DISCUSSION
We sequenced the HLA region of 24 patients with delayed and 20 with
immediate hypersensitivity to
penicillins in order to analyze
the risk association for all high-resolution alleles with delayed
hypersensitivity. We observed a strong association ofDRB3*02:02:01:02 and DRB3*02:02:01:01 alleles with the
risk of penicillin delayed
hypersensitivity in the 24 Italian patients. It is noteworthy that as
many as 83% of the cases carried a DRB3*02:02 allele. The
frequency of homozygous cases for the variants of the HLA-DRB3locus was higher in group A (with selective hypersensitivity to
ampicillin and amoxicillin) than in the less selective groups B and C,
suggesting that the association reflects the specificity of hapten
recognition. The association of the HLA-DRB3 locus with an
increased risk of penicillin delayed hypersensitivity was confirmed by
the in silico study of genetic variants of the HLA-DRB3genomic region in Spanish patients. The protein encoded by theHLA-DRB3 gene belongs to the HLA class II beta chain paralogs,
including DRB1, DRB4, and DRB5. It is part of a heterodimer consisting
of an alpha chain (DRA) and a beta one (DRB) and is involved in the
antigen presentation of peptides derived from extracellular proteins.
The association of HLA-DRB3*02:02 with the risk of penicillin
delayed hypersensitivity has never been reported for any other drug
category so far. The HLA-DRB3*02:02 allele is independently and
strongly associated with an increased risk of PLA2R -related
idiopathic membranous nephropathy in a Chinese
population.23 Therefore, our results suggest
investigating the increased risk of delayed reactions to penicillins in
this disease.
Only one study had previously evaluated the genetic determinants that
contribute to the risk of delayed hypersensitivity to penicillins. This
Italian case-control study assessed HLA-A2 and HLA-DRw52alleles in 24 patients with MPE caused by delayed hypersensitivity to
aminopenicillins and 522 subjects from the general
population.15 The HLA-A2 and HLA-DRw52alleles were significantly more prevalent among cases. However, we did
not replicate this result in the NGS of the MHC region in our study. A
French study assessed nine variants on genes controlling cytokine
production (i.e., IL1 , IL1B , IL1RN , IL2 ,IL4 , IL5 , IL10 , IL16 , and TNF ) in 118
patients with well-defined cutaneous adverse drug reactions and 236
controls.27 Several responsible drugs were considered
in the study, including
beta-lactams.
The haplotype combining IL1RN A2 and IL1B 511Calleles was associated with an increased risk of DRESS (OR = 3.22; 95%
CI: 1.23-8.41).27 However, the number of cases was too
limited to evaluate the specific risk of reactions to penicillins.
We compared our data with pharmacogenetic research on immediate
penicillin allergy. Most studies have evaluated genetic determinants of
immediate reactions to beta-lactams utilizing a candidate-gene approach.
They found an association with genes involved in IgE production, atopy,
and inflammation, including 3 genes validated by replications:ILR4 , NOD2 , and LGALS3 .13,28-30It is noteworthy that no association with HLA-DRB1*10:01 ,ILR4 , NOD2 , or LGALS3 was identified by GWAS in our
patients with delayed hypersensitivity reactions to penicillins. Despite
the vicinity of the HLA-DRB1 /3 /4 /5 loci in
chromosome 6, it is noteworthy that we did not find any association
between the risk of delayed reactions to penicillins and the rs7754768
and rs9268832 of the HLA-DRA |HLA-DRB5inter-region in a GWAS performed in Italian and Spanish
populations.11 Similarly, we found no risk association
of delayed reactions with the rs71542416 within the Class II HLA region,
which is associated with the risk of immediate beta-lactam allergy in
GWAS performed in Italian and Spanish populations.12
In conclusion, we showed that the HLA-DRB3*02:02 alleles are
strongly associated with an increased risk of delayed hypersensitivity
to penicillins, at least in Southwestern Europe. In regard to the
severity of some of the reactions, the interest for using the
determination of HLA-DRB3*02:02 alleles in the risk management of
delayed hypersensitivity to penicillins should be evaluated in further
studies of larger populations of different origin.