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C1q nephropathy is a rare kidney disease that can present with nephrotic syndrome and typically has the histologic phenotype of either minimal change disease or focal segmental glomerulosclerosis (FSGS). Disagreement exists about whether it is a distinct immune complex-mediated glomerulopathy or it resides in the spectrum of FSGS-minimal change disease. Two African American patients with C1q nephropathy histologically presenting as the collapsing variant of FSGS (collapsing C1q nephropathy) and rapid loss of kidney function were genotyped for polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9). Both cases were homozygous for the MYH9 E1 risk haplotype, the variant strongly associated with idiopathic FSGS, collapsing FSGS in human immunodeficiency virus-associated nephropathy, and focal global glomerulosclerosis (historically attributed to hypertensive nephrosclerosis). Collapsing C1q nephropathy with rapid progression to end-stage renal disease appears to reside in the MYH9-associated disease spectrum. [ABSTRACT FROM AUTHOR]

Background: The "clean eating" trend suggests that consuming fewer processed foods is important for healthy diets. Yet, a diet of mostly ultra-processed foods (UPFs) can meet recommendations from the Dietary Guidelines for Americans. Whether a diet comprised mostly of simple ingredient foods can provide a low-quality diet remains unexplored., Objectives: The objective of this study was to compare the diet quality, shelf stability, and cost of 2 similar nutrient-poor menus, one containing primarily UPFs and the other containing less-processed foods (LPW), as defined by the Nova classification system., Methods: A "Western" menu using LPW was developed to match the meals and recipes of a menu that contained more-processed foods (MPW). Processing level was determined using the Nova classification system. Final menus were assessed for nutrient quality and Healthy Eating Index (HEI) score. Shelf stability of foods/ingredients on both menus was determined from food storage guidance manuals. The condition of each food item when purchased (room temperature, frozen, refrigerated) was used to estimate the number of days until expiration. Food costs were determined from prices at grocery chains in Fall 2023., Results: The LPW had similar nutrient density and diet quality scores to the MPW (HEI scores of 44 and 43, respectively). The LPW included 20% energy (kcal) from UPFs, whereas the MPW included 67% energy from UPFs. Relative percentages of shelf-stable, frozen, and refrigerated foods were similar. Using the Kaplan-Meier survival analysis method, median time to expiration of the LPW menu items was 35 d compared with 120 d for the MPW items. The "per person" cost reflecting only the amount of the food used in the menu was $15.91/d for the LPW and $9.85/d for the MPW., Conclusions: Less-processed menus can have comparable diet quality with more-processed menus although being more costly and less shelf stable., Competing Interests: The authors report no conflicts of interest.

Background: The 2020-2025 Dietary Guidelines for Americans (DGA) includes a lacto-ovo vegetarian pattern (the healthy vegetarian dietary pattern [HVDP]) as a recommended dietary pattern during pregnancy., Objective: To adapt the HVDP for vegan, ovo-vegetarian, lacto-vegetarian, and pescatarian diets during pregnancy., Design: Using food pattern modeling, 4 adaptations of the HVDP were developed at energy levels that may be appropriate during pregnancy (1800, 2000, 2200, 2400, and 2600 kcal/day). Models were run both with and without the addition of a composite prenatal supplement., Main Outcome Measures: Main outcome measures were macro- and micronutrient adequacy without exceeding recommendations for saturated fat and added sugar., Statistical Analysis Performed: The 2020-2025 DGA Food Pattern Modeling Report was used to define food groups and nutrients in the HVDP. The HVDP was revised to remove dairy and/or eggs or to add seafood., Results: Across all examined energy levels (1800, 2000, 2200, 2400, and 2600 kcal per day), modeled dietary patterns provided sufficient macronutrients. Without prenatal supplements, each dietary pattern met most, but not all, micronutrient recommendations. Micronutrients that were below recommendations in patterns without supplements included vitamin D, iron, vitamin E, sodium, and choline. With the addition of a composite prenatal supplement to these patterns, the nutrients below 100% of recommendations were vitamin D, choline, and sodium., Conclusions: Overall, these results show that a HVDP and similar diets without meat, eggs, dairy, and/or seafood can provide most nutrients needed during pregnancy, albeit with some micronutrient challenges similar to those diets that include meat and other animal products., (Published by Elsevier Inc.)

Introduction: Variation in DNA methylation (DNAm) in adipose tissue is associated with the pathogenesis of obesity and insulin resistance. The activity of enzymes involved in altering DNAm levels is dependent on several metabolite cofactors., Objectives: To understand the role of metabolites as mechanistic regulators of epigenetic marks, we tested the association between selected plasma metabolites and DNAm levels in the adipose tissue of African Americans., Methods: In the AAGMEx cohort (N = 256), plasma levels of metabolites were measured by untargeted liquid chromatography-mass spectrometry; adipose tissue DNAm and transcript levels were measured by reduced representation bisulfite sequencing, and expression microarray, respectively., Results: Among the 21 one-carbon metabolism pathway metabolites evaluated, six were associated with gluco-metabolic traits (P FDR  < 0.05, for BMI, S I , or Matsuda index) in AAGMEx. Methylation levels of 196, 116, and 180 CpG-sites were associated (P < 0.0001) with S-adenosylhomocysteine (SAH), cystine, and hypotaurine, respectively. Cis-expression quantitative trait methylation (cis eQTM) analyses suggested the role of metabolite-level-associated CpG sites in regulating the expression of adipose tissue transcripts, including genes in G-protein coupled receptor signaling pathway. Plasma SAH level-associated CpG sites chr19:3403712 and chr19:3403735 were also associated with the expression of G-protein subunit alpha 15 (GNA15) in adipose. The expression of GNA15 was significantly correlated with BMI (β = 1.87, P = 1.9 × 10 -16 ) and S I (β = -1.61, P = 2.49 × 10 -5 )., Conclusion: Our study suggests that a subset of metabolites modulates the methylation levels of CpG sites in specific loci and, in turn, regulates the expression of transcripts involved in obesity and insulin resistance., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases, including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study, we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown., Methods: A total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and Rare Variant Influential Filtering Tool analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired-end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk., Results: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop, and that the genes therein belong to the same topologically associating domain. Chromatin immunoprecipitation followed by sequencing and chromatin interaction analysis with paired-end tag data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk., Interpretation: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325-337., (© 2023 American Neurological Association.)

