Cost-effectiveness analysis of genotyping for HLA-B*15:02 in Indonesian patients with epilepsy using a generic model.

Carbamazepine (CBZ)-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are strongly associated with the HLA-B*15:02 allele. Screening HLA-B*15:02 before CBZ administration might prevent CBZ-induced SJS/TEN by enabling clinicians to prescribe alternative therapy for positive patients. Similar to other Southeastern Asian countries, HLA-B*15:02 is highly prevalent in Indonesia. Therefore, we assessed the economic value of HLA-B*15:02 screening before CBZ prescription to patients with epilepsy in Indonesia. A generic cost-effectiveness model and decision support tool, developed to enable users to perform an initial cost-effectiveness analysis from a healthcare provider/payer perspective, were used to assess the value of HLA-B*15:02 genotyping. The incremental cost-effectiveness ratio of adopting universal HLA-B*15:02 screening was 656,444,671 Indonesian Rupiah (IDR)/quality-adjusted life year (QALY) gained for patients compared with 2,634,975,574 IDR/QALY gained for providing valproic acid (alternative drug) without screening. Thus, neither HLA-B*15:02 screening nor substitution with VPA meets the Indonesian threshold for cost effectiveness. However, the improved outcomes with this test in other Asian countries may inform the desirability of implementation in Indonesia even with suboptimal cost-effectiveness.

N-acetyltransferase 2 polymorphism and acetylation profiles in Buginese ethnics of Indonesia.

BACKGROUND: N-acetyltransferase 2 (NAT2) is a key enzyme involved in the phase II metabolism of aromatic amines and heterocyclic aromatic amines present in a wide range of xenobiotics. The aim of this study was to investigate the NAT2 polymorphism in the Buginese ethnic group of Indonesia to determine the frequency of NAT2 alleles in this population. RESULTS: We found six haplotypes consisting of six single-nucleotide polymorphisms and 12 NAT2 genotype variations. NAT2*6A haplotype (42%) showed the highest frequency, followed by NAT2*4 (33%), NAT2*7B (15%), NAT2*5B (5%), NAT2*12A (3%), and NAT2*13 (2%). In terms of phenotypes, the Buginese population comprised 18% rapid acetylators, 40% intermediate acetylators, and 42% slow acetylators. CONCLUSION: We confirmed the high-frequency slow acetylator phenotype in the Buginese population. The NAT2*6A/*6A genotype was the most frequent slow acetylator genotype, followed by NAT2*6A/*7B. The pattern of NAT2 alleles of Buginese is similar to Southeast Asian populations but not Northeast Asian populations. However, the slow acetylator frequencies in the Buginese population were higher than those in Northeast Asian populations and lower than those in Caucasians and some American populations.

NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis.

Drug-induced liver injury (DILI) is the most common adverse drug reaction in the treatment of tuberculosis (TB). Several studies showed that patients with TB and the slow-acetylator phenotype caused by NAT2 variants are highly susceptible to DILI caused by anti-TB drugs, hereafter designated AT-DILI. However, the role of NAT2 variants in AT-DILI has never been assessed for an Indonesian population. We recruited 50 patients with TB and AT-DILI and 191 patients with TB but without AT-DILI; we then used direct DNA sequencing to assess single-nucleotide polymorphisms in the coding region of NAT2. NAT2*6A was significantly associated with susceptibility to AT-DILI (P=7.7 × 10(-4), odds ratio (OR)=4.75 (1.8-12.55)). Moreover, patients with TB and the NAT2-associated slow-acetylator phenotype showed higher risk of AT-DILI than patients with the rapid- or intermediate-acetylator phenotypes (P=1.7 × 10(-4), OR=3.45 (1.79-6.67)). In conclusion, this study confirms the significance of the association between slow-acetylator NAT2 variants and susceptibility to AT-DILI in an Indonesian population.

Frequencies of HLA-B alleles in Indonesian Malay Ethnic.

