Open AccessHLA-B*07:02 and HLA-C*07:02 are associated with trimethoprim-sulfamethoxazole respiratory failure
Author(s) -
Jennifer Goldman,
Jenna Miller,
Neil Miller,
Robert Eveleigh,
Andrew Gibson,
Elizabeth Phillips,
Tomi Pastinen
Publication year - 2022
Publication title -
pharmacogenomics journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.804
H-Index - 85
eISSN - 1473-1150
pISSN - 1470-269X
DOI - 10.1038/s41397-022-00266-8
Subject(s) - human leukocyte antigen , genotyping , hla b antigens , immunology , haplotype , medicine , trimethoprim , population , cohort , biology , genetics , allele , genotype , gene , antigen , antibiotics , environmental health
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 = 0.1 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.