Research on Susceptible Genes and Immunological Pathogenesis of Cutaneous Adverse Drug Reactions in Chinese Hans

Abstract

Cutaneous adverse drug reactions (cADRs) include mild maculopapular exanthems (MPE), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). We used HLA high-resolution genotyping and genome wide association analysis (GWAS) to identify the genetic markers for cADRs induced by common culprit drugs in Han Chinese population. To further understand the immunopathogenesis of cADRs, and with the goal of developing treatment strategies, we compared the expression of cytoxic cytokines between the patients with cADRs and normal controls. Our data suggested that the carbamazepine induced SJS/TEN, allopurinol induced CADRs, methazolamide induced SJS/TEN and SASP induced DRESS were respectively strongly associated with HLA-B*15:02, HLA-B*58:01, HLA-B*59:01 and HLA-B*13:01. In addition, increased expression of cytotoxic cytokines in sera and tissues of cADRs patients were found, compared with healthy controls. Our findings may shed light on prediction and prevention of cADRs, provide clues to pathogenesis, and guide treatment strategies of these reactions.

Diagnostic utility of HLA‐B*5801 screening in severe allopurinol hypersensitivity syndrome: an updated systematic review and meta‐analysis

“…Another issue worth mentioning is that there may be genetic/ethnic differences in the HLA risk alleles that may be associated with allopurinol‐induced TEN/SJS. For example, previous studies have demonstrated a strong association between carbamazepine‐induced TEN/SJS and HLA‐B*1502 in Chinese and Southeast Asia populations in addition to HLA‐A*3101, whereas HLA‐B*1502 was not associated with carbamazepine‐induced TEN/SJS in Caucasian or Japanese populations . In contrast to carbamazepine, which was shown to have ethnic/population‐specific effects, the HLA‐B*5801 allele for detecting allopurinol‐hypersensitivities appears to be more universal, although it may have only moderate value in detecting these hypersensitivities in European (except Sardinian Italian) and Japanese populations where HLA‐B*5801 frequency is lower.…”

“…It is not clear why only 3% of HLA‐B*5801 positive patients developed SCAR after taking allopurinol, which suggests that other factors may also be involved in mediating the increased risk . Although the precise mechanisms involved in SCAR development and TEN/SJS are still unclear, several different factors have been postulated in their pathogenesis, which have mainly included those related to cell‐mediated immunity directed toward allopurinol and its active metabolite, oxypurinol, in addition to viruses, genetic factors and metabolic pathways . Cutaneous drug reactions may be caused by several different mechanisms .…”

“…Cutaneous drug reactions may be caused by several different mechanisms . TEN and SJS are characterized by massive keratinocyte apoptosis . Chung et al .…”

“…For example, previous studies have demonstrated a strong association between carbamazepine-induced TEN/SJS and HLA-B*1502 in Chinese and Southeast Asia populations in addition to HLA-A*3101, whereas HLA-B*1502 was not associated with carbamazepine-induced TEN/SJS in Caucasian or Japanese populations. 3,4,8,[55][56][57] In contrast to carbamazepine, which was shown to have ethnic/ population-specific effects, the HLA-B*5801 allele for detecting allopurinol-hypersensitivities appears to be more universal, although it may have only moderate value in detecting these hypersensitivities in European (except Sardinian Italian) and Japanese populations where HLA-B*5801 frequency is lower. The RegiSCAR study 2 revealed that HLA-B*5801 is a genetic marker (61.3%, 19 of 31 cases) for allopurinol-induced TEN/SJS.…”

“…24 Although the precise mechanisms involved in SCAR development and TEN/ SJS are still unclear, several different factors have been postulated in their pathogenesis, [60][61][62][63][64][65][66][67] which have mainly included those related to cell-mediated immunity directed toward allopurinol and its active metabolite, oxypurinol, in addition to viruses, genetic factors and metabolic pathways. 24,56,57,[60][61][62][63][64][65][66][67][68] Cutaneous drug reactions may be caused by several different mechanisms. 1,2 TEN and SJS are characterized by massive keratinocyte apoptosis.…”