Background: Among its recommended dietary patterns for Americans, including lactating mothers, the 2020 Dietary Guidelines for Americans (DGA) includes a Healthy Vegetarian Dietary Pattern (HVDP). However, the DGA does not provide guidance for adapting the HVDP for vegetarians who avoid dairy (ovo-vegetarian) or eggs (lacto-vegetarian), eat fish (pescatarians), or avoid all animal foods (vegan)., Objective: To determine whether models of the HVDP for different vegetarian diets could provide sufficient nutrition during lactation, a life stage with unique nutrient needs., Methods: Adaptations of the HVDP were developed at the 2200 and 2400 kcal levels using similar methods to the 2020 DGA. We compared these models with both the original HVDP and Dietary Reference Intakes (DRIs) for women ages 19 to 30 and ages 31 to 50 during lactation mo 1 to 12. All models were developed both with and without the addition of a multivitamin and -mineral prenatal supplement, commonly consumed by women throughout lactation., Results: All models (original HVDP, ovo-vegetarian, lacto-vegetarian, pescatarian, vegan) at all energy levels met the Adequate Macronutrient Distribution Ranges. Like the original HVDP and other dietary patterns in the DGA, the vegetarian adaptations in this study did not contain enough vitamin D, vitamin E, or choline to meet DRIs across all models and energy levels. With the prenatal supplement added, the models did not contain enough sodium, vitamin D, or choline. Some models also contained < 100% of the DRIs for sodium, zinc, vitamin A, and vitamin B6. Amounts of all other micronutrients met DRIs., Conclusions: Adaptations of the HVDP can provide adequate amounts of most nutrients, including nutrients of concern, during lactation to meet the needs of mothers during this life stage., Competing Interests: The authors report no conflicts of interest.

Background: A proposed topic for the 2025 Dietary Guidelines for Americans (DGA) Scientific Advisory Committee to address is the relationship between dietary patterns with ultra-processed foods (UPF) and body composition and weight status. Implementing the NOVA system, the most commonly applied framework for determining whether a food is "ultra-processed," in dietary guidance could omit several nutrient-dense foods from recommended healthy diets in the DGA., Objective: The purpose of this proof-of-concept study was to determine the feasibility of building a menu that aligns with recommendations for a healthy dietary pattern from the 2020 DGA and includes ≥80% kcal from UPF as defined by NOVA., Design: To accomplish this objective, we first developed a list of foods that fit NOVA criteria for UPF, fit within dietary patterns in the 2020 DGA, and are commonly consumed by Americans. We then used these foods to develop a 7-d, 2000 kcal menu modeled on MyPyramid sample menus and assessed this menu for nutrient content as well as for diet quality using the Healthy Eating Index-2015 (HEI-2015)., Results: In the ultra-processed DGA menu that was created, 91% of kcal were from UPF, or NOVA category 4. The HEI-2015 score was 86 out of a possible 100 points. This sample menu did not achieve a perfect score due primarily to excess sodium and an insufficient amount of whole grains. This menu provided adequate amounts of all macro- and micronutrients except vitamin D, vitamin E, and choline., Conclusions: Healthy dietary patterns can include most of their energy from UPF, still receive a high diet quality score, and contain adequate amounts of most macro- and micronutrients., (Published by Elsevier Inc.)

Cerebral small vessel disease is highly prevalent, particularly in marginalized communities, and its incidence is expected to increase given the aging global population. Cerebral small vessel disease contributes to risk for stroke, vascular cognitive impairment and dementia, late-life depression, and gait disorders. A growing body of evidence suggests that adverse outcomes, including cerebral small vessel disease, caused by traditional cardiovascular risk factors are at least partly mediated by epigenetic changes, some of them already beginning during fetal development. Societal and health care access inequities, summarized under the umbrella term social determinants of health, put a higher burden of cardiovascular risk factors on marginalized populations and expose them to an increased risk for adverse outcomes. Social epigenetics has begun to deliver solid evidence that social determinants of health lead to distinct epigenetic signatures that potentially mediate the biological effect of environmental exposures on cardiovascular risk factors. Here, we provide a review of the most recent advances in the epigenetics of cerebral small vessel disease risk factors and social determinants of health and call for research efforts combining insights from both fields to reach a deeper understanding of the causal pathways, ultimately facilitating discovery of new treatment targets for a disease whose burden is magnified by existing health disparities.

