Anderson, Christopher D.

Abstract Based on expert consensus, the American Society of Transplantation recommends 7–14 days of preventive antibiotic therapy for solid organ transplant recipients from donors with positive blood cultures. We evaluated management and outcomes of kidney transplant recipients from these donors.

Background: Epsilon (e) variants in the Apolipoprotein E (APOE) gene are well-established risk factors for spontaneous intracerebral hemorrhage (s-ICH). We tested the hypothesis that APOE-e variants are also associated with warfarin-related ICH (w-ICH) and examined interactions between APOE and warfarin. Methods: Prospective multicenter 2-stage (discovery and replication) study. ICH was classified as lobar and non-lobar based on admission head CT. In the discovery stage, w-ICH cases were matched with warfarin-exposed controls (w-controls). In replication, w-ICH cases were matched with non-warfarin controls (nw-controls). APOE was directly genotyped. Association testing was performed using multivariable logistic regression. Gene-environment interaction between APOE and warfarin was formally tested using a case only approach (combining s-ICH and w-ICH cases). Results: The discovery stage included 316 w-ICHs (43% lobar and 57% non-lobar) and 355 w-controls. Results are presented in the Table: APOE-e2 was associated with lobar and non-lobar w-ICH, and APOE-e4 was associated with lobar but not with non-lobar w-ICH. In case-only analysis, 885 s-ICHs were combined with w-ICHs (total n=1201) and no evidence of interaction between APOE and warfarin was found (all p>0.20). The replication included 63 w-ICHs (44% lobar and 56% non-lobar) and 990 nw-controls. The distribution of APOE variants was similar in w-controls (discovery) and nw-controls (replication) for both e2 (p=0.81) and e4 (p=0.88). In replication, APOE-e2 and e4 were associated with lobar but not with non-lobar w-ICH. Conclusions: APOE-e variants constitute strong risk factors for lobar w-ICH. An effect may also exist between APOE-e2 and non-lobar hemorrhages, but given the lack of replication larger sample sizes are required to properly assess this association. APOE exerts its effect independently of warfarin, although power limitations render this absence of interaction preliminary.

Objectives: Genetic and environmental influences contribute to differences in ischemic stroke phenotype across race-ethnic groups. The Causative Classification System (CSS) is an ischemic stroke phenotype characterization tool developed for etiological and causative classification. The CCS phenotypes across ethnic groups were analyzed and compared. Methods: The NINDS S troke G enetics N etwork (SiGN) is a large consortium aimed at identifying subtype-specific ischemic stroke susceptibility genes. Over 12,000 subjects at 22 sites across US and Europe were enrolled, with CSS locally adjudicated. Central CCS quality control was performed on all participants. Analysis was performed on 7,674 patients with complete workups. Findings: Significant ethnic differences were found in stroke etiology across ethnic groups (p <0.0001) with large artery atherosclerosis present most commonly in Asians, cardioembolic sources among Caucasian Europeans, and lacunar strokes among African Americans. African Americans were the youngest ethnic cohort analyzed (see Table 1). Conclusion: Significant differences in stroke subtypes are present across ethnic groups. Future genetic analyses may contribute to our understanding of these differences.

Purpose: Intracerebral hemorrhage (ICH) is the acute manifestation of a progressive disease of the cerebral small vessels. The severity of this disease appears to influence not only risk of ICH, but also the size of the hematoma. As the burden of high blood pressure(BP)-associated alleles is associated with hypertension-related end-organ damage, we sought to determine if this burden influences ICH admission hematoma volume (AHV). Methods: Prospective study undertaken in 441 ICH patients of European ancestry (210 deep and 231 lobar intracranial hematomas). Forty-three single-nucleotide polymorphisms (SNPs) known to be associated with high BP were genotyped in Illumina610-Quad. Single-SNP association analyses with AHV were performed using linear regression. Subsequently, a genetic risk score was calculated as the sum of the products generated by multiplying, at each of the 43 loci, the number risk alleles times the reported effect of that allele on BP. The score was utilized as the independent variable of univariate and multivariate regression models for 2 outcomes: AHV and poor clinical outcome (modified Rankin Scale 3-6). Principal components analysis was utilized to account for population structure. Results: Individually assessed, no single SNP was associated with AHV. In univariate linear regression, the genetic risk score was associated with AHV in all (deep and lobar) and deep locations (Figure 1), but not in lobar hemorrhages. In multivariate regression analyses, each additional standard deviation of the genetic risk score increased mean deep AHV by 21% (or 2.7-milliliter increase, beta=0.21, standard error=0.08, p=0.01) and risk poor clinical outcome by 55% (odds ratio=1.55, 95% confidence interval 1.05-2.28, p=0.03). No significant associations were observed when considering all (deep and lobar) and lobar hemorrhages. Conclusion: In deep ICH, increasing numbers of high BP-related alleles are associated with larger AHV and poor clinical outcome.

