Abstract
Severe Cutaneous Adverse Reactions (SCARs) are unpredictable reactions and generally not related to the mechanism of action of the drugs. These reactions are associated with significant mortality and short-term and long-term morbidity. The report from Health Product Vigilance Center (HPVC) in Thailand showed that antiepileptic, uric lowering, antimicrobial and NSAID drugs are the most common cause of SCARs. Previous studies reported that several HLA alleles have been discovered to be strongly associated with SCARs and some of them have been proposed as valid pharmacogenomic biomarkers for prediction of these life threatening reactions Apart from the genetic polymorphisms of the HLA gene, the genetic polymorphisms of drug-metabolizing enzymes and T-cell receptor repertoire have been shown to play some role in the risk of drug induced SCARs. This study was divided into 2 sections. The first section aimed to identify genes involved in drug-induced SCARs by using the whole genome sequencing technique under the Genomics Thailand project. Fifty samples obtained from new SCARs cases were sent to the Genomics Thailand project for gDNA extraction and whole genome sequencing (WGS). Some WGS results, approximately 30% of all samples, were sent back to the researcher. Genes involved in drug-induced SCARs were analyzed and the results showed the prevalent HLA alleles that found in SCARs patients. The second section aimed to extensively explore the association between the HLA class I alleles, genetic polymorphisms of drug-metabolizing enzyme genes and SCARs induced by antimicrobial drugs including co-trimoxazole and beta-lactam antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) in large sample sizes and a well-defined SCARs population. For co-trimoxazole-induced SCARs group, the results demonstrated that the HLA-B*13:01 allele was statistically significantly associated with co-trimoxazole-induced SCARs, especially DRESS. While the HLA-C*08:01 allele was significantly associated with SJS/TEN induced by co-trimoxazole, particularly in HIV/AIDS patients. However, no association was found between co-trimoxazole-induced SCARs and genetic polymorphisms of drug metabolizing enzymes including CYP2C9, NAT2, GCLC, GSTT1, GSTM1 and GSTP1. For beta-lactam antibiotics-related SCARs group, Six HLA alleles including HLA-A*01:01, HLA-B*50:01, HLA-C*06:02, HLA-DRB1*15:01, HLA-DQA1*03:01 and HLA-DQB1*03:02 were significantly associated with beta-lactam antibiotics-related SCARs. The highest risk of SCARs was observed in patients with the HLA-B*50:01 allele. Apart from the HLA risk alleles, the HLA-A*02:07 allele appeared to be a protective factor against beta-lactam antibiotics-related SCARs. For NSAIDs-induced SCARs group, two HLA alleles, HLA-B*56:01 and HLA-DQA1*01:02, were significantly associated with SCARs induced by NSAIDs. While the HLA-DRB1*15:02 allele appeared to be a protective factor against NSAIDs-induced SCARs.
