Association of HLA-A*11:01 with sulfonamide-related severe cutaneous adverse reactions in Japanese

Abstract

[Aim] Sulfonamides can cause Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS) as known as severe cutaneous adverse reactions (SCARs). Sulfamethoxazole (SMX) and salazosulfapyridine (SASP) are the most common sulfonamides used in Japan. We sought for new risk HLA candidates associated with the onset of sulfonamide-related SCARs in the Japanese patients.

[Materials and Methods] In total, 8 SJS/TEN and 7 DIHS patients were recruited under written informed consent through the nationwide case-collecting network system and the institutes belonging to the Japanese Research Committee on Severe Cutaneous Adverse Reaction, respectively. Each patient had taken SMX or SASP. HLA types and genome-wide single nucleotide polymorphisms (SNPs) were determined by Luminex and illumina BeadChip, respectively. The docking simulations were performed by using ASEDock software.

[Results and Discussion] We independently examined HLA types associated with SJS/TEN and DIHS cases in Japan and found a significantly higher prevalence of HLA-A*11:01 in both cases than in healthy volunteer population (odds ratio = 9.84; P = 2.67×10⁻⁵). Furthermore, we performed in silico docking simulations to predict interactions between HLA and sulfonamides SMX and SASP and found that they bound the peptide-binding groove of HLA-A*11:01 with binding energies of −5.60 and −6.67 kcal/mol, respectively. These findings suggested HLA-A*11:01 as a risk factor for sulfonamide-related onset of SCARs in the Japanese population.