A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.

ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Impact of dementia and socioeconomic disadvantage on days at home after traumatic brain injury among older Medicare beneficiaries: A cohort study.

INTRODUCTION: Time spent at home may aid in understanding recovery following traumatic brain injury (TBI) among older adults, including those with Alzheimer's disease and related dementias (ADRD). We examined the impact of ADRD on recovery following TBI and determined whether socioeconomic disadvantages moderated the impact of ADRD. METHODS: We analyzed Medicare beneficiaries aged ≥65 years diagnosed with TBI in 2010-2018. Home time was calculated by subtracting days spent in a care environment or deceased from total follow-up, and dual eligibility for Medicaid was a proxy for socioeconomic disadvantage. RESULTS: A total of 2463 of 20,350 participants (12.1%) had both a diagnosis of ADRD and were Medicaid dual-eligible. Beneficiaries with ADRD and Medicaid spent markedly fewer days at home following TBI compared to beneficiaries without either condition (rate ratio 0.66; 95% confidence interval [CI] 0.64, 0.69). DISCUSSION: TBI resulted in a significant loss of home time over the year following injury among older adults with ADRD, particularly for those who were economically vulnerable. HIGHLIGHTS: Remaining at home after serious injuries such as fall-related traumatic brain injury (TBI) is an important goal for older adults. No prior research has evaluated how ADRD impacts time spent at home after TBI. Older TBI survivors with ADRD may be especially vulnerable to loss of home time if socioeconomically disadvantaged. We assessed the impact of ADRD and poverty on a novel DAH measure after TBI. ADRD-related disparities in DAH were significantly magnified among those living with socioeconomic disadvantage, suggesting a need for more tailored care approaches.

Missense variants in SORT1 are associated with LDL-C in an Amish population.

Common noncoding variants at the human 1p13.3 locus associated with SORT1 expression are among those most strongly associated with low-density lipoprotein cholesterol (LDL-C) in human genome-wide association studies. However, validation studies in mice and cell lines have produced variable results regarding the directionality of the effect of SORT1 on LDL-C. This, together with the fact that the 1p13.3 variants are associated with expression of several genes, has raised the question of whether SORT1 is the causal gene at this locus. Using whole exome sequencing in members of an Amish population, we identified coding variants in SORT1 that are associated with increased (rs141749679, K302E) and decreased (rs149456022, Q225H) LDL-C. Further, analysis of plasma lipoprotein particle subclasses by ion mobility in a subset of rs141749679 (K302E) carriers revealed higher levels of large LDL particles compared to noncarriers. In contrast to the effect of these variants in the Amish, the sortilin K302E mutation introduced into a C57BL/6J mouse via CRISPR/Cas9 resulted in decreased non-high-density lipoprotein cholesterol, and the sortilin Q225H mutation did not alter cholesterol levels in mice. This is indicative of different effects of these mutations on cholesterol metabolism in the two species. To our knowledge, this is the first evidence that naturally occurring coding variants in SORT1 are associated with LDL-C, thus supporting SORT1 as the gene responsible for the association of the 1p13.3 locus with LDL-C.

Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.

Associations of Days Spent at Home Before Hip Fracture With Postfracture Days at Home and 1-Year Mortality Among Medicare Beneficiaries Living With Alzheimer's Disease or Related Dementias.

