Abstract TMP17: Polymorphisms In DNA Methylated Genes And Risk Of Intracranial Hemorrhage In Brain Arteriovenous Malformation Patients

Background: Brain arteriovenous malformations (BAVMs) are a tangle of abnormal vessels that directly shunt blood from the arterial to venous circulation and are a significant cause of intracranial hemorrhage (ICH). DNA methylation, an epigenetic mechanism, can regulate gene expression. Previous studies revealed significant correlations between BAVM development and DNA methylation levels of gene promoter regions in WTAP , METTL3 , NOS1AP , PLA2G7 , CDKN2A , CDKN2B , and PDGFD . Therefore, we investigated whether genetic variants in these candidate genes are associated with risk of ICH at clinical presentation in BAVM patients. Methods: A total of 383 single nucleotide polymorphisms (SNPs) were investigated using genome-wide data from 338 BAVM Caucasian patients, mapping within 20kb of the genes: WTAP (n=15), METTL3 (n=12), NOS1AP (n=190), PLA2G7 (n=15), CDKN2A / CDKN2B (n=22), and PDGFD (n=129). We used multivariable logistic regression analysis, adjusting for age, sex, and 3 principal components to adjust for population stratification. The Bonferroni method was used to correct for multiple comparisons (p=0.05/383 SNPs=0.00013). RegulomeDB scores were used to identify putative functional variants. Results: Two SNPs were associated with increased risk of ICH with BAVM at nominal p<0.05 but were not statistically significant: rs1263806 in METTL3 (OR=1.45, p=0.04) and rs1964052 in NOS1AP (OR=1.69, p=0.04). Ten SNPs were associated with decreased risk at nominal p<0.05: rs10757261, rs10757261, rs2811711, rs575427 in CDKN2A / CDKN2B ; rs528027, rs260866, rs260842, rs260850, rs7128670, and rs7113370 in PDGFD . No SNPs in WTAP and PLA2G7 were associated with ICH (p>0.05). One SNP, rs2811710 mapping to CDKN2A / CDKN2B (OR=0.6, p=0.02), is predicted to be functionally relevant as an expression quantitative trait loci (eQTL). Conclusions: Genetic variants in WTAP , METTL3 , NOS1AP , PLA2G7 , CDKN2A , CDKN2B , and PDGFD are not significantly associated with risk of ICH presentation in patients with BAVM.