An Association Analysis Of HLA And Allopurinol/β-lactam Antibiotics Induced Cutaneous Adverse Drug Reactions In A Han Population

ObjectiveAllopurinol and β-lactams are both widely used, served as an effective urate-lowering drug and a group of broad-spectrum antibiotics respectively. Although these drugs are important and unique in clinical practice, they are also the most frequent causes of cutaneous adverse drug reactions (cADRs). Recently, a strong association of HLA-B*5801with allopurinol-induced severe cutaneous adverse drug reactions (SCARs) was identified. Some studies also suggested that susceptibility to amoxicillin-clavulanate induced liver injury was influenced by multiple HLA Class I and II alleles. Thus, one aim of this study was to investigate the predisposition to different types of allopurinol-cADRs conferred by HLA-B in a Han population from east China. In this part, we did further genotype-phenotype analysis according to different subphenotypes. The validity of HLA-B*5801screening was also assessed. Another aim was to screen susceptibility genes (loci) to amoxicillin and cephalosporins based on Genome-wide association study.MethodsHLA-B genotyping was performed on38Chinese patients with allopurinol-cADRs, including22patients with maculopapular eruption (MPE),13patients with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and3patients of drug rash with eosinophilia and systemic symptoms (DRESS) from2008to2011. We conducted genome wide association analysis to screen potentially associated SNPs, including17patients with amoxicillin-induced cADRs and16ones with cephalosporins-cADRs. Besides, we located the susceptibility genes and the patterns of linkage disequilibrium (LD) around the associated SNPs.ResultOne hundred percent of the allopurinol-cADRs patients (38/38) carried HLA-B*5801, whereas only11.11%(7/63) in the allopurinol-tolerant patients (OR=580.07,p＜0.0001) and13.99%(80/572) in the Han Chinese population from the dbMHC database (OR=471.09,p＜0.0001) carried HLA-B*5801. Each type of allopurinol-cADRs revealed a statistically significant association with HLA-B*5801. In particular, the risk of allopurinol-induced MPE was significantly higher in patients with HLA-B*5801, with an OR of339.00(95%CI=18.58-6186.39, p<0.0001). The sensitivity and specificity of the HLA-B*5801allele for prediction of allopurinol-cADRs were100%and88.9%, respectively.From GWAS data, five SNPs showed evidence of the strongest associations with amoxicillin-cADRs within major histocompatibility complex (MHC) related region: rs11968268(OR=7.041,p=1.90×10-6),rs61235149(OR=6.537,p=5.03×10-6),rs9258756(OR=5.551,p=3.64×10-5), rs9258631(OR=5.400,p=4.96×10-5) and rs13207945(OR=5.148, p=3.20×10-5). They respectively located within HLA-A and HLA-W, HLA-H and HLA-G, HLA-DRB1and HLA-DQA1. The SNPs associated with cephalosporins-cADRs were identified in6p21.33. After investigating the susceptibility genes and the patterns of LD, we found NFKBIL1was in significant association with both amoxicillin and cephalosporins induced cADRs. We also found a statistically significant interaction between the genes outside the MHC and β-lactam antibiotics induced cADRs. We suggested that ARHGAP10, CNTN5, KCNJ3and HOXA were potentially correlated with amoxicillin-cADRs, while cephalosporins-cADRs were in association with KSR2, GPC6, FNDC3B and ENTPD3. However, it should be emphasized that given the small number of subjects in each group, further replication studies with a larger sample size will be necessary to provide a more definitive answer.Conclusion1. This is the first trial to investigate the association of HLA-B*58:01with mild cADRs caused by allopurinol.2. The strong association of both the mild and severe types of allopurinol-cADRs (MPE, SJS/TEN and DRESS) with the HLA-B*58:01allele were observed in a Han population from east China.3. The results indicated that the prospective use of a genetic test of HLA-B*5801might reduce the prevalence of allopurinol-induced cADRs.4. Five SNPs showed evidence of the strongest associations with amoxicillin-cADRs within major histocompatibility complex (MHC) related region:rs11968268, rs61235149, rs9258756, rs9258631and rs13207945. They respectively located within HLA-A and HLA-W, HLA-H and HLA-G, HLA-DRB1and HLA-DQA1.5. We identified SNPs in6p21.33associated with cephalosporins-cADRs.6. We found NFKBIL1was in significant association with both amoxicillin and cephalosporins induced cADRs.7. We suggested that ARHGAP10, CNTN5, KCNJ3and HOXA were potentially correlated with amoxicillin-cADRs, while cephalosporins-cADRs were in association with KSR2, GPC6, FNDC3B and ENTPD3.