BACKGROUND: Hip fracture is a disabling event experienced disproportionately by older adults with Alzheimer's disease or related dementias (ADRD). Claims information recorded prior to a hip fracture could provide valuable insights into recovery potential for these patients. Thus, our objective was to identify distinct trajectories of claims-based days at home (DAH) before a hip fracture among older adults with ADRD and evaluate associations with postfracture DAH and 1-year mortality. METHODS: We conducted a cohort study of 16 576 Medicare beneficiaries living with ADRD who experienced hip fracture between 2010 and 2017. Growth mixture modeling was used to estimate trajectories of DAH assessed from 180 days prior to fracture until index fracture admission, and their joint associations with postfracture DAH trajectories and 1-year mortality. RESULTS: Before a hip fracture, a model with 3 distinct latent DAH trajectories was the best fit. Trajectories were characterized based on their temporal patterns as Consistently High (n = 14 980, 90.3%), Low but Increasing (n = 809, 5.3%), or Low and Decreasing (n = 787, 4.7%). Membership in the Low and Decreasing prefracture DAH trajectory was associated with less favorable postfracture DAH trajectories, and a 65% higher 1-year mortality rate (hazard ratio 1.65, 95% confidence interval 1.45-1.87) as compared to those in the Consistently High trajectory. Similar albeit weaker associations with these outcomes were observed for hip fracture survivors in the Low but Improving prefracture DAH trajectory. CONCLUSIONS: Distinct prefracture DAH trajectories among hip fracture survivors with ADRD are strongly linked to postfracture DAH and 1-year mortality, which could guide development of tailored interventions.

Association of parity with body mass index and cardiometabolic risk in high-parous women.

OBJECTIVE: Postpregnancy weight retention contributes to obesity, but the long-term effect of parity on body mass index (BMI) and other cardiometabolic risk factors is unclear. We aimed to evaluate the relationship between parity and BMI among highly parous Amish women, both before and after menopause, and to evaluate the associations of parity with glucose, blood pressure, and lipids. METHODS: We conducted a cross-sectional study among 3,141 Amish women 18 years or older from Lancaster County, PA, who participated in our community-based Amish Research Program between 2003 and 2020. We evaluated the association between parity and BMI across different age groups, both before and after the menopausal transition. We further assessed associations between parity and cardiometabolic risk factors among the 1,128 postmenopausal women. Finally, we evaluated the association of change in parity with change in BMI in 561 women followed longitudinally. RESULTS: Approximately 62% of women in this sample (mean age, 45.2 y) reported having four or more children, and 36% reported having seven or more. A one-child increase in parity was associated with increased BMI in both premenopausal women (estimate [95% confidence interval], 0.4 kg/m 2 [0.2-0.5]) and to a lesser degree in postmenopausal women (0.2 kg/m 2 [0.02-0.3], Pint = 0.02), suggesting that the impact of parity on BMI decreases over time. Parity was not associated with glucose, blood pressure, total cholesterol, low-density lipoprotein, or triglycerides ( Padj > 0.05). CONCLUSIONS: Higher parity was associated with increased BMI in both premenopausal and postmenopausal women, but more so in younger/premenopausal women. Parity was not associated with other indices of cardiometabolic risk.

Persistence of Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant in Children and Utility of Rapid Antigen Testing as an Indicator of Culturable Virus.

We screened 65 longitudinally collected nasal swab samples from 31 children aged 0-16 years who were positive for severe acute respiratory syndrome coronavirus 2 Omicron BA.1. By day 7 after onset of symptoms, 48% of children remained positive by rapid antigen test. In a sample subset, we found 100% correlation between antigen test results and virus culture.

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Selective adipocyte loss of Angiopoietin-2 prompts female-specific obesity and metabolic syndrome.

Thermogenic fat differentiation and function can be promoted through multiple pathways, resulting in a common cell phenotype characterized by the expression of Uncoupling Protein-1 and the ability to dissipate energy, but local and systemic stimuli are necessary to promote adequate thermogenic fat vascularization, which is a precondition for the transport of substrate and the dissipation of heat. Angiopoietin-2 is an important driver of vascularization, and its transcription is in part promoted by estrogen signaling. In this study we demonstrate that adipose tissue-specific knock out of Angiopoietin-2 causes a female-specific reduced thermogenic fat differentiation and function, resulting in obesity and impaired glucose tolerance with end-organ features consistent with metabolic syndrome. In humans, angiopoietin-2 levels are higher in females than in males, and are inversely correlated with adiposity and age more strongly in pre-menopause when compared to post-menopause. Collectively, these data indicate a novel and important role for estrogen-mediated Angiopoietin-2 adipose tissue production in the protection against calorie overload in females, and potentially in the development of postmenopausal weight gain.

