Sains Malaysiana 49(2)(2020): 237-248

http://dx.doi.org/10.17576/jsm-2020-4902-02

Impact of Nitric Oxide Synthase 2 Gene Variant on Risk of Anti-Tuberculosis Drug- Induced Liver Injury in the Malaysian Population

(Kesan Variasi Gen Nitrik Oksida Synthase 2 terhadap Risiko Kerosakan Hati Akibat Ubat Anti-Tuberkulosis dalam Populasi Malaysia)

VISHALA SIVAPALAN¹*, SHAMSUL MOHD ZAIN², SHENGNAN JIN³, SZE LING CHAN³, JIAJUN LIU⁴, ZAHURIN MOHAMED² & ROSMAWATI MOHAMED¹

¹Department of Medicine, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia

²Department of Pharmacology, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia

³Translational Laboratory in Genetic Medicine (TLGM), A*Star, 117609, Singapore

⁴Genome Institute of Singapore, A*Star, 60 Biopolis St., 138672, Singapore

Received: 4 August 2019/Accepted: 5 December 2019

ABSTRACT

Liver injury is a great threat associated with anti-tuberculosis (anti-TB) medication. Genetic variations in genes encoding drug-metabolising enzymes further enhance this threat. We aimed to explore genetic contributions by evaluating the impact of single nucleotide polymorphisms (SNPs) within the anti-tuberculosis (AT) metabolism pathway genes and within their respective chromosomes on anti-tuberculosis drug- induced liver injury (AT-DILI). Patients (n= 90) were recruited and 170 SNPs were genotyped using Illumina array and validated using Sanger Sequencing. The well-studied N-acetyltransferase 2 (NAT2*6) rs1799930 and cytochrome P450 2E1 (CYP2E1) C1/C1 were not significantly associated with AT-DILI in our cohort but nitric oxide synthase (NOS2A) rs11080344-C was found to be significantly higher in the cases than the controls (OR 2.73, 95% CI 1.12-6.64, P= 0.027). Association studies on all other SNPs within the anti-tuberculosis metabolism pathway genes and within their respective chromosomes also found no significant report. Our study suggests that genetic variation in NOS2A could influence the occurrence of AT-DILI.

Keywords: Adverse effect; genetic variations; liver injury; nitric oxide; tuberculosis

ABSTRAK

Kerosakan hati adalah ancaman besar yang dikaitkan dengan pengambilan ubat-ubatan anti-tuberkulosis. Variasi genetik dalam gen yang mengekod enzim yang terlibat dalam metabolisme ubat meningkatkan ancaman tersebut. Tujuan kami adalah untuk mengkaji pengaruh genetik dengan menilai impak polimorfisme nukleotid tunggal (SNPs) di dalam gen-gen yang terlibat dalam laluan metabolisme ubat-ubatan anti-tb dan dalam kromosom masing-masing terhadap kecenderungan kerosakan hati akibat ubat anti-tuberkulosis (AT-DILI). Pesakit (n=90) direkrut dan 170 SNPs digenotip menggunakan tatasusunan Illumina dan disahkan menggunakan penjujukan Sanger. Gen N-asetiltransferase 2 (NAT2*6) rs1799930 dan sitokrom P450 2E1 (CYP2E1) C1/C1 yang dikaji secara meluas tidak mempunyai kaitan signifikan dengan AT-DILI dalam kohort kami tetapi nitrik oksida sintase (NOS2A) rs11080344-C didapati secara signifikannya lebih tinggi dalam subjek kes berbanding dengan subjek kawalan (OR 2.73, 95% CI 1.12-6.64, P= 0.027). Kajian SNPs lain yang terlibat di dalam gen dalam laluan matabolisme ubat-ubatan anti-tuberkulosis dan kromosom masing-masing juga tidak menunjukkan kaitan yang signifikan. Kajian kami mencadangkan bahawa variasi genetik di dalam NOS2A boleh mempengaruhi kejadian AT-DILI.

Kata kunci: Kerosakan hati; kesan buruk; nitrik oksida; tuberkulosis; variasi genetic

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*Corresponding author; email: vishalasivapalan87@gmail.com