Background:
Allopurinol-induced severe cutaneous adverse reactions (
SCARs), including drug
rash with
eosinophilia and systemic symptoms (DRESS),
Stevens-Johnson syndrome (SJS) and toxic epidermal
necrosis (TEN), are life-threatening autoimmune reactions. Evidence is growing that epigenetic variation, particularly DNA methylation, is associated with
autoimmune diseases. However, the potential role of aberrant DNA methylation in
allopurinol-
SCARs is largely unknown. Objective: To address the knowledge gap between
allopurinol-
SCARs and DNA methylation, we studied the DNA methylation profiles in peripheral blood cells from
allopurinol-
SCARs and
allopurinol-tolerant subjects. Methods: A genome-scale DNA methylation profiling was conducted using the Illumina Infinium HumanMethylation450 (HM450) platform on 15 patients with
allopurinol-
SCARs (3 TEN, 2 SJS/TEN overlap and 10 SJS) and 20 age- and gender-matched
allopurinol-tolerant controls at disease onset. Pyrosequencing was used to validate the candidate CpG (
cytosine-guanine dinucleotide) sites in an independent cohort of 40
allopurinol-
SCARs and 48
allopurinol-tolerants. Results: After bioinformatics analysis of methylation data obtained from HM450 BeadChip, we identified 41 differentially methylated CpG loci (P < 0.05) annotated to 26 genes showing altered DNA methylation between
allopurinol-
SCARs and
allopurinol-tolerants. Among these genes, significant hypomethylation of PSORS1C1 (cg24926791) was further validated in a larger sample cohort, showing significant difference between DRESS and controls (P = 0.00127), ST (SJS and TEN) and controls (P = 3.75 × 10-13), and
SCARs and controls (P = 5.93 × 10-15). Conclusions: Our data identified differentially methylated genes between
allopurinol-
SCARs and
allopurinol-tolerant controls and showed that PSORS1C1 hypomethylation was associated with
allopurinol-
SCARs (OR = 30.22, 95%CI = 4.73-192.96) during disease onset, suggesting that aberrant DNA methylation may be a mechanism of
allopurinol-
SCARs. Limitations: Firstly, the data come from whole blood samples known to possess epigenetic heterogeneity, i. e., blood samples comprise a heterogeneous cell population with varying proportions of distinct cell-types with different DNA methylation patterns. Consequently, the interpretation of DNA methylation results should be performed with great caution due to the heterogeneous nature of the sample. Secondly, whether the identified disease-associated changes of epigenome precede disease onset, or result from the
disease progression, needs further investigation. Comparing the methylation status before patients develop
allopurinol-
SCARs and after may help examine methylation levels from disease onset to
disease progression.