Black-white Differences in Left Ventricular Hypertrophy Rates Among Young Adults with Ischemic Stroke.

OBJECTIVES: Few studies have addressed Black-White differences in left ventricular hypertrophy (LVH) in young stroke patients without a history of hypertension. METHODS: A case-only cross-sectional analysis performed in 2019 of data from the Stroke Prevention in Young Adults Study, a population-based case-control study of ischemic stroke patients ages 15-49. The main outcomes were hypertension indicators at the time of stroke hospitalization: self-reported history of hypertension, LVH by echocardiography (Echo-LVH) and LVH by electrocardiogram (ECG-LVH). The prevalence of Echo-LVH was further determined in those with and without a history of hypertension. Adjusted odds ratios and 95% confidence intervals comparing blacks and whites were calculated by logistic regression. RESULTS: The study population included 1028 early-onset ischemic stroke patients, 48% Black cases, 54% men, median age 43 years (interquartile range, 38-46 years). Overall, the prevalence of hypertension history, Echo-LVH and ECG-LVH were 41.3%, 34.1% and 17.5%, respectively. Each of the hypertension indicators were more frequent in men than in women and in Black cases than in White cases. Black patients without a history of hypertension had higher rates of Echo-LVH than their white counterparts, 40.3% vs 27.7% (age and obesity adjusted OR 1.8; 95% CI 1.02-3.4) among men and 20.9% vs 7.6% (adjusted OR 2.7; 95% CI 1.2-6.2) among women. CONCLUSIONS: LVH was common in young patients with ischemic stroke, regardless of self-reported history of hypertension. These findings emphasize the need for earlier screening and more effective treatment of hypertension in young adults, particularly in the Black population.

Changes in Critical Bronchiolitis After COVID-19 Lockdown.

Introduction In response to the coronavirus disease 2019 (COVID-19) pandemic, state and local governments implemented mitigation strategies, including lockdowns, thereby averting the typical fall/winter 2020 bronchiolitis season and reducing the incidence of respiratory viruses, such as respiratory syncytial virus (RSV). Florida implemented a strict lockdown from April 1, 2020, to April 30, 2020. The removal of lockdown precautions on September 25, 2020, was followed by an atypical out-of-season surge of bronchiolitis in April 2021. Anecdotally, this surge appeared to be associated with both increased poly-viral coinfections and disease severity. Objective To determine if the bronchiolitis out-of-season surge differed from historical seasonal case patterns. Methods A single-center retrospective cohort study of admissions to the pediatric intensive care unit (PICU) with International Classification of Diseases, Tenth Revision (ICD-10) codes of bronchiolitis, from December 9, 2019, to February 29, 2020 (12 weeks, pre-lockdown group or PreLD), was compared to March 29, 2021, to June 19, 2021 (12 weeks, post-lockdown group or PostLD). Variables used for comparison were gender, ethnicity, age, viral coinfections, viruses detected, PICU length of stay, hospital length of stay, mortality, maximum respiratory support needed, mechanical ventilation days, extracorporeal life support (ECLS) days, and severity of disease measured by Pediatric Logistic Organ Dysfunction-2 (PELOD-2) and Pediatric Sequential Organ Failure Assessment (pSOFA). Categorical data were analyzed using Fisher's exact test, and a t-test was used for continuous variables. A two-sided p < 0.05 was considered significant. Results A total of 135 subjects were analyzed from the two cohorts. More patients were admitted during the PostLD phase (87 vs. 48). The PostLD group had a higher age at admission (11.2 ± 12.3 vs. 6.6 ± 7.5, p = 0.0075), but there were no differences in gender or race/ethnicity. The PostLD group also exhibited a higher proportion of RSV infections (73 vs. 16, p < 0.0001) and poly-viral infections (p < 0.0001). Higher coronavirus OC43 (9 vs. 0, p = 0.0263) and parainfluenza types 1-4 (human parainfluenza virus (HPIV)) (19 vs. 1, p = 0.0017) detections, yet fewer human metapneumovirus (HMPV) detections (0 vs. 4, p = 0.0147), were observed PostLD. No differences were found in hospital length of stay, PICU length of stay, mortality, mechanical ventilation days, ECLS days, or severity of illness scores based on PELOD-2 or pSOFA scores. Conclusion In the bronchiolitis out-of-season surge, there were an increased number of admissions to the PICU. Those patients were older, and more likely to have RSV, as well as a coinfection with coronavirus OC43 or HPIV, yet less likely to have HMPV. No difference in length of stay or disease severity was demonstrated.

