Influence of Pharmacogenomics Polymorphism and Non- Genetics Factors on Allopurinol-Induced Cutaneous Adverse Drug Reactions in Thai Patients Running title: Genetics of Allopurinol-induced CADRs in Thais

Allopurinol is causing substantial morbidity and mortality particularly in Asian population by producing cutaneous adverse drug reactions (cADRs). The goal of this study was to identify genetic biomarkers of single nucleotide polymorphisms (SNPs) for allopurinol induced cADRs among Thai patients. We conducted a case-control association study after enrolling 57 Thai patients with allopurinol induced cADRs and 101 allopurinol tolerant controls. Genetic biomarkers and associated SNPs located on chromosome 6p21 were examined by TaqMan® SNP genotyping assays in both case and controls. Out of 15 SNPs in nine genes, four combined SNPs ( rs3099844 of HCP5 ; rs9263726 of PSORS1C1 ; rs9263733 of POLR2LP and rs9263745 of CCHCR1 ) were significantly associated with allopurinol induced cADRs compared to tolerant controls (OR 3.2; 95% CI 24.2-266.8; P = 1.9x10 − 24 ). Overall sensitivity, specificity, positive predictive value and negative predictive value of these combinations were 84%, 94%, 9% and 100%, respectively. The SNPs were not in absolute linkage disequilibrium with HLA-B*58:01 , however, the variant alleles of these SNPs combination were detected in 89.5% (51/57) of the cases. The findings suggest that these SNPs could be used as an alternative novel biomarker in predicting cADRs in patients taking allopurinol especially in those with absence of HLA-B*58:01 allele but still experiencing cADRs.