285 Genetic Variation in the SLC22A1-3 Genes Influence the Risk of Congenital Anomalies

Abstract

OBJECTIVES/GOALS: Congenital anomalies (CA) are common, but the cause is often unknown. The interplay between known environmental teratogens, such as medication use in pregnancy, and genetic predisposition impacts CA risk, but such interactions are poorly understood. We test the hypothesis that pharmacogenomic (PGx) variation impacts CA risk. METHODS/STUDY POPULATION: We performed a drug absorption, distribution, metabolism, and excretion (ADME) gene-wide association study (GWAS), which tests for a possible association between ADME gene single nucleotide polymorphisms and individuals with CAs. This analysis was performed in BioVU and utilized billing codes to identify 5,845 cases, individuals with at least one CA, and 50,059 controls of genetically European ancestry. Using Plink software we analyzed 5,398 SNPs in 292 ADME genes across cases and controls. Results from this analysis drove us to further investigate the association between CA risk and SLC22A1-3. Next, we performed PrediXcan analyses to estimate the association between genetically predicted gene expression (GPGE) of SLC22A1-3 genes across all available tissues in the GTEx resource and CA risk. RESULTS/ANTICIPATED RESULTS: The ADME GWAS identified multiple variants on chromosome 6 in the region of SCL22A1-3 that were associated with the risk for CAs. The most significant variants were rs2048327, rs2292334, rs3088442, rs1810126, rs376563, and rs7758229, p DISCUSSION/SIGNIFICANCE: The combination of the known crucial pharmacological roles of OCT1-3 and the results of our ADME GWAS / PrediXcan analyses demonstrates that PGx burden, specifically variation in the SLC22A1-3 genes, influences the risk of developing CAs. This new understanding has the potential to personalize care for pregnant individuals to reduce the risk of CAs.