Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Peer reviewe

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Effect of Primary Prophylactic Antiseizure Medication for Seizure Prevention Following Intracerebral Hemorrhage in the ERICH Study

Intracerebral hemorrhage (ICH) has the highest morbidity and mortality rate of any stroke subtype and clinicians often administer prophylactic antiseizure medications (ASMs) as a means of preventing post-stroke seizures, particularly following lobar ICH. However, evidence for ASM efficacy in preventing seizures and reducing disability is lacking given limited randomized trials. Herein, we report analysis from a large prospective observational study that evaluates the effect of primary prophylactic ASM administration on seizure occurrence and disability following ICH. Primary analysis was performed on 1630 patients with ICH enrolled in the ERICH study. A propensity score for administration of prophylactic ASM was developed and patients were matched by the closest propensity score (difference < 0.1). McNemar's test was used to compare occurrence of in-hospital seizure and disability, defined by modified Rankin Score (mRS) ≥ 3 at 3 months post ICH. Of the 815 matched pairs of patients treated with primary prophylactic ASM, there was no significant difference in seizure occurrence (p = 0.4631) or disability (p = 0.4653). Subset analysis of 280 matched pairs of patients with primary lobar ICH similarly revealed no significant difference in seizure occurrence (p = 0.1011) or disability (p = 1.00) between prophylactically treated and untreated patients. Although current guidelines do not recommend primary prophylactic ASM following ICH, clinical use remains widespread. Data from the ERICH study did not find an association between administering primary prophylactic ASM and preventing seizures or reducing disability following ICH, thus providing evidence to influence clinical practice and patient care

Intracranial pressure monitoring in patients with spontaneous intracerebral hemorrhage

OBJECTIVE The utility of ICP monitoring and its benefit with respect to outcomes after ICH is unknown. The aim of this study was to compare intracerebral hemorrhage (ICH) outcomes in patients who underwent intracranial pressure (ICP) monitoring to those who were managed by care-guided imaging and/or clinical examination alone. METHODS This was a retrospective analysis of data from the Ethnic/Racial variations of Intracerebral Hemorrhage (ERICH) study between 2010 and 2015. ICH patients who underwent ICP monitoring were propensity-score matched, in a 1:1 ratio, to those who did not undergo ICP monitoring. The primary outcome was 90-day mortality. Secondary outcomes were in-hospital mortality, hyperosmolar therapy use, ICH evacuation, length of hospital stay, and 90-day modified Rankin Scale (mRS) score, excellent outcome (mRS score 0-1), good outcome (mRS score 0-2), Barthel Index, and health-related quality of life (HRQoL; measured by EQ-5D and EQ-5D visual analog scale [VAS] scores). A secondary analysis for patients without intraventricular hemorrhage was performed. RESULTS The ICP and no ICP monitoring cohorts comprised 566 and 2434 patients, respectively. The matched cohorts comprised 420 patients each. The 90-day and in-hospital mortality rates were similar between the matched cohorts. Shift analysis of 90-day mRS favored no ICP monitoring (p < 0.001). The rates of excellent (p < 0.001) and good (p < 0.001) outcome, Barthel Index (p < 0.001), EQ-5D score (p = 0.026), and EQ-5D VAS score (p = 0.004) at 90 days were lower in the matched ICP monitoring cohort. Rates of mannitol use (p < 0.001), hypertonic saline use (p < 0.001), ICH evacuation (p < 0.001), and infection (p = 0.001) were higher, and length of hospital stay (p < 0.001) was longer in the matched ICP monitoring cohort. In the secondary analysis, the matched cohorts comprised 111 patients each. ICP monitoring had a lower rate of 90-day mortality (p = 0.041). Shift analysis of 90-day mRS, Barthel Index, and HRQoL metrics were comparable between the matched cohorts. CONCLUSIONS The findings of this study do not support the routine utilization of ICP monitoring in patients with ICH

Abstract W P259: ICH &FUNC Scores in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) Study