Background: Prior studies have shown an association between mutations within the oxidative phosphorylation (OXPHOS) pathway and familial ischemic stroke syndromes. We investigated whether common autosomal and mitochondrial genetic variants within OXPHOS genes were associated with sporadic ischemic stroke in case-control. Methods: This multicenter association study was performed using a discovery cohort of 1643 individuals and a validation cohort of 2432 individuals from sites participating in the International Stroke Genetics Consortium. We employed a gene-set enrichment analysis (GSEA) using all 95 genes structurally involved in OXPHOS to determine the probability that the OXPHOS gene-set harbored more variants associated with stroke than predicted by chance. We then constructed a genetic score consisting of common variants within these genes. This genetic score was developed in the discovery cohort, and then tested for association with ischemic stroke in the validation cohort. Results: GSEA identified an aggregate association between the OXPHOS gene-set and ischemic stroke (p = 0.012). Based on this result, we constructed and validated a genetic score which demonstrated an association between OXPHOS genetic variation and ischemic stroke (odds ratio (OR) = 1.17, p = 0.008). In order to further distill the association between OXPHOS and stroke, we developed and tested additional scores for each of the five OXPHOS respiratory complexes. This sub-analysis revealed an independent association between OXPHOS Complex I and ischemic stroke (OR = 1.06, p = 0.050). Conclusions: This pathway-based study, informed by GSEA, employing independent discovery and validation cohorts, establishes an association between common genetic variants within OXPHOS genes and ischemic stroke. Analysis of variants within each OXHPOS Complex suggests that Complex I mediates this effect. Further studies are needed to identify the individual variants which influence ischemic stroke risk. Such discoveries offer the promise of new therapeutic targets for the prevention and treatment of stroke.

Background: Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar and non-lobar based on the location of the hemorrhage, with genetic variation contributing to risk of both subtypes. We report the first genome wide association study (GWAS) of this condition. Methods: The discovery phase included GWAS data (Illumina 610 or Affymetrix 6.0) from 6 ICH studies that enrolled subjects of European ancestry in the US and Europe. Cases were classified as lobar or non-lobar ICH based on head CT. ICH-free controls were selected from ambulatory clinics or by random digit dialing. Standard quality controls filters were applied and principal component analysis was used to account for population structure. Unobserved genotypes were inferred by imputation to 1000 genomes references panels. Association testing was carried out using logistic regression, assuming additive effects, and including age, gender and principal components in the model. Meta-analyses were completed using the inverse normal method, weighting by sample size. Replication of signals with p<1x10E-6 was pursued in an independent multi-ethnic study utilizing direct genotyping. Results: The discovery phase included 1545 cases (664 lobar and 881 non-lobar) and 1481 controls, and tested 5,358,103 SNPs. Two loci were identified: for lobar ICH, an intergenic region located on chromosome 12q21.1 (rs11179580: minor allele frequency [MAF] 0.22, OR 1.54, 95% CI 1.33 - 1.84; p = 6.7x10E-8); and for non-lobar ICH, a region on chromosome 1q22 encompassing the PMF1 and SLC25A44 genes (rs2984613: MAF 0.31, OR 1.45, 95% CI 1.2 - 1.64; p = 8.9x10E-9). Replication included 1256 cases (329 whites, 506 blacks and 421 Hispanics) and 760 controls (237 whites, 346 blacks and 177 Hispanics) and confirmed both loci: 12q21.1 (p = 0.037, meta-analysis p = 2.3x10E-8) and 1q22 (p = 3.0x10E-4, meta-analysis p = 2.2x10E-11). Conclusions: Two new susceptibility loci for ICH were identified, both showing location-specificity. These results confirm the presence of biological heterogeneity across ICH subtypes and highlight that different genetic risk factors may contribute to the small vessel diseases that underlie each ICH subtype.

Introduction: Long-term cardiac monitoring studies have unveiled low-burden, occult atrial fibrillation (AF) in some patients with otherwise cryptogenic stroke (CS). But occult AF is also found in some normal individuals and patients with stroke of known cause (KS). Clinical management would be aided by estimates of how often occult AF in a patient with CS is causal versus incidental. Methods: Through systematic search, we identified all case-control and cohort studies applying identical long-term monitoring techniques to both CS and KS patients. We performed a random-effects meta-analyses across these studies to determine the best estimate of the differential frequency of occult AF in CS and KS among all patients, and across age subgroups. We then applied Bayes’ theorem (method of Alsheikh-Ali et al, Stroke 2009) to determine the probability that occult AF is causal or incidental. Results: The systematic search identified 3 case-control and cohort studies enrolling 575 patients (337 CS, 238 KS). Methods of long-term monitoring were implantable loop recorder in 191 (33.2%), extended mobile external cardiac monitor in 277 (48.2%), and patch/event/Holter monitoring in 107 (18.6%). In formal meta-analysis, the summary odds ratio for occult AF in CS vs KS in all patients was 1.72 (95%CI 0.91-3.25) (Figure). With application of Bayes theorem, the corresponding probabilities indicated that, when present, occult AF in CS patients is causal in 44.4% and incidental in 55.6%. Only one study reported age-specific subgroup data: these suggested occult AF in CS patients was causal in 93% of patients <65y vs 5.6% of patients ≥65y, but estimates had limited precision. Conclusions: In patients with cryptogenic stroke, when occult AF is found, it is likely causal in about 44% of patients, who may benefit from anticoagulation, and likely incidental in about 56% of patients, who may not benefit from anticoagulation. Figure