Background: The HLA-B alleles have been used as a marker to predict drug-induced adverse reactions and as a major contributor to hypersensitivity reactions. We examined the feasibility of HLA-B alleles as pharmacogenomic markers of drug-induced hypersensitivity in an Indonesian Malay Ethnic. Methods: Fifty-eight Indonesian individuals of Malay ethnicity were enrolled in this study. HLA-B alleles were determined using reverse sequence-specific oligonucleotide probe coupled with xMAP technology. Results: HLA-B*15:02 (15.52%), HLA-B*35:05 (9.48%), and HLA-B*07:05 (7.76%) were frequent alleles in the Indonesian Malay ethnic populations. We discovered at least eight pharmacogenomics markers of drug-induced hypersensitivity: HLA-B*15:02, HLA-B*15:21, HLA-B*13:01, HLA-B*35:05, HLA-B*38:02, HLA-B*51:01, HLA-B*57:01, and HLA-B*58:01. HLA-B*15:02 was in the same serotype group with HLA-B*15:21, which is a B-75 serotype associated with genetic predisposition for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis. The Indonesian population, represented by Malay, Javanese, and Sundanese ethnicities, was similar to South East Asian, Han Chinese, and Taiwanese populations based on HLA-B*15:02 frequency as the most common allele found in Malay ethnics. Conclusion: We provided valuable information on the frequency of drug hypersensitivity-associated HLA-B alleles in Indonesian Malay ethnic population, which can improve treatment safety.

Detection of DNA methylation from buccal swabs using nanopore sequencing to study stunting.

Stunting is the result of chronic malnutrition due to the lack of micronutrient-based methyl donors required for epigenetic programming during the first 1000 days of life. Methylation studies using bisulfite conversion from blood DNA are invasive and may not be practical for large-scale epidemiological investigation or nutrition intervention programs. Buccal epithelial methylation may reflect early germline methylation. Therefore, buccal cells can serve as convenient sample sources to collect biomarkers associated with the risk of stunting. This study aims to describe the feasibility of nanopore adaptive sampling in detecting DNA methylation from children's buccal DNA. We used adaptive sampling of Oxford Nanopore Technology on barcoded samples to describe differential methylation associated with malnutrition. Overall, the level of 5-methylcytosine (5mC) was lower in stunted children than in normal children. We also found differentially methylated regions at the MIR6724 and RNA45SN1 gene loci on chromosome 21, which was higher in stunted children than in normal children. We described and detected differential DNA methylation in the locus previously not known to be associated with stunting. Interestingly, this locus on chromosome 21 has been implicated in the stunted phenotype of Down syndrome.

Genetic characterization of N-acetyltransferase 2 variants in acquired multidrug-resistant tuberculosis in Indonesia.

Background: Owing to the high resistance rate of tuberculosis (TB) to isoniazid, which is metabolized by N-acetyltransferase 2 (NAT2), we investigated the associations between NAT2 variants and multidrug-resistant (MDR)-TB. Materials & methods: The acetylator status based on NAT2 haplotypes of 128 patients with MDR-TB in Indonesia were compared with our published data from patients with anti-TB drug-induced liver injury (AT-DILI), TB and the general population. Results:NAT2*4 was more frequent in the MDR-TB group than in the AT-DILI group, TB controls and general controls. NAT2*4/*4 was significantly more frequent in patients with MDR-TB than in those with AT-DILI. NAT2*5B/7B, *6A/6A and *7B/*7B were detected at lower frequencies in patients with AT-DILI. Rapid acetylators were significantly more frequent in patients with MDR-TB than in those with AT-DILI. Conclusion: These results provide an initial data for optimizing TB treatment in the Indonesian population, and suggest that NAT2 genotyping may help to select appropriate treatment by predicting TB-treatment effect.

Prevalence of pharmacogenomic variants in 100 pharmacogenes among Southeast Asian populations under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm).

Pharmacogenomics can enhance the outcome of treatment by adopting pharmacogenomic testing to maximize drug efficacy and lower the risk of serious adverse events. Next-generation sequencing (NGS) is a cost-effective technology for genotyping several pharmacogenomic loci at once, thereby increasing publicly available data. A panel of 100 pharmacogenes among Southeast Asian (SEA) populations was resequenced using the NGS platform under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm). Here, we present the frequencies of pharmacogenomic variants and the comparison of these pharmacogenomic variants among different SEA populations and other populations used as controls. We investigated the different types of pharmacogenomic variants, especially those that may have a functional impact. Our results provide substantial genetic variations at 100 pharmacogenomic loci among SEA populations that may contribute to interpopulation variability in drug response phenotypes. Correspondingly, this study provides basic information for further pharmacogenomic investigations in SEA populations.