Background: Intracerebral hemorrhage (ICH) has an estimated heritability of 29%. We developed a genomic risk score for ICH and determined its predictive power in comparison to standard clinical risk factors., Methods: We combined genome-wide association data from individuals of European ancestry for ICH and related traits in a meta-genomic risk score ([metaGRS]; 2.6 million variants). We tested associations with ICH and its predictive performance in addition to clinical risk factors in a held-out validation dataset (842 cases and 796 controls). We tested associations with risk of incident ICH in the population-based UK Biobank cohort (486 784 individuals, 1526 events, median follow-up 11.3 years)., Results: One SD increment in the metaGRS was significantly associated with 31% higher odds for ICH (95% CI, 1.16-1.48) in age-, sex- and clinical risk factor-adjusted models. The metaGRS identified individuals with almost 5-fold higher odds for ICH in the top score percentile (odds ratio, 4.83 [95% CI, 1.56-21.2]). Predictive models for ICH incorporating the metaGRS in addition to clinical predictors showed superior performance compared to the clinical risk factors alone (c-index, 0.695 versus 0.686). The metaGRS showed similar associations for lobar and nonlobar ICH, independent of the known APOE risk locus for lobar ICH. In the UK Biobank, the metaGRS was associated with higher risk of incident ICH (hazard ratio, 1.15 [95% CI, 1.09-1.21]). The associations were significant within both a relatively high-risk population of antithrombotic medications users, as well as among a relatively low-risk population with a good control of vascular risk factors and no use of anticoagulants., Conclusions: We developed and validated a genomic risk score that predicts lifetime risk of ICH beyond established clinical risk factors among individuals of European ancestry. Whether implementation of the score in risk prognostication models for high-risk populations, such as patients under antithrombotic treatment, could improve clinical decision making should be explored in future studies.

Introduction: The 2020-2025 Dietary Guidelines for Americans (DGA) includes a Healthy Vegetarian Dietary Pattern (HVDP) with dairy foods and eggs as one of its three recommended dietary patterns for non-pregnant, non-lactating healthy adults. This study evaluates whether pescatarian, lacto-vegetarian, and "pescavegan" adaptations of the HVDP can be nutritionally adequate if modeled with foods recommended by the DGA., Methods: The nutrient composition of these three alternative models of the HVDP were assessed at 1, 800-, 2, 000-, 2, 200-, and 2,400- kcal/day using similar food pattern modeling procedures as the 2020 DGA. For the pescatarian and pescavegan models, 0.5 ounce-equivalent of refined grains per day was replaced with seafood. For the lacto-vegetarian and pescavegan models, eggs were replaced with equal proportions of the other vegetarian protein foods. In the pescavegan model, dairy foods were replaced by a dairy alternative group comprised of fortified soy milk and soy yogurt., Results: All models at all energy levels were within Acceptable Macronutrient Distribution Ranges (AMDRs) for all macronutrients, contained ≤5% of total kcal from saturated fat, and met recommendations for most micronutrients. Nutrients provided below the Dietary Reference Intakes (DRIs) in these models included iron, sodium, vitamin D, vitamin E, and choline. Micronutrients provided at less than 50% of their respective DRIs included vitamin D and choline., Discussion: Adapting the HVDP for lactovegetarian, pescatarian, and pescavegan dietary patterns provided adequate amounts of macronutrients and most micronutrients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hess and Comeau.)

Our knowledge of the cell-type-specific mechanisms of insulin resistance remains limited. To dissect the cell-type-specific molecular signatures of insulin resistance, we performed a multiscale gene network analysis of adipose and muscle tissues in African and European ancestry populations. In adipose tissues, a comparative analysis revealed ethnically conserved cell-type signatures and two adipocyte subtype-enriched modules with opposite insulin sensitivity responses. The modules enriched for adipose stem and progenitor cells as well as immune cells showed negative correlations with insulin sensitivity. In muscle tissues, the modules enriched for stem cells and fibro-adipogenic progenitors responded to insulin sensitivity oppositely. The adipocyte and muscle fiber-enriched modules shared cellular-respiration-related genes but had tissue-specific rearrangements of gene regulations in response to insulin sensitivity. Integration of the gene co-expression and causal networks further pinpointed key drivers of insulin resistance. Together, this study revealed the cell-type-specific transcriptomic networks and signaling maps underlying insulin resistance in major glucose-responsive tissues. A record of this paper's transparent peer review process is included in the supplemental information., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Genome wide association studies show there is a genetic component to severe COVID-19. We find evidence that the genome-wide genetic association signal with severe COVID-19 is correlated with that of systemic lupus erythematosus (SLE), having formally tested this using genetic correlation analysis by LD score regression. To identify the shared associated loci and gain insight into the shared genetic effects, using summary level data we performed meta-analyses, a local genetic correlation analysis and fine-mapping using stepwise regression and functional annotation. This identified multiple loci shared between the two traits, some of which exert opposing effects. The locus with most evidence of shared association is TYK2, a gene critical to the type I interferon pathway, where the local genetic correlation is negative. Another shared locus is CLEC1A, where the direction of effects is aligned, that encodes a lectin involved in cell signaling, and the anti-fungal immune response. Our analyses suggest that several loci with reciprocal effects between the two traits have a role in the defense response pathway, adding to the evidence that SLE risk alleles are protective against infection., Competing Interests: The authors have declared that no competing interests exist.

