We have identified an underrecognized severe adverse drug reaction (ADR) of trimethoprim-sulfamethoxazole (TMP-SMX) associated respiratory failure in previously healthy children and young adults. We investigated potential genetic risk factors associated with TMP-SMX induced respiratory failure in a cohort of seven patients. We explored whole genome sequence among seven patients representing nearly half of all reported cases worldwide and 63 unrelated control individuals in two stages: (1) human leukocyte antigen (HLA) locus variation as several other ADRs have been associated HLA genetic variants and (2) coding variation to catalog and explore potential rare variants contributing to this devastating reaction. All cases were either heterozygous (carriers) or homozygous for the common HLA-B*07:02–HLA-C*07:02 haplotype. Despite the small sample size, this observation is statistically significant both in conservative comparison to maximum reported population frequencies (binomial P = 0.00017 for HLA-B and P = 0.00028 for HLA-C) and to our control population assessed by same HLA genotyping approach (binomial P = 0.000001 for HLA-B and P = 0.000018 for HLA-C). No gene elsewhere in the genome harnessed shared rare case enriched coding variation. Our results suggests that HLA-B*07:02 and HLA-C*07:02 are necessary for a patient to develop respiratory failure due to TMP-SMX.

我们发现甲氧苄氨嘧啶-磺胺甲恶唑 (TMP-SMX) 在既往健康的儿童和年轻人中存在与呼吸衰竭相关的未被充分认识的严重药物不良反应 (ADR)。我们在 7 名患者的队列中研究了与 TMP-SMX 诱导的呼吸衰竭相关的潜在遗传风险因素。我们分两个阶段探索了 7 名患者（占全球所有报告病例的近一半）和 63 名无关对照个体的全基因组序列：(1) 人类白细胞抗原 (HLA) 基因座变异，因为其他几个 ADR 已与 HLA 遗传变异相关；(2)对变异进行编码，以编目并探索导致这种破坏性反应的潜在罕见变异。所有病例均为常见HLA-B*07:02–HLA-C*07:02单倍型的杂合子（携带者）或纯合子。尽管样本量较小，但这一观察结果在与最大报告人群频率（HLA-B 的二项式P = 0.00017，HLA-C 的P = 0.00028）和通过相同 HLA 基因分型方法评估的对照人群的保守比较中均具有统计学意义（二项式P = 0.000001 (HLA-B) 和P = 0.000018 (HLA-C)。基因组中的其他基因没有利用共享的罕见病例丰富的编码变异。我们的结果表明HLA-B*07:02和HLA-C*07:02对于患者因 TMP-SMX 发生呼吸衰竭是必需的。