Genome-wide association study for adverse reactions of antiepileptic drugs in Korean epilepsy patients

Abstract

Skin rash is a well-known adverse drug reaction to antiepileptic drugs (AEDs), and can be caused by AED withdrawal. To date, drug research has focused on carbamazepine (CBZ) in many populations (including Korean), and HLA gene polymorphisms as clinical biomarkers of CBZ-induced skin rash have been identified. Lamotrigine (LTG) is another rash-inducing AED, but biomarkers for LTG-induced skin rash have not been identified. Therefore, 34 epilepsy patients with skin rash derived from LTG were genotyped using the Affymetrix 500k SNP array, and an age-matched healthy Korean population cohort containing 1,214 individuals (which were genotyped using the Affymetrix 5.0 SNP array in 2007) was recruited by the Korean NIH. A total of 33 cases and 1,080 control subjects were analyzed as 1 case subject and 134 control subjects were removed according to the individual and marker quality control (QC) thresholds. Genome-wide association (GWA) was analyzed using the PLINK software, and imputation analysis was performed at sites not covered by the SNP array chip. Six markers of GWA analyses, which were selected by manual review among sites with p values lower than 10-5, and 23 markers manually selected from the imputation analyses were newly genotyped in the replication cohort of LTG-medicated epilepsy patients (59 with skin rash and 98 without skin rash). Of the 29 selected markers, rs13287547 from GWA analysis and rs12668095, rs17149848, and rs79007183 from imputation analysis were significant (p values of 0.027, 0.009, 0.024, and 0.025 based on allelic analysis, respectively). Rs13287547 and rs12668095 were located at intergenic locations near the C9orf92/BNC2 and TNS3 genes, and rs17149848 and rs79007183 were located at intronic regions within GRM8 and CRAMP1L genes, respectively. This study may facilitate the identification of clinical biomarkers for lamotrigine-induced skin