Aims: To determine genetic susceptibility markers for carbamazepine (CBZ) and allopurinol-induced severe cutaneous adverse reactions (SCARs) in Vietnamese. Methods: A case–control study was performed involving 122 patients with CBZ or allopurinol-induced SCARs and 120 drug tolerant controls. Results: HLA-B*58:01 was strongly associated with allopurinol-induced SCARs and strongly correlated with SNP rs9263726. HLA-B*15:02 was associated with CBZ-induced Stevens–Johnson syndrome/toxic epidermal necrolysis but not with drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms. No association was found between HLA-A*31:01 and CBZ-induced SCARs. HLA-B*58:01 and rs3909184 allele A with renal insufficiency were shown to increase the risk of allopurinol-induced SCARs. Conclusion: HLA-B*58:01 and HLA-B*15:02 confer susceptibility to allopurinol-induced SCARs and CBZ-induced SJS/TEN in Vietnamese. SNP rs9263726 can be used as a surrogate marker in identifying HLA-B*58:01.

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Aim: To examine gene expression in different clinical phenotypes of allopurinol-induced severe cutaneous adverse reactions (SCARs). Materials & methods: Gene expression profiling was performed using microarray on 11 RNA samples (four controls, three hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms, four Stevens–Johnson syndrome/toxic epidermal necrolysis) followed by quantitative real-time PCR in a total of 11 SCARs patients and 11 controls. Results: The biological pathways which were significantly enriched in differentially expressed genes in Stevens–Johnson syndrome/toxic epidermal necrolysis compared with hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms patients included; cell surface interactions at the vascular wall, immunoregulatory interactions at the immunological synapse and MyD88 signaling pathways. Overexpression of miR146a occurred in allopurinol-tolerant HLA-B*58:01 carriers. Conclusion: Biological pathways are identified which appear to be implicated in determining clinical phenotypes in allopurinol-induced SCARs. Overexpression of miR146a is potentially important for allopurinol tolerance in HLA-B*58:01 carriers.

RATIONALE: In Vietnam, carbamazepine (CBZ) and allopurinol have been observed to be the leading causes of severe cutaneous adverse reactions (SCARs). Previously, we reported a strong association between CBZ-induced SJS/TEN and HLA-B*15:02 allele. Herein, we extended our study to determine genetic susceptibility to CBZ and allopurinol-induced SCARs in Vietnamese. METHODS: 95 cases of SCARs and 80 controls have been recruited since 2015. DNA samples were extracted from peripheral blood leukocytes. Real-time PCR TaqManä Probe and SYBR were used for HLA genotyping. A SNP (rs9263726 A>G) in PSORS1C1 gene was genotyped using PCR-RFLP. RESULTS: 25 of 26 SJS/TEN patients and 3 of 6 HSS/DRESS patients were positive for HLA-B*15:02 allele in comparison with 6 of 40 controls. An Odds ratio (OR) for CBZ-induced SJS/TEN was 141.7 (95%CI: 16.0 to 1252.1, P < 0.0001) and 5.7 (95%CI: 0.9 to 35.0, P 5 0.0618) for HSS/ DRESS. HLA-A*31:01 was absent in patients and present in one control. For allopurinol-induced SCARs, 58 of 63patients were HLA-B*58:01 positive while only 3 controls possessed this allele. A very strong association between HLA-B*58:01 allele and allopurinol-induced SCARs was confirmed with OR of 143.1 (95%CI: 32.3 to 634.5, p< 0.0001). A complete linkage was observed between the A allele (rs9263726) and HLA-B*58:01 allele. CONCLUSIONS: We confirm that HLA-B*15:02 increases the susceptibility to CBZ-induced SJS/TEN, but not for HSS/DRESS, with no involvement of HLA-A*31:01. This SNP rs9263726 can be used as a surrogate marker to test for HLA-B*58:01 in the Vietnamese population. This agrees with what was reported in the Japanese population.

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