The 2020 Dietary Guidelines for Americans (DGA) recommends a Healthy Vegetarian Dietary Pattern (HVDP) but does not provide guidance for dairy-free vegetarian (ovo-vegetarian) or vegan diets. A recent study from our lab modeled ovo-vegetarian and vegan HVDPs for healthy adults and found minimal impacts on nutrient content. However, since these models provide only recommendations for food group amounts, the objective of this study was to determine the feasibility of implementing the 2000 kcal ovo-vegetarian and vegan models by developing sample menus and evaluating them for nutrient adequacy and diet quality. We implemented a search strategy for ovo-vegetarian and vegan recipes on the MyPlate.gov website, using the most frequently consumed foods from each food group as a guide. We then developed 5-day sample menus for each model and analyzed these menus for diet quality using the Healthy Eating Index Score-2015 (HEI-2015) and nutrient content. The HEI-2015 scores were 99.4 and 98.4 for the vegan and ovo-vegetarian menus, respectively. These sample menus did not achieve a perfect score of 100 due to sodium and refined grains (both menus), added sugars (ovo-vegetarian menu only), and fatty acid profiles (vegan menu only). Mean total energy was 1860 kcal (vegan) and 1880 kcal (ovo-vegetarian). Amounts of all macronutrients were within the Acceptable Macronutrient Distribution Ranges, but amounts of some micronutrients were below 90% of recommended levels. Healthy adults may be able to follow ovo-vegetarian and vegan diets with careful planning, but this study reveals challenges in meeting micronutrient needs with these eating patterns. PRACTICAL APPLICATION: This study assessed the quality and nutrient adequacy of sample vegan and dairy-free vegetarian menus developed based on adaptations of the 2000 kcal vegetarian dietary pattern from the 2020 Dietary Guidelines for Americans. We found that our sample vegan and dairy-free vegetarian menus, created with publicly available resources, contained enough servings of fruits, vegetables, grains, protein foods, dairy, and oils, but did not provide enough vitamin D, vitamin E, choline, zinc (for males), and iron (for females). Following vegan and ovo-vegetarian diets requires careful planning to ensure sources of these micronutrients are included in adequate amounts., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Journal of Food Science published by Wiley Periodicals LLC on behalf of Institute of Food Technologists.)

Apolipoprotein E alleles have been associated with both Alzheimer's disease (AD) and intracerebral hemorrhage (ICH). In addition, ICH is associated with a markedly high risk of subsequent dementia compared to other subtypes of stroke. We sought to evaluate if other genetic markers for AD were also associated with ICH. We examined whether published AD risk single nucleotide polymorphisms (SNPs) and haplotypes were associated with ICH utilizing genome-wide association study data from 2 independent studies (genetic and environmental risk factors for hemorrhagic stroke [GERFHS] study and genetics of cerebral hemorrhage with anticoagulation [GOCHA]). Analyses included evaluation by location of ICH. GERFHS and GOCHA cohorts contained 745 ICH cases and 536 controls for analysis. The strongest association was on 1q32 near Complement receptor type 1 (CR1), where rs6701713 was associated with all ICH (P = .0074, odds ratio [OR] = 2.07) and lobar ICH (P = .0073, OR = 2.80). The 51 most significant 2-SNP haplotypes associated with lobar ICH were identified within the Clusterin (CLU) gene. We identified that variation within CR1 and CLU, previously identified risk factors for AD, and are associated with an increased risk for ICH driven primarily by lobar ICH. Previous work implicated CR1 and CLU in cerebral amyloid clearance, the innate immune system, and cellular stress response., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Transcriptomic analysis in metabolically active tissues allows a systems genetics approach to identify causal genes and networks involved in metabolic disease. Outbred heterogeneous stock (HS) rats are used for genetic mapping of complex traits, but to-date, a systems genetics analysis of metabolic tissues has not been done. We investigated whether adiposity-associated genes and gene coexpression networks in outbred heterogeneous stock (HS) rats overlap those found in humans. We analyzed RNAseq data from adipose tissue of 415 male HS rats, correlated these transcripts with body weight (BW) and compared transcriptome signatures to two human cohorts: the "African American Genetics of Metabolism and Expression" and "Metabolic Syndrome in Men." We used weighted gene coexpression network analysis to identify adiposity-associated gene networks and mediation analysis to identify genes under genetic control whose expression drives adiposity. We identified 554 orthologous "consensus genes" whose expression correlates with BW in the rat and with body mass index (BMI) in both human cohorts. Consensus genes fell within eight coexpressed networks and were enriched for genes involved in immune system function, cell growth, extracellular matrix organization, and lipid metabolic processes. We identified 19 consensus genes for which genetic variation may influence BW via their expression, including those involved in lipolysis (e.g., Hcar1) , inflammation (e.g., Rgs1 ), adipogenesis (e.g., Tmem120b ), or no previously known role in obesity (e.g., St14 and Ms4a6a). Strong concordance between HS rat and human BW/BMI associated transcripts demonstrates translational utility of the rat model, while identification of novel genes expands our knowledge of the genetics underlying obesity.

