Abstract 13682: Single Nucleotide Polymorphisms in the Ddah1 Gene Are Associated With Delayed Cerebral Ischemia in Patients With Subarachnoid Hemorrhage

Abstract

Introduction: Delayed cerebral ischemia (DCI) is a major cause of lethality and poor long-term neurological outcome in patients with subarachnoid hemorrhage (SAH). Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are regulators of vascular NO synthesis from L-arginine. We previously reported that elevated concentrations of both, ADMA and SDMA at ICU admission are associated with the incidence of DCI during follow-up. Dimethylarginines (DMAs) are synthesized by PRMT enzymes; ADMA is metabolized by DDAH1 and DDAH2, whilst SDMA is metabolized by AGXT2. Hypothesis: We hypothesized that common genetic variants in genes encoding the core enzymes of DMA metabolism may predispose individuals for the development of DCI after SAH. Methods: We measured L-arginine, ADMA and SDMA in plasma and cerebrospinal fluid (CSF) of 51 SAH patients at ICU admission and followed them for clinical status and neurological outcome until 30 days post-discharge. Single nucleotide polymorphisms (SNPs) in the NOS3, DDAH1, DDAH2, PRMT1, and AGXT2 genes were analyzed by PCR, and genotypes were related to biomarker levels and outcome. The primary outcome was the incidence of DCI, which was defined as the appearance of new infarctions on cranial computed tomography or magnetic resonance imaging. Results: 18 out of 51 SAH patients developed DCI. DCI patients did not significantly differ from those without DCI in clinical scores. However, patients who developed DCI had higher plasma ADMA and SDMA levels and higher SDMA levels in CSF at admission. DDAH1 gene variation was associated with plasma ADMA (p=0.02), whilst AGXT2 gene variation was associated with plasma SDMA (p=0.02). There was a strong association of all three DDAH1 SNPs that we analyzed with DCI, with carriers of the minor allele of DDAH1 rs233112 having a significantly increased relative risk of developing DCI (RR=2.61 (1.25-5.43), p=0.002). Conclusions: Sequence variation in the DDAH1 gene is associated with the incidence of DCI in SAH patients, suggesting that SNPs in the DDAH1 gene, which regulates plasma ADMA concentration, significantly influences the risk of cerebral ischemia after subarachnoid hemorrhage.