Introduction: The Intracerebral Hemorrhage (ICH) Score and Functional Outcome (FUNC) Score are prediction scales used to estimate outcome. These scales have not yet been validated in large minority cohorts. Our goal was to evaluate the predictive ability of the ICH and FUNC Score for white, black, and Hispanic patients. Methods: ERICH is an ongoing study of genetic and environmental risk factors for spontaneous ICH. The analysis included 847 cases enrolled prior to 1/1/2013 that had chart abstraction, baseline interview, CT imaging, GCS, and 3-month follow-up data available. Spearman’s rank correlation was used to assess the correlation between each score and 3-month modified Rankin Scale (mRS) score by ethnicity. Regression models were used to determine the predictive ability of each score. Results: Patients analyzed were 42% non-Hispanic black, 34% Hispanic, and 24% non-Hispanic white. Black and Hispanic subjects were younger compared with white subjects (p<.0001) and had higher proportions of deep ICH (p=.0013). Spearman’s rank correlations for ICH Score/FUNC Score and mRS at 3 months post ICH were 0.53/0.53 for black subjects, 0.66/0.63 for Hispanics, and 0.55/0.54 for whites. Both ICH and FUNC Scores had better predictive ability for minorities compared with whites (ICH Score, B = 0.87 black, 1.02 Hispanic, 0.76 white, p<.0001; FUNC Score, B = 0.56 black, 0.65 Hispanic, 0.49 white, p<.0001). Multiple regression demonstrated independent contributions by both scores for each ethnicity. Figure 1 demonstrates distribution of mortality by score. Conclusions: Both the ICH Score and FUNC Score were independently predictive of functional outcome at 3 months. Importantly, each score exhibits higher predictive ability in minority populations compared with whites. Whether or not this difference is attributed to minority status or baseline differences in age or ICH location requires further study

Assessment of the interaction of age and sex on 90-day outcome after intracerebral hemorrhage

Because age affects hormonal production differently in women compared with men, we sought to define sex and age interactions across a multiracial/ethnic population after intracerebral hemorrhage (ICH) to uncover evidence that loss of gonadal hormone production would result in loss of the known neuroprotective effects of gonadal hormones. Clinical and radiographic data from participants in the Ethnic/Racial Variations of Intracerebral Hemorrhage study and the Genetic and Environmental Risk Factors for Hemorrhagic Stroke study prior to December 2013 were used. Relationships among sex, age, and outcome after ICH in 616 non-Hispanic black, 590 Hispanic, and 868 non-Hispanic white participants were evaluated using multivariable logistic regression analysis. Poor outcome was defined as modified Rankin Scale score ≥3 at 90 days after ICH. Sex differences were found in multiple variables among the racial/ethnic groups, including age at onset, premorbid neurologic status, and neurologic outcome after ICH. Overall, no sex-age interaction effect was found for mortality ( = 0.183) or modified Rankin Scale score ( = 0.378) at 90 days after ICH. In racial/ethnic subgroups, only the non-Hispanic black cohort provided possible evidence of a sex-age interaction on 90-day modified Rankin Scale score ( = 0.003). Unlike in ischemic stroke, there was no evidence that patient sex modified the effect of age on 90-day outcomes after ICH in a large multiracial/ethnic population. Future studies should evaluate biological reasons for these differences between stroke subtypes. NCT01202864

Abstract 211: Do Women Receive Less Aggressive Care Following Intracerebral Hemorrhage?

Background: Several studies have shown that women with ischemic stroke receive fewer proven therapies for secondary prevention. A small study found that women receive early DNR orders after intracerebral hemorrhage (ICH) more often than men ( Stroke 2013; 44: 3229) but national data regarding sex differences in ICH are lacking. Objective: To compare comorbidities and use of surgical treatments and palliative care between men and women with ICH. We tested the hypothesis that women receive less aggressive care after ICH. Methods: ERICH is a multi-center study of ICH risk factors and outcomes. We compared clinical variables, treatments (e.g., hematoma evacuation), and use of DNR orders in men compared with women. Chi square tests(categorical items) and t-tests (continuous items) were performed. Multivariable analyses assessed the likelihood of ICH surgery and/or palliative care after adjustment for variables that were significant (p<.05) in univariate analyses. Results: 2964 patients (1220 women) were analyzed. Mean age was higher in women (65.0 vs. 59.9, p<.0001). There was no sex difference in hypertension frequency but women had a higher proportion of previous stroke (24.1% vs. 19.3%, p=.002), dementia (6.1% vs. 3.4%, p=.0007), and anticoagulant use (12.8% vs. 10.1%, p=.02). Men had a higher proportion of cocaine use (10.1% vs. 4.7%, p<.0001) and higher initial SBP (187.5 mm vs. 183.5 mm, p=.007). A higher proportion of women reported living alone (23.1% vs. 18.0%, p=.0005) and a higher proportion of women had a lobar ICH (36.9% vs. 27.4%, p<.0001). After adjustment for age, dementia, prior stroke, anticoagulant use, and ICH location, there was no difference in surgical treatment between men and women (OR=0.92, 95%CI=0.67-1.26, p=.59). Although a higher proportion of women were made DNR/comfort care (19.4% vs. 15.3%, p=.003), this finding was no longer significant after adjustment for ICH score, prior stroke, and dementia (OR for male sex=.96, 95%CI=0.77-1.22, p=.76). Conclusions: Despite sex differences in several categories, no observable sex differences were found in use of surgical therapies or use of DNR/comfort care in an American population. Future work should focus on whether sex differences exist following ICH in patient-centered outcomes

Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.

Background: The effects of empagliflozin, an inhibitor of sodium–glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known. Methods: We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. Results: A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events. Conclusions: Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care