Introduction: Intracerebral hemorrhage (ICH) is the most severe subtype of stroke. Its mortality rate is high, and most survivors experience significant disability., Objective: To assess primary patient risk factors associated with mortality and neurologic disability 3 months after ICH in a large, racially and ethnically balanced cohort., Design, Setting, and Participants: This cohort study included participants from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, which prospectively recruited 1000 non-Hispanic White, 1000 non-Hispanic Black, and 1000 Hispanic patients with spontaneous ICH to study the epidemiological characteristics and genomics associated with ICH. Participants included those with uniform data collection and phenotype definitions, centralized neuroimaging review, and telephone follow-up at 3 months. Analyses were completed in November 2021., Exposures: Patient demographic and clinical characteristics as well as hospital event and imaging variables were examined, with characteristics meeting P < .20 considered candidates for a multivariate model. Elements included in the ICH score were specifically analyzed., Main Outcomes and Measures: Individual characteristics were screened for association with 3-month outcome of neurologic disability or mortality, as assessed by a modified Rankin Scale (mRS) score of 4 or greater vs 3 or less under a logistic regression model. A total of 25 characteristics were tested in the final model, which minimized the Akaike information criterion. Analyses were repeated removing individuals who had withdrawal of care., Results: A total of 2568 patients (mean [SD] age, 62.4 [14.7] years; 1069 [41.6%] women and 1499 [58.4%] men) had a 3-month outcome determination available, including death. The final logistic model had a significantly higher area under the receiver operating characteristics curve (C = 0.88) compared with ICH score alone (C = 0.76; P < .001). Among characteristics associated with neurologic disability and mortality were larger log ICH volume (OR, 2.74; 95% CI, 2.36-3.19; P < .001), older age (OR per 1-year increase, 1.04; 95% CI, 1.02-1.05; P < .001), pre-ICH mRS score (OR, 1.62; 95% CI, 1.41-1.87; P < .001), lobar location (OR, 0.22; 95% CI, 0.16-0.30; P < .001), and presence of infection (OR, 1.85; 95% CI, 1.42-2.41; P < .001)., Conclusions and Relevance: The findings of this cohort study validate ICH score elements and suggest additional baseline and interim patient characteristics were associated with variation in 3-month outcome.

Objective: Identify and characterize circulating metabolite profiles associated with adiposity to inform precision medicine., Methods: Untargeted plasma metabolomic profiles in the Insulin Resistance Atherosclerosis Family Study (IRASFS) Mexican American cohort (n = 1108) were analyzed for association with anthropometric (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, WHR) and computed tomography measures (visceral adipose tissue, VAT; subcutaneous adipose tissue, SAT; visceral-to-subcutaneous ratio, VSR) of adiposity. Genetic data, inclusive of genome-wide array-based genotyping, whole exome sequencing (WES) and whole genome sequencing (WGS), were evaluated to identify the genetic contributors. Phenotypic and genetic association signals were replicated across ancestries. Transcriptomic data were analyzed to explore the relationship between genetic and metabolomic data., Results: A partially characterized metabolite, tentatively named metabolonic lactone sulfate (X-12063), was consistently associated with BMI, WC, WHR, VAT, and SAT in IRASFS Mexican Americans (P MA <2.02 × 10 -27 ). Trait associations were replicated in IRASFS African Americans (P AA  < 1.12 × 10 -07 ). Expanded analyses revealed associations with multiple phenotypic measures of cardiometabolic health, e.g. insulin sensitivity (S I ), triglycerides (TG), diastolic blood pressure (DBP) and plasminogen activator inhibitor-1 (PAI-1) in both ancestries. Metabolonic lactone sulfate levels were heritable (h 2 > 0.47), and a significant genetic signal at the ZSCAN25/CYP3A5 locus (P MA  = 9.00 × 10 -41 , P AA  = 2.31 × 10 -10 ) was observed, highlighting a putative functional variant (rs776746, CYP3A5∗3). Transcriptomic analysis in the African American Genetics of Metabolism and Expression (AAGMEx) cohort supported the association of CYP3A5 with metabolonic lactone sulfate levels (P FDR  = 6.64 × 10 -07 )., Conclusions: Variant rs776746 is associated with a decrease in the transcript levels of CYP3A5, which in turn is associated with increased metabolonic lactone sulfate levels and poor cardiometabolic health., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Importance: Black and Hispanic individuals have an increased risk of intracerebral hemorrhage (ICH) compared with their White counterparts, but no large studies of ICH have been conducted in these disproportionately affected populations., Objective: To examine the prevalence, odds, and population attributable risk (PAR) percentage for established and novel risk factors for ICH, stratified by ICH location and racial/ethnic group., Design, Setting, and Participants: The Ethnic/Racial Variations of Intracerebral Hemorrhage Study was a case-control study of ICH among 3000 Black, Hispanic, and White individuals who experienced spontaneous ICH (1000 cases in each group). Recruitment was conducted between September 2009 and July 2016 at 19 US sites comprising 42 hospitals. Control participants were identified through random digit dialing and were matched to case participants by age (±5 years), sex, race/ethnicity, and geographic area. Data analyses were conducted from January 2019 to May 2020., Main Outcomes and Measures: Case and control participants underwent a standardized interview, physical measurement for body mass index, and genotyping for the ɛ2 and ɛ4 alleles of APOE, the gene encoding apolipoprotein E. Prevalence, multivariable adjusted odds ratio (OR), and PAR percentage were calculated for each risk factor in the entire ICH population and stratified by racial/ethnic group and by lobar or nonlobar location., Results: There were 1000 Black patients (median [interquartile range (IQR)] age, 57 [50-65] years, 425 [42.5%] women), 1000 Hispanic patients (median [IQR] age, 58 [49-69] years; 373 [37.3%] women), and 1000 White patients (median [IQR] age, 71 [59-80] years; 437 [43.7%] women). The mean (SD) age of patients with ICH was significantly lower among Black and Hispanic patients compared with White patients (eg, lobar ICH: Black, 62.2 [15.2] years; Hispanic, 62.5 [15.7] years; White, 71.0 [13.3] years). More than half of all ICH in Black and Hispanic patients was associated with treated or untreated hypertension (PAR for treated hypertension, Black patients: 53.6%; 95% CI, 46.4%-59.8%; Hispanic patients: 46.5%; 95% CI, 40.6%-51.8%; untreated hypertension, Black patients: 45.5%; 95% CI, 39.%-51.1%; Hispanic patients: 42.7%; 95% CI, 37.6%-47.3%). Lack of health insurance also had a disproportionate association with the PAR percentage for ICH in Black and Hispanic patients (Black patients: 21.7%; 95% CI, 17.5%-25.7%; Hispanic patients: 30.2%; 95% CI, 26.1%-34.1%; White patients: 5.8%; 95% CI, 3.3%-8.2%). A high sleep apnea risk score was associated with both lobar (OR, 1.68; 95% CI, 1.36-2.06) and nonlobar (OR, 1.62; 95% CI, 1.37-1.91) ICH, and high cholesterol was inversely associated only with nonlobar ICH (OR, 0.60; 95% CI, 0.52-0.70); both had no interactions with race and ethnicity. In contrast to the association between the ɛ2 and ɛ4 alleles of APOE and ICH in White individuals (eg, presence of APOE ɛ2 allele: OR, 1.84; 95% CI, 1.34-2.52), APOE alleles were not associated with lobar ICH among Black or Hispanic individuals., Conclusions and Relevance: This study found sleep apnea as a novel risk factor for ICH. The results suggest a strong contribution from inadequately treated hypertension and lack of health insurance to the disproportionate burden and earlier onset of ICH in Black and Hispanic populations. These findings emphasize the importance of addressing modifiable risk factors and the social determinants of health to reduce health disparities.

