycin, accompanied by a proton pump inhibitor (PPI) is widely employed for the eradication therapy of Helicobacter pylori infection [1,2,3,4], an eradication that can reduce gastric mucosal inflammation, and show improvement in chronic gastritis [4,5,6,7]. There is consensus that PPI is an important drug for first-, second-, and even third-line therapy for H. pylori eradication [1,4]. PPI is an acid-activated prodrug that is inactive in its native form [10] and is mainly metabolized in the liver. CYP2C19 is an enzyme primarily responsible for metabolizing most PPIs, including omeprazole, esomeprazole, lansoprazole, and pantoprazole [8], with the exception of rabeprazole, which is primarily metabolized by non-enzymatic reduction to form thioether [9]. CYP2C19 plays an important role in converting these PPIs into hydroxyl compounds through aromatic hydroxylation reactions before being metabolized by CYP3A4 into sulfone [8,9,11]

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Results

Conclusion