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Genetic associations in beta-lactam allergy

机译：β-内酰胺过敏的遗传关联

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Immediate reactions to beta-lactams (BLs) are the mostcommon allergic reactions against drugs and can be lifethreatening.The genetic risk factors influencing thesereactions are poorly known, except those which werepreviously identified as predictors of atopy and inflammation.Two polymorphisms of nucleotide-binding oligomerizationdomain 2 (NOD2), a gene associated withchronic inflammatory bowel diseases, influence the riskof BL allergy (BLA), in Italy and Spain. G>A at locus308 of TNF-a, a key gene of inflammation, is a significantindependent predictor of the primary risk of BLA,in central Italy. TNF-a is part of an extended haplotypeHLA-A1-B8-DR3-DQ2, suggesting a potential implicationof drug recognition by major histocompatibilitycomplex. Several studies in Europe, US and China convergein showing also that immediate-type allergic reactionsto BLs are predicted by genes, which influence IgEproduction, IL-13, IL-4 and IL4RA. The combination ofthe less frequent allele of the IL13 R130Q polymorphismwith any of the predominant homozygous genotypesof 3 polymorphisms of IL4RA was more significantly associatedwith the risk of BL allergy than any polymorphismconsidered alone, in Italy. In contrast, in Spain, IL13 andIL4RA had no epistatic influence and only IL4RA I50Vand Q551R were predictors of BL allergy (39). These genevariants were also associated with IgE against prevalentallergens and total IgE, respectively. The association of IgEagainst house dust mite with BL allergy could take part inthe high frequency of BL allergy in Spain, where the exposureto house dust mite is higher than in colder Europeancountries. A polymorphism in the gene promoter of thehigh-affinity receptor for IgE (FcεR1b) is a predictor forincreased IgE sensitization to cephalosporins, in exposedhealth care workers from Korea. Very recently, we haveperformed a genome wide-association study (GWAS) inimmediate-type BL allergic subjects and matched controlsfrom Spain, with replication of significant associations inan Italian population. The results of this GWAS highlightthe importance of drug presentation in the genetic susceptibilityof BLA. In conclusion, the predictors ofimmediate allergic reactions to betalactams reflect theimportance of genetic and environmental factors throughmechanisms related to IgE production and antigenpresentation.
机译：对β-内酰胺（BLs）的即时反应是对药物最常见的过敏反应，可能危及生命。除先前被确定为特应性和炎症的预测因素外，影响这些反应的遗传风险因素鲜为人知。核苷酸结合寡聚域的两个多态性2（NOD2）是一种与慢性炎症性肠病相关的基因，在意大利和西班牙会影响BL过敏（BLA）的风险。在意大利中部，炎症的关键基因TNF-a的308位点的G> A是BLA初级风险的重要独立预测因子。 TNF-α是扩展单倍型HLA-A1-B8-DR3-DQ2的一部分，表明主要组织相容性复合物可能对药物识别有潜在影响。在欧洲，美国和中国的一些研究表明，BLs的立即型过敏反应是由基因预测的，这些基因会影响IgE的产生，IL-13，IL-4和IL4RA。在意大利，IL13 R130Q多态性频率较低的等位基因与IL4RA 3个多态性的任何主要纯合基因型的组合与BL变态反应的风险相比，单独考虑的任何多态性更显着。相反，在西班牙，IL13和IL4RA没有上皮性影响，只有IL4RA I50V和Q551R是BL过敏的预测因子（39）。这些基因变体也分别与针对流行性变应原的IgE和总IgE相关。 IgEagainst屋尘螨与BL过敏的关联可能是西班牙BL过敏的高发地区，在西班牙，屋尘螨的暴露程度高于较寒冷的欧洲国家。 IgE的高亲和力受体（FcεR1b）基因启动子中的多态性是导致韩国暴露的医护人员IgE对头孢菌素敏感性增高的预测因子。最近，我们进行了基因组广泛关联研究（GWAS），对中型BL过敏受试者和来自西班牙的匹配对照进行了研究，并在意大利人群中复制了重要的关联。 GWAS的结果突出了药物呈递对BLA遗传易感性的重要性。总之，对β-内酰胺类立即过敏反应的预测因子反映了通过与IgE产生和抗原呈递相关的机制，遗传和环境因素的重要性。

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