Human Leukocyte Antigens-Associated Severe Cutaneous Adverse Drug Reactions in Vietnamese

Severe cutaneous adverse reactions (SCARs)- Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Acute Generalized Exanthematous Pustulosis (AGEP), cause high mortality (10-50%) and morbidity (60%). Carbamazepine (CBZ) and allopurinol (A), the most common culprits, are strongly associated with specific genotypes: HLA-B*15:02/HLA-A*31:01 with CBZ; HLA-B*58:0 with A-induced SCARs, especially in Asians. Screening for risk alleles prevents CBZ- and A-induced SCARs. Lack of suitable screening methods, unclear patho-mechanisms and poor understanding of co-factors’ role, have to date prevented clinical translation in Vietnam. Aiming to reduce mortality and morbidity from SCARs, it was necessary to establish any associations between HLA genes and A and CBZ-induced SCARs in Vietnamese, then develop simple, rapid and cost-effective assays for risk alleles. To better understand patho-mechanisms and the role of co-factors, gene expression profiling was undertaken in A-induced SCARS. Chapters 4-7, each present novel, cost-effective, rapid real-time-PCR based assays screening for HLA-B*57:01/58:01 (4), HLA-B*58:01 (5), HLA-B*15:02 (6) and HLA-A*31:01/HLA-B*15:02 (7). In Chapter 8, a case control study of 122 patients with SCARs caused by CBZ or A and 120 drug tolerant controls determined genetic susceptibilities. Key findings were: HLA-B*15:02 and HLA-B*58:01 are pharmacogenomic risk factors for CBZ-induced SJS/TEN and A-induced SCARs in Vietnamese. The risk of developing SCARs with A is increased by having HLA-B*58:01, rs3909184 allele A and renal insufficiency. HLA-B*15:02 was confirmed as a major risk factor for CBZ-induced SCARs in Vietnamese. No association was found between HLA-A*31:01 and CBZ-induced SCARs. The single nucleotide polymorphism, rs9263726, in psoriasis susceptibility 1 candidate 1 (PSORS1C1) gene, was identified as a marker for HLA-B*58:01. The restriction fragment length polymorphism (RFLP) method developed will simplify screening. Finally, gene expression profiling study data (Chapter 9) provide insights into patho-mechanisms of A-induced SCARs and a potential role for miR146a as a co-factor in A tolerance in HLA-B*58:01 carriers. Taken together, a framework to enable screening in Vietnam