Citations

Intracerebral haemorrhage (ICH) and small vessel ischaemic stroke (SVS) are the most severe manifestations of cerebral small vessel disease. In a cross-phenotype genome-wide association analysis, Chung et al. identify two novel associations at 2q33 and 13q34 plus a previously identified locus at 1q22 for non-lobar ICH and SVS risk.

Introduction: Risk of lobar and non-lobar intracerebral hemorrhage (ICH) varies among blacks, whites and Hispanics. We sought to determine whether these differences could be due to variability in the effects of Apolipoprotein E (APOE) epsilon (ε) alleles, the most potent genetic risk factor for ICH. Methods: Primary ICH cases and controls were collected from US and European sites contributing to the International Stroke Genetic Consortium (ISGC). We meta-analyzed the effects of APOE allele status on ICH risk applying a two-stage clustering approach based on race/ethnicity and the contributing study. Models were adjusted for age, sex, history of hypertension, hypercholesterolemia, warfarin, statin and antiplatelet use, smoking and alcohol use. A propensity score analysis was used to model the influence of APOE against the burden of hypertension across races/ethnicities. Results: 13,124 subjects (54.5% male, median age 66 years) were included. In whites, APOE ε2 (odds ratio (OR)=1.85, 95% confidence interval (CI)=1.27-2.69, p<0.001) and APOE ε4 (OR=1.94, 95% CI=1.58-2.38, p<0.001) were independently associated with lobar ICH risk, however within self-identified Hispanics and blacks, no associations were found (Figure). After propensity score-matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among whites (OR=1.12, 95% CI=1.08-1.17) and Hispanics (OR=1.07, 95% CI=1.01-1.15, p=0.01), but not blacks (OR=1.02 95% CI=0.98-1.07, p=0.251). APOE ε2 and ε4 did not show an effect on non-lobar ICH risk in any race/ethnicity. Conclusion: APOE ε4 and ε2 alleles affect lobar ICH risk variably by race and ethnicity. Associations are confirmed in whites but can be shown in Hispanics only when the excess burden of hypertension is propensity score-matched. Further studies are needed to explore interactions between APOE alleles and environmental exposures that vary by race and ethnicity in representative populations at risk for ICH.

Background and Purpose— Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. Methods— We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P <5×10 − 8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0–2 versus 3–6) modified Rankin Scale using ordinal and logistic regression, respectively. Results— The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P =4.4×10 −8 ) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P =4.3×10 −8 ) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 ( P =0.04; meta-analysis P =2.5×10 −9 ; heterogeneity, P =0.16) but not for 22q13 ( P =0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P =0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P =0.045). Conclusions— We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

The incidence and prevalence of most cardiovascular disorders increase with age, and cardiovascular disease ( CVD ) is the leading cause of death and major disability in adults aged 75 and older. Despite the effect of CVD on quality of life, morbidity, and mortality in older adults, individuals aged 75 and older have been markedly underrepresented in most major cardiovascular trials, and virtually all trials have excluded older adults with complex comorbidities, significant physical or cognitive disabilities, frailty, or residence in nursing homes and assisted living facilities. As a result, current guidelines are unable to provide evidence‐based recommendations for diagnosis and treatment of older adults typical of those encountered in routine clinical practice. The objectives of this scientific statement are to summarize current guideline recommendations as they apply to older adults, identify critical gaps in knowledge that preclude informed evidence‐based decision‐making, and recommend future research to close existing knowledge gaps. To achieve these objectives, a detailed review was conducted of current American College of Cardiology/American Heart Association ( ACC / AHA ) and American Stroke Association ( ASA ) guidelines to identify content and recommendations that explicitly targeted older adults. A pervasive lack of evidence to guide clinical decision‐making in older adults with CVD was found, as well as a paucity of data on the effect of diagnostic and therapeutic interventions on outcomes that are particularly important to older adults, such as quality of life, physical function, and maintenance of independence. Accordingly, there is a critical need for a multitude of large population‐based studies and clinical trials that include a broad spectrum of older adults representative of those seen in clinical practice and that incorporate relevant outcomes important to older adults in the study design. The results of these studies will provide the foundation for future evidence‐based guidelines applicable to older adults and enhance person‐centered care of older individuals with CVD in the United States and around the world.

ObjectiveIn observational epidemiologic studies, higher plasma high‐density lipoprotein cholesterol (HDL‐C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL‐C; as such, medicines that inhibit CETP and raise HDL‐C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL‐C also increase risk for ICH.MethodsWe performed 2 candidate‐gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL‐C as well as ICH risk.ResultsTwelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10−4) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL‐C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10−6).InterpretationGenetic variants in CETP associated with increased HDL‐C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL‐raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730–740

Background and Purpose— The risk of intracranial aneurysm (IA) rupture in asymptomatic members of families who have multiple affected individuals is not known. Methods— First-degree unaffected relatives of those with a familial history of IA who had a history of smoking or hypertension but no known IA were offered cerebral MR angiography (MRA) and followed yearly as part of a National Institute of Neurological Diseases and Stroke-funded study of familial IA (Familial Intracranial Aneurysm [FIA] Study). Results— A total of 2874 subjects from 542 FIA Study families were enrolled. After study enrollment, MRAs were performed in 548 FIA Study family members with no known history of IA. Of these 548 subjects, 113 subjects (20.6%) had 148 IAs by MRA of whom 5 subjects had IA ≥7 mm. Two subjects with an unruptured IA by MRA/CT angiography (3-mm and 4-mm anterior communicating artery) subsequently had rupture of their IA. This represents an annual rate of 1.2 ruptures per 100 subjects (1.2% per year; 95% CI, 0.14% to 4.3% per year). None of the 435 subjects with a negative MRA have had a ruptured IA. Survival curves between the MRA-positive and -negative cohorts were significantly different ( P =0.004). This rupture rate of unruptured IA in the FIA Study cohort of 1.2% per year is approximately 17 times higher than the rupture rate for subjects with an unruptured IA in the International Study of Unruptured Aneurysm Study with a matched distribution of IA size and location 0.069% per year. Conclusions— Small unruptured IAs in patients from FIA Study families may have a higher risk of rupture than sporadic unruptured IAs of similar size, which should be considered in the management of these patients.

Background and Purpose— Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is thought to be heritable with mounting evidence for genetic predisposition. The concept of shared risk for these conditions is challenged by differences in age of diagnosis and demographic characteristics. We performed a genomewide linkage analysis in multiplex families with both IA and AA from the Familial Intracranial Aneurysm study. Methods— Available medical records of subjects who reported IA or abdominal/thoracic AA were reviewed with adjudication as definite/probable, possible, or not a case. To identify genes contributing to the susceptibility for IA and AA, genomewide linkage analysis was performed in the 26 multiplex IA families who had members who also had thoracic or abdominal AA. Individuals (n=91) were defined as affected if they had an IA (definite/probable) or an aortic or thoracic AA (definite/probable). Results— Maximum logarithm of odds (LOD) scores were found on chromosomes 11 (144 cM; LOD=3.0) and 6 (33 cM; LOD=2.3). In both chromosomal regions, analyses of these same 26 families considering only IA as the disease phenotype produced LOD scores of 1.8 and 1.6, respectively. Conclusions— Our linkage analysis in these 26 families using the broadest disease phenotype, including IA, abdominal AA, and thoracic AA, supports the concept of shared genetic risk. The chromosome 11 locus appears to confirm earlier independent associations in IA and AA. The chromosome 6 finding is novel. Both warrant further investigation.