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.

Association of HLA-A, -B, and -DRB1 with pulmonary tuberculosis in western Javanese Indonesia.

Genetic studies of pulmonary tuberculosis (PTB), including those of human leukocyte antigen (HLA) genes, have been reported in several populations. Some studies also have reported these genes to have a stronger role in severe tuberculosis. We investigated HLA class I and II alleles and haplotypes to ascertain their role in susceptibility and resistance to new and recurrent PTB in 257 PTB patients (216 new and 41 recurrent PTB patients) and 236 healthy controls in Western Javanese (Indonesia). HLA-B*4006 was associated with new PTB (p = 0.044, p(adj) = ns), whereas HLA-B*1802, HLA-B*4001 and HLA-DRB1*1101 were associated with recurrent PTB (p = 0.013, p(adj) = 0.016; p = 0.015, p(adj) = 0.028; and p = 0.008, p(adj) = 0.027 for new PTB vs recurrent PTB, respectively). Except for HLA-B*4006, those associations remained significant after adjustment for age and gender by logistic regression analysis, although they disappeared after correction for multiple testing. Haplotype HLA-B*1802-DRB1*1202 was associated with susceptibility to recurrent PTB (p = 0.014, odds ratio = 3.8, 95% confidence interval = 1.18-12.27). In contrast, HLA-DRB1*1202 in the absence of HLA-B*1802 showed a significant association with resistance to recurrent PTB (p = 8.2 x 10(-4), odds ratio = 0.32, 95% confidence interval = 0.16-0.64), suggesting that stronger susceptibility effect of HLA-B*1802 masked the protective effect of HLA-DRB1*1202. Further studies using larger number of patients with recurrent PTB will be needed to confirm our findings.

Polymorphisms of promoter and coding regions of the arylamine N-acetyltransferase 2 (NAT2) gene in the Indonesian population: proposal for a new nomenclature.

Polymorphisms of arylamine N-acetyltransferase 2 (NAT2) are reportedly associated with the risk of drug toxicities and development of various diseases. The present study examined NAT2 polymorphisms in both promoter and coding regions in the Indonesian population using PCR direct sequencing. The promoter and coding regions of NAT2 displayed 23 polymorphisms/variations, including eight new ones. Seven haplotypes in the promoter region and six haplotypes in the coding region were inferred. The haplotypes in promoter and coding regions showed limited combinations, and 13 combined haplotypes were inferred. The most frequent haplotypes were U1 (38.9%), U2 (33.5%) in the promoter region and NAT2*4 (37.3%), NAT2*6A (36.8%) in the coding region. When converted to predicted phenotypes, the studied population comprised 65.4% rapid acetylators and 35.6% slow acetylators according to bimodal distribution. According to trimodal distribution, frequencies of predicted phenotypes were 13.6, 50.8 and 35.6% for rapid, intermediate and slow acetylators, respectively. Frequencies of NAT2 alleles for the Indonesian population resembled those of other Southeast Asian populations. We also propose a new NAT2 nomenclature composed of haplotypes in the promoter region and conventional NAT2 haplotypes in the coding region, symbolized by NAT2*4.U1, NAT2*4.U2, NAT2*4.U3, NAT2*4.U5, NAT2*4.U6, NAT2*4.U7, NAT2*6A.U1, NAT2*7B.U2, NAT2*7B.U3, NAT2*5B.U1, NAT2*5B.U4, NAT2*12A.U4 and NAT2*13.U1.