Identification of Novel Biomarkers for Drug Hypersensitivity After Sequencing of the Promoter Area in 16 Genes of the Vitamin D Pathway and the High-Affinity IgE Receptor

Abstract

The prevalence of allergic diseases and drug hypersensitivity reactions (DHRs) during recent years is increasing. Both, allergic diseases and DHRs seem to be related to an interplay between environmental factors and genetic susceptibility. In recent years, a large effort in the elucidation of the genetic mechanisms involved in these disorders has been made, mostly based on case-control studies, and typically focusing on isolated SNPs. These studies provide a limited amount of information, which now can be greatly expanded by the complete coverage that Next Generation Sequencing techniques offer. In this study, we analyzed the promoters of sixteen genes related to the Vitamin D pathway and the high-affinity IgE receptor, including FCER1A, MS4A2, FCER1G, VDR, GC, CYP2R1, CYP27A1, CYP27B1, CYP24A1, RXRA, RXRB, RXRG, IL4, IL4R, IL13 , and IL13RA1 . The study group was composed of patients with allergic rhinitis plus asthma (AR+A), patients with hypersensitivity to beta-lactams (BLs), to NSAIDs including selective hypersensitivity (SH) and cross-reactivity (CR), and healthy controls without antecedents of atopy or adverse drug reactions. We identified 148 gene variations, 43 of which were novel. Multinomial analyses revealed that three SNPs corresponding to the genes FCER1G (rs36233990 and rs2070901), and GC (rs3733359), displayed significant associations and, therefore, were selected for a combined dataset study in a cohort of 2,476 individuals. The strongest association was found with the promoter FCER1G rs36233990 SNP that alters a transcription factor binding site. This SNP was over-represented among AR+A patients and among patients with IgE-mediated diseases, as compared with control individuals or with the rest of patients in this study. Classification models based on the above-mentioned SNPs were able to predict correct clinical group allocations in patients with DHRs, and patients with IgE-mediated DHRs. Our findings reveal gene promoter SNPs that are significant predictors of drug hypersensitivity, thus reinforcing the hypothesis of a genetic predisposition for these diseases.

Genetic association of beta-lactams-induced hypersensitivity reactions: A systematic review of genome-wide evidence and meta-analysis of candidate genes

“…By screening titles and abstracts, we identified 45 studies for full-text review. Based on the study selection criteria, 31 studies (27 candidate gene studies, 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 3 GWASs, 61 , 62 , 63 and 1 next-generation sequencing [next-generation sequencing, NGS]-based genotyping 64 ) fulfilled the study criteria and were included in this study ( Fig. 1 ).…”

“… Gene Single nucleotide variant ID No. of studies (reference) Culprit Drugs Hypersensitivity types IR NIR SCARs FceRIb 1. rs569108 (E237G): A > G 4 34 , 38 , 45 , 60 BLs ✓ ✓ 2. rs569108: T > C 2 52 , 60 BLs ✓ FceRIG 1. rs35233990 1 55 BLs NA 2. rs2070901 1 55 BLs NA IL 4R 1. rs1801275 (Gln576Arg, Q576R, Q551R) 8 35 , 37 , 38 , 43 , 46 , 49 , 52 , 54 BLs ✓ ✓ 2. rs1805010 (I50 V, I75 V) 6 37 , 38 , 41 , 43 , 49 , 56 BLs ✓ ✓ 3. rs1805015 (S478P) 3 37 , 49 , 56 …”

Gene–Smoking Interaction Analysis for the Identification of Novel Asthma-Associated Genetic Factors

“…However, we did not find significant results for KDM4C and MYL7. ATF3 [111,112], BCL6 [113,114], EGR1 [115,116], ELF3 [117], EP300 [118,119], FOXA1 [93], FOXA2 [94,95], FOXA3 [94,120], HDAC2 [121,122], IRF2 [123], JUND [124,125], KAT8 [126,127], NFIL3 [103,104], NFYC [128], PRDM1 [129,130], RAD21 [131,132], RARA [105], RXRA [100,101], RXRB [133], SMAD4 [106], SP1 [134], THRB [135,136], YY1 [137,138] a The CADD PHRED score 10 means risk of top rank 10%, 20 means risk of top rank 1%; b the DANN score ranges from 0 to 1, where 1 represents the highest possibility for pathogenicity; c asthma-related transcription factor that controls the rate of transcription of genetic information from DNA to messenger RNA by binding to a specific DNA sequence; d scores range from 1 to 7, with lower values indicating that the variant is more likely to be located in the functional region.…”

The nuts and bolts of omics for the clinical allergist

“…Early evidence is gathering for genetic biomarkers of allergic disease, including asthma, 10 food allergy, 11 atopic dermatitis, 12 allergic rhinitis, 13 and drug allergy. 13,14 However, despite the association of these genetic variants with allergic diseases, the impact on how the disease manifests or varies is often unknown, and the effect of the individual variant is often small. As a result, using genomic data alone often can only provide an incomplete picture of the individual patient's personalized risk of disease.…”