Hubungan Variasi Genetika NAT2 Terhadap Risiko Adverse Drug Reaction (ADR) dan Outcome Klinis Pasien Tuberkulosis Suku Jawa

LUCIA VITA INANDHA DEWI, Prof.Dr.apt.Lukman Hakim,M.Sc; Prof.Dr.apt.Sisimindari,S.U; Prof.dr.Ngatidjan,M.Sc,Sp.FK(K)

2020 | Disertasi | DOKTOR ILMU FARMASI

polimorfisme NAT2 berkaitan dengan risiko ADR dan efektivitas pengobatan. Penelitian polimorfisme NAT2 pada suku Jawa dengan sistem penelusuran 3 riwayat etnis belum pernah dilakukan, penelitian tentang hubungan NAT2 dengan ADR hepatotoksisitas telah banyak dikerjakan namun terhadap ADR neurologi dan dermatologi belum banyak dikaji. Tujuan penelitian adalah mengidentifikasi polimorfisme NAT2 dan mengevaluasi hubungannya dengan ADR dan outcome klinis. Penelitian dilakukan secara prospektif terhadap 33 responden suku Jawa, dan mendapat terapi Obat Anti Tuberkulosis (OAT) kategori 1, metode penelitian adalah cross sectional. Identifikasi polimorfisme NAT2 dilakukan dengan metode Polimerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), Monitoring ADR dilakukan dari bulan ke-2 hingga bulan ke-6 pengobatan, pemeriksaan SGPT/SGOT dilakukan pada bulan ke-2 pengobatan, outcome klinis diamati pada akhir pengobatan. Analisis hubungan genotip dengan ADR dilakukan dengan analisis bivariate chi-square, analisis hubungan Genotip dengan outcome klinis dilakukan menggunakan analisis multivariate regresi multinomial. Hasil penelitian menunjukkan terdapat polimorfisme gen NAT2 dengan persentase mutasi pada 3 SNP yaitu C481T, G590A, dan G857A sebesar 27%, 54%, dan 31%. persentase jumlah allel NAT2*4, NAT2*7, NAT2*6, NAT2*5 sebesar 36.8%, 27.6%, 22.4%, dan 11.8%. Secara trimodal terdapat 3 kelompok prediksi fenotip yaitu tipe fast (rapid) acetylator, intermediate, dan slow acetylator sebesar 6%, 76%, dan 12%. Tidak dijumpai adanya ADR hepatotoksisitas pada seluruh subyek, ADR yang timbul adalah gangguan gastrointestinal, dermatologi dan neurologi sebanyak 36,4%, 9%, dan 27%. Secara statistik tidak terdapat hubungan antara genotip dengan ADR (p-value =0,324>0,05) dan outcome klinis (p-value = 0,581>0,05 ) namun berdasar fenomena klinis ADR yang timbul serta temuan allel NAT2*6 dan *7 dalam persentase tinggi hasil penelitian ini dapat menjadi informasi perlunya monitoring ADR pada pasien suku Jawa.

NAT2 polymorphisms are associated with ADR risk and treatment effectiveness. Research on NAT2 polymorphism in Javanese with a 3 ethnic history tracing system has never been carried out. Research on the relationship between NAT2 and ADR hepatotoxicity has been done a lot, but neurological and dermatological ADR has not been widely studied. The study aimed to identify NAT2 polymorphisms and evaluate their association with ADR and clinical outcomes. The study was conducted prospectively on 33 Javanese respondents and received category 1 Anti-Tuberculosis Drug (OAT) therapy. The research method was cross-sectional. Identification of NAT2 polymorphisms was carried out by the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method, ADR monitoring was carried out from the 2nd to 6th month of treatment, SGPT / SGOT examinations were carried out at the 2nd month of treatment, clinical outcomes were observed. at the end of treatment. Analysis of the relationship between genotypes and ADR was carried out using bivariate chi-square analysis. The results showed that there was a NAT2 gene polymorphism with the percentage of mutations in 3 SNPs, namely C481T, G590A, and G857A of 27%, 54%, and 31%. the percentage of allele NAT2 * 4, NAT2 * 7, NAT2 * 6, NAT2 * 5 was 36.8%, 27.6%, 22.4%, and 11.8%. In trimodal, there were 3 groups of phenotypic predictions, namely the fast (rapid) acetylation, intermediate, and slow acetylation types of 6%, 76%, and 12%. There were no hepatotoxicity ADRs in all subjects, ADRs that arose were gastrointestinal, dermatological, and neurological disorders as much as 36.4%, 9%, and 27%. Statistically, there is no relationship between genotype with ADR (p-value = 0.324> 0.05) and clinical outcome (p-value = 0.581> 0.05) Clinically, the percentage of NAT2 * 6 and * 7 alleles as predictor alleles of high ADR as well as the clinical phenomenon of ADR that appears to provide information that Javanese tuberculosis patients need ADR monitoring during tuberculosis treatment.

Kata Kunci : Polimorfisme NAT2,Genotip NAT2,Isoniazid,ADR Obat Anti Tuberkulosis