Differences in Multiple Risk Factors Between Black and White Individuals With Young-Onset Ischemic Stroke.

BACKGROUND AND OBJECTIVES: Stroke in young adults constitutes 15%-18% of all ischemic stroke cases. Black individuals have an excess risk of ischemic stroke especially in young adults. Although it is known that Black patients have a higher prevalence of hypertension and diabetes, few studies have addressed the association of concurrent multiple vascular risk factors with the excess risk of early-onset stroke among Black individuals. METHODS: A population-based case-control study of early-onset ischemic stroke, ages 15-49 years, was conducted in the Baltimore-Washington DC region between 1992 and 2007. Presence of the risk factors of obesity, hypertension, diabetes, and current smoking were obtained from both cases and controls by an in-person interview. Risk factor groups were defined as (1) 1 risk factor, (2) 2 risk factors, (3) 3 risk factors, and (4) 4 risk factors. Logistic regression analysis adjusting for age and sex was used to evaluate the association between each risk factor group and ischemic stroke compared with the reference group with no risk factors. RESULTS: The study included 1,034 cases and 1,091 controls. Of the cases, 47% were Black, 54% were men, and the mean (±SD) age was 41.0 (±6.9) years. The odds of having a stroke increased exponentially as the number of risk factors increased, 2.1, 2.6, 7.6, 16.5, all p < 0.001, for groups 1-4, respectively. When stratified by race, Black individuals were approximately 6 times more likely to have all 4 risk factors. DISCUSSION: The risk of stroke in young adults increased exponentially with the number of risk factors. Young Black patients with ischemic stroke were approximately 6 times more likely to have the co-occurrence of obesity, hypertension, diabetes, and smoking compared with their White counterparts. Targeting public health interventions to identify and improve care to Black young adults with multiple stroke risk factors may have substantial impact on lowering risk of stroke.

An Amish founder population reveals rare-population genetic determinants of the human lipidome.

Identifying the genetic determinants of inter-individual variation in lipid species (lipidome) may provide deeper understanding and additional insight into the mechanistic effect of complex lipidomic pathways in CVD risk and progression beyond simple traditional lipids. Previous studies have been largely population based and thus only powered to discover associations with common genetic variants. Founder populations represent a powerful resource to accelerate discovery of previously unknown biology associated with rare population alleles that have risen to higher frequency due to genetic drift. We performed a genome-wide association scan of 355 lipid species in 650 individuals from the Amish founder population including 127 lipid species not previously tested. To the best of our knowledge, we report for the first time the lipid species associated with two rare-population but Amish-enriched lipid variants: APOB_rs5742904 and APOC3_rs76353203. We also identified novel associations for 3 rare-population Amish-enriched loci with several sphingolipids and with proposed potential functional/causal variant in each locus including GLTPD2_rs536055318, CERS5_rs771033566, and AKNA_rs531892793. We replicated 7 previously known common loci including novel associations with two sterols: androstenediol with UGT locus and estriol with SLC22A8/A24 locus. Our results show the double power of founder populations and detailed lipidome to discover novel trait-associated variants.

Black-White Differences in Ischemic Stroke Risk Factor Burden in Young Adults.

