Premium
Deep sequencing of prostaglandin‐endoperoxide synthase ( PTGE) genes reveals genetic susceptibility for cross‐reactive hypersensitivity to NSAID
Author(s) -
GarcíaMartín Elena,
GarcíaMenaya Jesús M.,
Esguevillas Gara,
CornejoGarcía José A.,
Doña Inmaculada,
JuradoEscobar Raquel,
Torres María J.,
BlancaLópez Natalia,
Canto Gabriela,
Blanca Miguel,
Laguna José J.,
Bartra Joan,
Rosado Ana,
Fernández Javier,
Cordobés Concepción,
Agúndez José A.G.
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15366
Subject(s) - single nucleotide polymorphism , gene , exon , biology , genetics , intron , allele , microbiology and biotechnology , genotype
Background and Purpose Cross‐reactive hypersensitivity to nonsteroidal anti‐inflammatory drugs (NSAIDs) is a relatively common adverse drug event caused by two or more chemically unrelated drugs and that is attributed to inhibition of the COX activity, particularly COX‐1. Several studies investigated variations in the genes coding for COX enzymes as potential risk factors. However, these studies only interrogated a few single nucleotide variations (SNVs), leaving untested most of the gene sequence. Experimental Approach In this study, we analysed the whole sequence of the prostaglandin‐endoperoxide synthase genes, PTGS1 and PTGS2 , including all exons, exon‐intron boundaries and both the 5′ and 3′ flanking regions in patients with cross‐reactive hypersensitivity to NSAIDs and healthy controls. After sequencing analysis in 100 case–control pairs, we replicated the findings in 540 case–control pairs. Also, we analysed copy number variations for both PTGS genes. Key Results The most salient finding was the presence of two PTGS1 single nucleotide variations, which are significantly more frequent in patients than in control subjects. Patients carrying these single nucleotide variations displayed a significantly and markedly lower COX‐1 activity as compared to non‐carriers for both heterozygous and homozygous patients. Conclusion and Implications Although the risk single nucleotide variations are present in a small proportion of patients, the strong association observed and the functional effect of these single nucleotide variations raise the hypothesis of genetic susceptibility to develop cross‐reactive NSAID hypersensitivity in individuals with an impairment in COX‐1 enzyme activity.