Glutathione S-transferase M1 and T1 null allele frequencies among Indonesian ethnics toward improved disease risk assessment.

Genetic variations in the glutathione S-transferase genes GSTT1 and GSTM1 have been widely studied, and homozygous deletions or null genotypes have been reported in different populations. Previous studies suggest that individuals who are homozygous-null at the GSTM1 or GSTT1 locus may have an increased risk of environmentally related cancers and drug-induced hepatotoxicity. The aim of the present study was to determine the GSTM1 and GSTT1 polymorphisms in 154 healthy, unrelated individuals from the Javanese-Sundanese and Malay ethnic populations of Indonesia to provide a resource for improving the prognosis of possible susceptibilities in specific populations. The subjects were genotyped for the presence of GSTM1 and GSTT1 using the multiplex polymerase chain reaction technique. The GSTM1-null genotype was more frequent among Javanese-Sundanese ethnics (99%) than among the Indonesian Malay (67.2%). Similarly, Javanese-Sundanese ethnics showed a higher frequency of the GSTT1-null genotype (66.7%) than the Indonesian Malay (36.2%). Analysis of the combined distribution of the GSTM1 and GSTT1 genes revealed that 66.7% of the individuals from the Javanese-Sundanese population lack both the genes, whereas only 21.1% of the Indonesian Malay is GSTM1-null and GSTT1-null. This study contributes significant information on the variability of GSTT1 and GSTM1 gene polymorphisms worldwide, which can provide new knowledge about the relationship between ethnicity and the prevalence of certain diseases.

NAT2 slow acetylator is associated with anti-tuberculosis drug-induced liver injury severity in indonesian population.

Aim: We investigated the contribution of NAT2 variants and acetylator status to anti-tuberculosis drug-induced liver injury (AT-DILI) severity. Materials & methods: 100 patients with clinically severe AT-DILI and 210 non-AT-DILI controls were subjected to NAT2 genotyping by direct DNA sequencing. Results: NAT2 slow acetylator was significantly associated with AT-DILI risk (p = 2.7 × 10-7; odds ratio [95% CI] = 3.64 [2.21-6.00]). Subgroup analysis of NAT2 ultra-slow acetylator revealed a stronger association with AT-DILI risk (p = 4.3 × 10-6; odds ratio [95% CI] = 3.37 [2.00-5.68]). Subset analysis of NAT2 acetylator status and severity grade confirmed these results in AT-DILI patients with more severe disease whereas fast and intermediate acetylator phenotypes were associated with a decreased AT-DILI risk. Conclusion: We elucidated the role of NAT2 phenotypes in AT-DILI in Indonesian population, suggesting that NAT2 genotype and phenotype determination are important to reduce AT-DILI risk.

Association of the HLA-B alleles with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in the Javanese and Sundanese population of Indonesia: the important role of the HLA-B75 serotype.

Carbamazepine (CBZ) is a common cause of life-threatening cutaneous adverse drug reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Previous studies have reported a strong association between the HLA genotype and CBZ-induced SJS/TEN. We investigated the association between the HLA genotype and CBZ-induced SJS/TEN in Javanese and Sundanese patients in Indonesia. Nine unrelated patients with CBZ-induced SJS/TEN and 236 healthy Javanese and Sundanese controls were genotyped for HLA-B and their allele frequencies were compared. The HLA-B*15:02 allele was found in 66.7% of the patients with CBZ-induced SJS/TEN, but only in 29.4% of tolerant control (p = 0.029; odds ratio [OR]: 6.5; 95% CI: 1.2-33.57) and 22.9% of healthy controls (p = 0.0021; OR: 6.78; 95% CI: 1.96-23.38). These findings support the involvement of HLA-B*15:02 in CBZ-induced SJS/TEN reported in other Asian populations. Interestingly, we also observed the presence of the HLA-B*15:21 allele. HLA-B*15:02 and HLA-B*15:21 are members of the HLA-B75 serotype, for which a greater frequency was observed in CBZ-induced SJS/TEN (vs tolerant control [p = 0.0078; OR: 12; 95% CI: 1.90-75.72] and vs normal control [p = 0.0018; OR: 8.56; 95% CI: 1.83-40]). Our findings suggest that screening for the HLA-B75 serotype can predict the risk of CBZ-induced SJS/TEN more accurately than screening for a specific allele.