Intensive blood pressure control decreases the rate of cardiovascular events by >25% compared with standard blood pressure control. We sought to determine whether the decrease in cardiovascular events seen with intensive blood pressure control is associated with an increased rate of other causes of hospitalization. This is a post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial) in 9361 adult participants with hypertension and elevated cardiovascular risk. Participants were randomly assigned to an intensive or standard systolic blood pressure goal (<120 or <140 mm Hg, respectively). The primary outcome was hospitalization rates per 100 person-years for hospitalizations not associated with SPRINT primary events. After excluding hospitalizations linked to SPRINT primary events, there were 4678 participants with a rate of 19.70 hospitalizations per 100 person-years, compared with 4683 participants with a rate of 19.65 ( P =0.37). Equivalence testing shows that these hospitalization rates were statistically equivalent at the P =0.05 level. Of those with hospitalizations, >1 hospitalization was seen in 38.8% of intensive arm participants and 41.9% of standard arm participants ( P =0.08). The mean cumulative count of nonprimary event hospitalizations was comparable between the two arms. The most common causes of hospitalization were cardiovascular (23.6%) followed by injuries, including bone and joint therapeutic procedures (15.7%), infections (12.0%), and nervous systems disorders (10.7%). No categories of hospitalization were statistically more common in the intensive arm compared with the standard arm. Thus, the decrease in cardiovascular events seen with intensive blood pressure control is not associated with an increased rate of other causes of hospitalization. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in type 2 diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans (AAs) from the African American Genetics of Metabolism and Expression cohort, we performed cis -expression quantitative trait methylation ( cis -eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts. We identified significantly associated cytosine-guanine dinucleotide regions for 82 transcripts (false discovery rate [FDR]- P < 0.05). The strongest eQTM locus was observed for the proopiomelanocortin ( POMC ; ρ = -0.632, P = 4.70 × 10 -27 ) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 cytosine-guanine dinucleotide regions associated (FDR- P < 0.05) with the Matsuda index, S I , and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, S I , and/or BMI in EWAS. These associated genes include FERMT3 , ITGAM , ITGAX , and POMC In summary, applying an integrative multiomics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity., (© 2020 by the American Diabetes Association.)

Sex differences in adipose tissue distribution and function are associated with sex differences in cardiometabolic disease. While many studies have revealed sex differences in adipocyte cell signaling and physiology, there is a relative dearth of information regarding sex differences in transcript abundance and regulation. We investigated sex differences in subcutaneous adipose tissue transcriptional regulation using omic-scale data from ∼3000 geographically and ethnically diverse human samples. We identified 162 genes with robust sex differences in expression. Differentially expressed genes were implicated in oxidative phosphorylation and adipogenesis. We further determined that sex differences in gene expression levels could be related to sex differences in the genetics of gene expression regulation. Our analyses revealed sex-specific genetic associations, and this finding was replicated in a study of 98 inbred mouse strains. The genes under genetic regulation in human and mouse were enriched for oxidative phosphorylation and adipogenesis. Enrichment analysis showed that the associated genetic loci resided within binding motifs for adipogenic transcription factors (e.g., PPARG and EGR1). We demonstrated that sex differences in gene expression could be influenced by sex differences in genetic regulation for six genes (e.g., FADS1 and MAP1B ). These genes exhibited dynamic expression patterns during adipogenesis and robust expression in mature human adipocytes. Our results support a role for adipogenesis-related genes in subcutaneous adipose tissue sex differences in the genetic and environmental regulation of gene expression., (© 2020 Anderson et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes., Methods: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel., Results: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes., Conclusions: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

