While HLA-B*1502 is unlikely to be associated with carbamazepine-related or aromatic anti-epileptic agent-related SJS/TEN, HLA-B*5801 was significantly associated with allopurinol-related SJS/TEN in Japanese.
This study identified several UGT1A1 haplotypes significantly associated with the reduced AUC ratio (*28 and *6) and with the increased total bilirubin level (*28, *60, and *IB) and suggested that the novel haplotype *IB might be functionally important. These findings will be useful for further pharmacogenetic studies on adverse reactions to irinotecan.
The haplotypes significantly associated with reduced area under concentration curve ratios and neutropenia contained UGT1A1*6 or *28, and both of them should be genotyped before irinotecan is given to Japanese and probably other Asian patients.
This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.
Haplotype *3 harboring a nonsynonymous SNP, 208G>A (Ala70Thr), decreased clearance of gemcitabine, and increased incidences of neutropenia when patients were coadministered platinum-containing drugs or fluorouracil.
Stevens-Johnson syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucous membranes. Cold medicines including non-steroidal anti-inflammatory drugs (NSAIDs) and multi-ingredient cold medications are reported to be important inciting drugs. We used two sample sets of Japanese patients to investigate the association between HLA genotypes and cold medicine-related SJS/TEN (CM-SJS/TEN), including acetaminophen-related SJS/TEN (AR-SJS/TEN) with severe mucosal involvement such as severe ocular surface complications (SOC). HLA-A*02:06 was strongly associated with CM-SJS/TEN with SOC and AR-SJS/TEN with SOC. HLA-B*44:03 was also detected as an independent risk allele for CM-, including AR-SJS/TEN with SOC. Analyses using data obtained from CM-SJS/TEN patients without SOC and patients with CM-unrelated SJS/TEN with SOC suggested that these two susceptibility alleles are involved in the development of only CM-SJS/TEN with SOC patients.
Summary
Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life‐threatening severe cutaneous adverse reactions. Recently, strong associations of HLA‐B*1502 with carbamazepine‐induced SJS/TEN have been found in Han Chinese patients. These associations have been confirmed in several Asian populations, excluding Japanese. SJS patients carrying HLA‐B*1508, HLA‐B*1511, or HLA‐B*1521, which are members of the HLA‐B75 type along with HLA‐B*1502, were detected in studies in India and Thailand. In the current study, we genotyped the HLA‐B locus from 14 Japanese typical and atypical SJS/TEN patients in whom carbamazepine was considered to be involved in the onset of adverse reactions. Although there were no HLA‐B*1502 carriers, four patients had HLA‐B*1511. Our data suggest that HLA‐B*1511, a member of HLA‐B75, is a risk factor for carbamazepine‐induced SJS/TEN in Japanese.
Gemcitabine is a deoxycytidine analogue that has a broad spectrum of antitumour activity in many solid tumours including pancreatic cancer. We have recently carried out a pharmacogenomic study in cancer patients treated with gemcitabine, and found that one genetic polymorphism of an enzyme involved in gemcitabine metabolism can cause interindividual variations in the pharmacokinetics and toxicity of this agent. In this paper, we review recent genetic studies of gemcitabine, and discuss the possibility of individualised cancer chemotherapy based on a pharmacogenomic approach.
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