Background: Nonimmediate (delayed) allergic reactions to
penicillins are common and some of them can be life-threatening. The
genetic factors influencing these reactions are unknown/poorly
known/poorly understood. We assessed the genetic predictors of a delayed
penicillin allergy that cover the HLA loci. Methods: Using
next-generation sequencing (NGS), we genotyped the MHC region in 24
patients with delayed hypersensitivity compared with 20 patients with
documented immediate hypersensitivity to penicillins recruited in Italy.
Subsequently, we analyzed in silico Illumina Immunochip
genotyping data that covered the HLA loci in 98 Spanish patients with
delayed hypersensitivity and 315 with immediate hypersensitivity
compared to 1,308 controls. Results: The two alleles
DRB3*02:02:01:02 and DRB3*02:02:01:01 were reported in twenty cases with
delayed reactions (83%) and ten cases with immediate reactions (50%),
but not in the Allele Frequency Net Database. Bearing at least one of
the two alleles increased the risk of delayed reactions compared to
immediate reactions, with an OR of 8.88 (95% CI, 3.37–23.32; P
<0.0001). The haplotype (ACAA) from rs9268835, rs6923504,
rs6903608, and rs9268838 genetic variants of the HLA-DRB3 genomic region
was significantly associated with an increased risk of delayed
hypersensitivity to penicillins (OR, 1.7; 95% CI: 1.06–1.92;
P=0.001), but not immediate hypersensitivity.
Conclusion: We showed that the HLA-DRB3 locus is
strongly associated with an increased risk of delayed penicillin
hypersensitivity, at least in Southwestern Europe. The determination of
HLA-DRB3*02:02 alleles in the risk management of severe delayed
hypersensitivity to penicillins should be evaluated further in larger
population samples of different origins.
Analysis and Optimal Design for Association Studies Using Next-Generation Sequencing With Case-Control Pools