Insulin resistance (IR) is a harbinger of type 2 diabetes (T2D) and partly determined by genetic factors. However, genetically regulated mechanisms of IR remain poorly understood. Using gene expression, genotype, and insulin sensitivity data from the African American Genetics of Metabolism and Expression (AAGMEx) cohort, we performed transcript-wide correlation and expression quantitative trait loci (eQTL) analyses to identify IR-correlated cis -regulated transcripts ( cis -eGenes) in adipose tissue. These IR-correlated cis -eGenes were tested in the European ancestry individuals in the Metabolic Syndrome in Men (METSIM) cohort for trans-ethnic replication. Comparison of Matsuda index-correlated transcripts in AAGMEx with the METSIM study identified significant correlation of 3,849 transcripts, with concordant direction of effect for 97.5% of the transcripts. cis -eQTL for 587 Matsuda index-correlated genes were identified in both cohorts. Enoyl-CoA hydratase domain-containing 3 ( ECHDC3 ) was the top-ranked Matsuda index-correlated cis -eGene. Expression levels of ECHDC3 were positively correlated with Matsuda index, and regulated by cis -eQTL, rs34844369 being the top cis -eSNP in AAGMEx. Silencing of ECHDC3 in adipocytes significantly reduced insulin-stimulated glucose uptake and Akt Ser 473 phosphorylation. RNA sequencing analysis identified 691 differentially expressed genes in ECHDC3 -knockdown adipocytes, which were enriched in γ-linolenate biosynthesis, and known IR genes. Thus, our studies elucidated genetic regulatory mechanisms of IR and identified genes and pathways in adipose tissue that are mechanistically involved in IR., (© 2019 by the American Diabetes Association.)

Background: Patients with spontaneous intracerebral hemorrhage (ICH) are predisposed to venous thromboembolic (VTE) complications, such as deep vein thrombosis and pulmonary embolism., Objective: To evaluate, in a multicenter, retrospective cohort study, the rate of VTE complications in ICH patients during acute hospitalization, identify potential risk factors, and assess their association with functional outcome., Methods: We retrospectively analyzed prospectively collected data from 19 centers and 41 sites that participated in the Ethnic/Racial Variations of Intracerebral Hemorrhage study, from August 2010 to February 2016. We compared ICH patients with VTE complications to those without VTE complications. Statistical analyses were performed to determine predictors of VTE complications and poor outcome (modified Rankin Scale ≥ 4) at discharge and 3-mo follow-up., Results: Of the 2902 ICH patients who were eligible for analysis, 87 (3.0%) had VTE complications: 57 (2.0%) had only deep vein thrombosis, 19 (0.7%) had only pulmonary embolism, and 11 (0.4%) had both. In the multivariable logistic regression analysis, a prior history of VTE (odds ratio [OR] = 6.8; P < .0001), intubation (OR = 4.0; P < .0001), and presence of IVH (OR = 1.8; P = .0157) were independent predictors of VTE complications. After controlling for ICH volume and location, IVH, age, and presenting Glasgow Coma Scale, the occurrence of VTE complications was an independent predictor of poor outcome at discharge (OR = 2.9; P = .002) and 3-mo follow-up (OR = 2.1; P = .02)., Conclusion: Although VTE complications are uncommon after ICH, they are associated with significantly worse outcomes. Further studies will be needed to determine the optimal treatment regimen for the prevention and treatment of VTE complications in ICH patients., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Context: Excessive body iron stores are a risk factor for decreased insulin sensitivity (SI) and diabetes. We hypothesized that transcriptional dysregulation of genes involved in iron metabolism in adipocytes causes insulin resistance., Objective and Design: To define the genetic regulation of iron metabolism and its role in SI, we used gene expression, genotype, and SI data from an African American cohort (N = 256). Replication studies were performed in independent European ancestry cohorts. In vitro studies in human adipocytes were performed to define the role of a selected gene in causing insulin resistance., Results: Among 62 transcripts representing iron homeostasis genes, expression of 30 in adipose tissue were correlated with SI. Transferrin (TF) and ferritin heavy polypeptide were most positively and negatively associated with SI, respectively. These observations were replicated in two independent European ancestry adipose data sets. The strongest cis-regulatory variant for TF expression (rs6785596; P = 7.84 × 10-18) was identified in adipose but not muscle or liver tissue. Variants significantly affected the normal relationship of serum ferritin to insulin resistance. Knockdown of TF in differentiated Simpson-Golabi-Behmel syndrome adipocytes by short hairpin RNA decreased intracellular iron, reduced maximal insulin-stimulated glucose uptake, and reduced Akt phosphorylation. Knockdown of TF caused differential expression of 465 genes, including genes involved in glucose transport, mitochondrial function, Wnt-pathway/ SI, chemokine activity, and obesity. Iron chelation recapitulated key changes in the expression profile induced by TF knockdown., Conclusion: Genetic regulation of TF expression in adipose tissue plays a novel role in regulating SI.

African Americans carrying two apolipoprotein L1 gene (APOL1) renal risk variants have a high risk for nephropathy. However, only a minority develops end-stage renal disease (ESRD). Hence, modifying factors likely contribute to initiation of kidney disease such as endogenous (HIV infection) or exogenous (interferon treatment) environmental modifiers. In this report, genome-wide association studies and a meta-analysis were performed to identify novel loci for nondiabetic ESRD in African Americans and to detect genetic modifiers in APOL1-associated nephropathy. Two African American cohorts were analyzed, 1749 nondiabetic ESRD cases and 1136 controls from Wake Forest and 901 lupus nephritis (LN)-ESRD cases and 520 controls with systemic lupus erythematosus but lacking nephropathy from the LN-ESRD Consortium. Association analyses adjusting for APOL1 G1/G2 renal-risk variants were completed and stratified by APOL1 risk genotype status. Individual genome-wide association studies and meta-analysis results of all 2650 ESRD cases and 1656 controls did not detect significant genome-wide associations with ESRD beyond APOL1. Similarly, no single nucleotide polymorphism showed significant genome-wide evidence of an interaction with APOL1 risk variants. Thus, although variants with small individual effects cannot be ruled out and are likely to exist, our results suggest that APOL1-environment interactions may be of greater clinical importance in triggering nephropathy in African Americans than APOL1 interactions with other single nucleotide polymorphisms., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