BACKGROUND AND PURPOSE: Although the US Black population has a higher incidence of stroke compared with the US White population, few studies have addressed Black-White differences in the contribution of vascular risk factors to the population burden of ischemic stroke in young adults. METHODS: A population-based case-control study of early-onset ischemic stroke, ages 15 to 49 years, was conducted in the Baltimore-Washington DC region between 1992 and 2007. Risk factor data was obtained by in-person interview in both cases and controls. The prevalence, odds ratio, and population-attributable risk percent (PAR%) of smoking, diabetes, and hypertension was determined among Black patients and White patients, stratified by sex. RESULTS: The study included 1044 cases and 1099 controls. Of the cases, 47% were Black patients, 54% were men, and the mean (±SD) age was 41.0 (±6.8) years. For smoking, the population-attributable risk percent were White men 19.7%, White women 32.5%, Black men 10.1%, and Black women 23.8%. For diabetes, the population-attributable risk percent were White men 10.5%, White women 7.4%, Black men 17.2%, and Black women 13.4%. For hypertension, the population-attributable risk percent were White men 17.2%, White women 19.3%, Black men 45.8%, and Black women 26.4%. CONCLUSIONS: Modifiable vascular risk factors account for a large proportion of ischemic stroke in young adults. Cigarette smoking was the strongest contributor to stroke among White patients while hypertension was the strongest contributor to stroke among Black patients. These results support early primary prevention efforts focused on smoking cessation and hypertension detection and treatment.

Exome Array Analysis of 9721 Ischemic Stroke Cases from the SiGN Consortium.

Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly associated with all ischemic stroke at array-wide threshold (i.e., p < 4.7 × 10-7), including two common SNPs in ABO that have previously been associated with stroke. Twelve of the remaining 13 variants were extremely rare in European Caucasians (MAF < 0.1%) and the associations were driven by African American samples. There was no evidence for replication of these associations in either TOPMed Stroke samples (n = 5613 cases) or UK Biobank (n = 5874 stroke cases), although power to replicate was very low given the low allele frequencies of the associated variants and a shortage of samples from diverse ancestries. Our study highlights the need for acquiring large, well-powered diverse cohorts to study rare variants, and the technical challenges using array-based genotyping technologies for rare variant genotyping.

Genetic and functional evidence links a missense variant in B4GALT1 to lower LDL and fibrinogen.

Increased blood levels of low-density lipoprotein cholesterol (LDL-C) and fibrinogen are independent risk factors for cardiovascular disease. We identified associations between an Amish-enriched missense variant (p.Asn352Ser) in a functional domain of beta-1,4-galactosyltransferase 1 (B4GALT1) and 13.9 milligrams per deciliter lower LDL-C (P = 4.1 × 10­19) and 29 milligrams per deciliter lower plasma fibrinogen (P = 1.3 × 10­5). B4GALT1 gene­based analysis in 544,955 subjects showed an association with decreased coronary artery disease (odds ratio = 0.64, P = 0.006). The mutant protein had 50% lower galactosyltransferase activity compared with the wild-type protein. N-linked glycan profiling of human serum found serine 352 allele to be associated with decreased galactosylation and sialylation of apolipoprotein B100, fibrinogen, immunoglobulin G, and transferrin. B4galt1 353Ser knock-in mice showed decreases in LDL-C and fibrinogen. Our findings suggest that targeted modulation of protein galactosylation may represent a therapeutic approach to decreasing cardiovascular disease.

Genomics of Postprandial Lipidomics in the Genetics of Lipid-Lowering Drugs and Diet Network Study.

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry. A total of 413 unique lipids were identified. Heritable and responsive lipid species were examined for association with single-nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array. The most statistically significant SNP findings were replicated in the Amish Heredity and Phenotype Intervention (HAPI) Heart Study. We further followed up findings from GOLDN with a regional analysis of cytosine-phosphate-guanine (CpGs) sites measured on the Illumina HumanMethylation450 array. A total of 132 lipids were both responsive to the meal challenge and heritable in the GOLDN study. After correction for multiple testing of 132 lipids (α = 5 × 10-8/132 = 4 × 10-10), no SNP was statistically significantly associated with any lipid response. Four SNPs in the region of a known lipid locus (fatty acid desaturase 1 and 2/FADS1 and FADS2) on chromosome 11 had p < 8.0 × 10-7 for arachidonic acid FA(20:4). Those SNPs replicated in HAPI Heart with p < 3.3 × 10-3. CpGs around the FADS1/2 region were associated with arachidonic acid and the relationship of one SNP was partially mediated by a CpG (p = 0.005). Both SNPs and CpGs from the fatty acid desaturase region on chromosome 11 contribute jointly and independently to the diet response to a high-fat meal.

