Cushman, Mary

AbstractHigher and lower hemoglobin concentrations are associated with coronary heart disease (CHD), but whether this risk is consistent across age, sex, and race is unclear. The Reasons for Geographic And Racial Differences in Stroke (REGARDS) study is an observational cohort study of 30 239 black, and white, adults aged 45 and older recruited 2003‐7. Participants were included if they had hemoglobin measures, were CHD‐free at baseline, and had all baseline variables. The primary outcome was incident CHD. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for incident CHD by hemoglobin concentration. This was expressed as a continuous variable and divided into age‐, sex‐, and race‐specific quintiles. The 16 332 participants were included, contributing 114 362 person‐years of follow‐up and 915 incident CHD events. The mean age was 63 years, 35% were male, 41% were black, and the mean baseline hemoglobin was 13.6 g/dL (SD 1.4). A significant non‐linear association between hemoglobin and CHD was identified (P < .001). This association differed significantly by race (P = .025) but not by sex or age. In whites, the risk for incident CHD was higher in the lowest (HR 2.28, 95% CI 1.61, 3.33) and highest (HR 1.94, 95% CI 1.35, 2.79) hemoglobin quintiles relative to the third quintile. For blacks, only those in the lowest hemoglobin quintile had an increased risk for incident CHD events (HR 1.70, 95% CI 1.20, 2.41). Hemoglobin is an independent risk factor for CHD in whites and blacks but with different hemoglobin concentrations conferring different risks.

INTRODUCTION: African-Americans (blacks) have higher risk of stroke and coronary heart disease (CHD) - collectively referred to here as cardiovascular disease (CVD), than Caucasian-Americans (whites). Though partly explained by traditional cardiovascular risk factors, half of the excess risk in blacks is not explained by known risk factors. Recent data suggest increased risk of CVD and mortality in individuals with clonal hematopoiesis, which often presents as cytopenia. Using peripheral blood cytopenia as a marker of clonal hematopoiesis, we examined the association between cytopenia and risk of CVD and mortality in blacks and whites. METHODS: The REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study enrolled 30,239 US black and white adults between 2003 and 2007 (41% black). Socio-demographics and medical history were obtained by telephone interview, and laboratory studies (including complete blood count [CBC]) and physical exam from an in-home visit at baseline. Participants or their proxies were contacted every 6 months to ascertain CVD events, hospitalizations or deaths, and medical records were reviewed to confirm these events. Cytopenia was defined using thresholds in Table 1 as presence of 2 or more of the following: i) hemoglobin in age-, sex-, and race-specific lowest 5th percentile; ii) white cell count in race-specific lowest 5th percentile; iii) platelet count in lowest 5th percentile, and iv) macrocytosis (MCV >98fL). Participants with pre-baseline history of stroke (for analyses including stroke or CVD mortality) or CHD (for analyses including CHD or CVD mortality) and those with missing CBC were excluded. Cox proportional hazards models were used to calculate hazard ratios (HRs) of incident CVD and mortality associated with cytopenia. Models adjusted for socio-demographics (Model 1), Framingham stroke or CHD risk factors (Model 2), and estimated glomerular filtration rate and C-reactive protein (Model 3) were used. Differences in the association of cytopenia with outcomes by race were tested using cross-product interaction terms, using a p of <0.1 for interaction. RESULTS: The study included 19,544 participants who were followed for a median of ~9 years. There were 798 (4.3% of those at risk) incident stroke cases and 727 (4.3%) incident CHD cases; 1033 (5.3%) died of CVD, and 3933 (20.1%) died of all-causes. Cytopenia was present in 378 (1.9%) participants, ranging from 0.9% to 3.5% in blacks, 1.4 to 3.9% in whites, 1.6 to 3.9% in men, and 0.9 to 1.8% in women, with increasing prevalence by age. There was no association between cytopenia and stroke or CHD risk in any model. However, cytopenia was associated with increased risk of all-cause mortality (HR=1.73, 95%CI: 1.34-2.22), and CVD mortality (HR=1.56, 95% CI: 1.11-2.19) in the extended risk factor Model 3 and also in CVD risk factor adjusted model (Model 2), with little evidence of confounding (Table 2). While the race by cytopenia interaction term was not significant in any model for incident CHD or mortality, the interaction for cytopenia by race for stroke was statistically significant (p-interaction=0.08) in Model 2. The HR of stroke for cytopenia in blacks was 0.86 (95%CI: 0.46-1.61), and for whites was 1.96 (95%CI: 1.0-3.82). CONCLUSION: In this large biracial cohort, cytopenia was associated with increased all-cause and CVD mortality. Cytopenia was a race-specific risk factor for stroke affecting white Americans but not black Americans. With growing knowledge on the role of clonal hematopoiesis in CVD risk and mortality, further work is needed to determine if our phenotype of cytopenia is accurate in classifying clonal hematopoiesis and for determining the mortality risk. Given these findings, assessing clonal hematopoiesis and outcomes related to clonal hematopoiesis in diverse populations is critical to understanding the interactions between somatic mutations in hematopoietic cells and CVD/mortality risk. Disclosures Safford: Amgen: Research Funding.

Background and Purpose— White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods— In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results— At 17q25, we confirmed the association of multiple common variants in TRIM65 , FBF1 , and ACOX1 ( P <6×10 −7 ). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P EA =4.5×10 −8 ) partially independent of known common signal ( P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1 , CARF , and WDR12 (lead, rs2351524; P all =1.9×10 −10 ). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P rs34136221 =2.8×10 −8 ). Conclusions— Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

Background and Purpose— Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. Methods— The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10 296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14 549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research–generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. Conclusions— The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.

ABSTRACTVenous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two‐stage genome‐wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community‐based studies. Genotypes for genome‐wide single‐nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study‐design appropriate regression methods. Meta‐analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case‐control studies. In the combined data from these two stages, additional genome‐wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10−6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

Background and Purpose— We compared the associations of self-reported atrial fibrillation (AF) and ECG-detected AF with incident stroke in the Risk of Stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Methods— In this analysis, 27 109 participants aged 45 years or older without previous stroke were included. Stroke cases were identified and adjudicated during an average of 4.4 years of follow-up. Cox proportional hazards analysis was used to calculate hazard ratios (HR) of self-reported AF, ECG-detected AF, and AF detected by either method with incident stroke. We also examined the predictive ability of the Framingham Stroke Risk Score (FSRS) when the component AF was defined by different methods. Results— After adjustment for components of the FSRS, self-reported AF, ECG-detected AF, and AF by either method were predictive of incident stroke (HR, 1.41; 95% CI, 1.05–1.88; HR, 1.90; 95% CI, 1.10–3.27; HR, 1.53; 95% CI, 1.16–2.01, respectively). When self-report, ECG, or either method, separately, were considered as the method of AF ascertainment in the FSRS, the HR per 1% increase in the FSRS were identical across AF ascertainment methods (HR, 1.04; 95% CI, 1.03–1.04; HR, 1.04; 95% CI, 1.04–1.05; HR, 1.04; 95% CI, 1.03–1.04; respectively). Conclusions— Self-reported AF is a strong predictor of stroke that can be used interchangeably or in combination with ECG-detected AF in stroke risk prediction models.