Safety and Immune Effects of Blocking CD40 Ligand in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Costimulation by CD40 and its ligand CD40L (CD154) is important for the functional differentiation of T cells. Preclinical studies have recognized the importance of this costimulatory interaction in the pathogenesis of experimental models of multiple sclerosis (MS). To determine safety, pharmacokinetics, and immune effect of a humanized monoclonal antibody (mAb) against CD40 ligand (toralizumab/IDEC-131) in patients with relapsing-remitting MS (RRMS). METHODS: This single-institution open-label dose-escalation study (phase I) enrolled 12 patients with RRMS to receive 4 doses of 1, 5, 10, or 15 mg/kg of humanized αCD40L (toralizumab) IV infusion every other week. Patients were followed up to 18 weeks, annually, and finally at 5 years. In addition to safety and pharmacokinetics, other secondary and exploratory measurements are immune effects, clinical, MRI, laboratory, and neuropsychological evaluations. RESULTS: Fifteen adverse events, all of mild to moderate severity, were considered to be of possible or of unknown relationship to treatment. No serious adverse events, including thromboembolic events, occurred during the 18-week defined study period. Annual and long-term follow-up at 5 years revealed no delayed toxicity. Pharmacokinetics were nonlinear between the 5 and 10 mg/kg dose groups. The serum half-life of toralizumab was consistent between the dose groups with a mean of 15.3 days (SD = 1.9). Flow cytometry revealed no depletion of lymphocyte subsets. An increase in the CD25+/CD3+ and CD25+/CD4+ ratio and a shift toward an anti-inflammatory cytokine response were seen after treatment. DISCUSSION: Our study suggests that blocking CD40L is safe and well tolerated in patients with RRMS while increasing CD25 + T cells and anti-inflammatory cytokine profile. These findings support further studies to assess the efficacy of blocking CD40L as a potential treatment of RRMS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence on the safety, pharmacokinetics, and immune effects of an mAb to CD40L in patients with RRMS.

Marijuana Use and the Risk of Early Ischemic Stroke: The Stroke Prevention in Young Adults Study.

BACKGROUND AND PURPOSE: Few studies have examined the dose-response and temporal relationships between marijuana use and ischemic stroke while controlling for important confounders, including the amount of tobacco smoking. The purpose of our study was to address these knowledge gaps. METHODS: A population-based case-control study with 1090 cases and 1152 controls was used to investigate the relationship of marijuana use and early-onset ischemic stroke. Cases were first-ever ischemic stroke between the ages of 15 and 49 identified from 59 hospitals in the Baltimore-Washington region. Controls obtained by random digit dialing from the same geographic region were frequency-matched to cases by age, sex, region of residence and, except for the initial study phase, race. After excluding subjects with cocaine and other vasoactive substance use, the final study sample consisted of 751 cases and 813 controls. All participants underwent standardized interviews to characterize stroke risk factors and marijuana use. Unconditional logistic regression analysis was used to assess the relationships between marijuana use and risk of ischemic stroke, adjusting for age, sex, race, study phase, the amount of current tobacco smoking, current alcohol use, hypertension, and diabetes. RESULTS: After adjusting for other risk factors, including the amount of current tobacco smoking, marijuana use was not associated with ischemic stroke, regardless of the timing of use in relationship to the stroke, including ever use, use within 30 days, and use within 24 hours. There was a nonsignificant trend towards increased stroke risk among those who smoked marijuana at least once a week (odds ratio, 1.9 [95% CI, 0.8-4.9]). CONCLUSIONS: These analyses do not demonstrate an association between marijuana use and an increased risk of early-onset ischemic stroke, although statistical power was limited for assessing the association among very heavy users.