BANK1 is a susceptibility gene for several systemic autoimmune diseases in several populations. Using the genome-wide association study (GWAS) data from Europeans (EUR) and African Americans (AA), we performed an extensive fine mapping of ankyrin repeats 1 ( BANK1 ). To increase the SNP density, we used imputation followed by univariate and conditional analysis, combined with a haplotypic and expression quantitative trait locus (eQTL) analysis. The data from Europeans showed that the associated region was restricted to a minimal and dependent set of SNPs covering introns two and three, and exon two. In AA, the signal found in the Europeans was split into two independent effects. All of the major risk associated SNPs were eQTLs, and the risks were associated with an increased BANK1 gene expression. Functional annotation analysis revealed the enrichment of repressive B cell epigenomic marks (EZH2 and H3K27me3) and a strong enrichment of splice junctions. Furthermore, one eQTL located in intron two, rs13106926, was found within the binding site for RUNX3, a transcriptional activator. These results connect the local genome topography, chromatin structure, and the regulatory landscape of BANK1 with co-transcriptional splicing of exon two. Our data defines a minimal set of risk associated eQTLs predicted to be involved in the expression of BANK1 modulated through epigenetic regulation and splicing. These findings allow us to suggest that the increased expression of BANK1 will have an impact on B-cell mediated disease pathways.

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)-positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies., Methods: Patients with RF-positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single-nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF-positive polyarticular JIA., Results: As expected, the HLA region was strongly associated with RF-positive polyarticular JIA (P = 5.51 × 10 -31 ). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF-negative polyarticular JIA risk loci were associated with RF-positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF-positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF-negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF-positive polyarticular JIA was more similar to that of RA patients with age at onset 16-29 years than to that of RA patients with age at onset ≥70 years., Conclusion: RF-positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood-onset presentation of autoantibody-positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies., (© 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Introduction: High ultrafiltration (UF) rates can result in intradialytic hypotension and are associated with increased mortality. The effects of a weight-based UF rate limit on intradialytic hypotension and the potential for unwanted fluid weight gain and hospitalizations for volume overload are unknown., Methods: This retrospective cohort study examined 123 in-center hemodialysis patients at one facility who transitioned to 13 mL/kg/h maximum UF rates. Patients were studied for an 8 week UF rate limit exposure period and compared to the 8-week period immediately prior, during which the cohort served as its own historical control. The primary outcomes were frequency of intradialytic hypotension events and percentage of treatments with a hypotension event., Findings: The delivered UF rate was lower during the exposure compared to the baseline period (mean UF rate 7.90 ± 4.45 mL/kg/h vs. 8.92 ± 5.64 mL/kg/h; P = 0.0005). The risk of intradialytic hypotension was decreased during the exposure compared to baseline period (event rate per treatment 0.0569 vs. 0.0719, OR 0.78 [95% CI 0.62-1.00]; P = 0.0474), as was the risk of having a treatment with a hypotension event (percentage of treatments with event 5.2% vs. 6.8%, OR 0.75 [95% CI 0.58-0.96]; P = 0.0217). Subgroup analyses demonstrated that these findings were attributable to patients with high baseline UF rates. Statistically significant differences in all-cause or volume overload-related hospitalization were not observed during the exposure period., Discussion: A weight-based UF rate limit of 13 mL/kg/h was associated with a decrease in the rate of intradialytic hypotension events among in-center hemodialysis patients., (© 2017 International Society for Hemodialysis.)

Objective: Tissue-specific gene expression is associated with individual metabolic measures. However, these measures may not reflect the true but latent underlying biological phenotype. This study reports gene expression associations with multidimensional glucometabolic characterizations of obesity, glucose homeostasis, and lipid traits., Methods: Factor analysis was computed by using orthogonal rotation to construct composite phenotypes (CPs) from 23 traits in 256 African Americans without diabetes. Genome-wide transcript expression data from adipose and muscle were tested for association with CPs, and expression quantitative trait loci (eQTLs) were identified by associations between cis-acting single-nucleotide polymorphisms (SNPs) and gene expression., Results: The factor analysis identified six CPs. CPs 1 through 6 individually explained 34%, 12%, 9%, 8%, 6%, and 5% of the variation in 23 glucometabolic traits studied. There were 3,994 and 929 CP-associated transcripts identified in adipose and muscle tissue, respectively; CP2 had the largest number of associated transcripts. Pathway analysis identified multiple canonical pathways from the CP-associated transcripts. In adipose and muscle, significant cis-eQTLs were identified for 558 and 164 CP-associated transcripts (q-value < 0.01), respectively., Conclusions: Adipose and muscle transcripts comprehensively define pathways involved in regulating glucometabolic disorders. Cis-eQTLs for CP-associated genes may act as primary causal determinants of glucometabolic phenotypes by regulating transcription of key genes., (© 2018 The Obesity Society.)

Objective: Systemic inflammatory response syndrome (SIRS) may be related to poor outcomes after intracerebral hemorrhage (ICH)., Methods: The Ethnic/Racial Variations of Intracerebral Hemorrhage study is an observational study of ICH in whites, blacks, and Hispanics throughout the United Sates. SIRS was defined by standard criteria as 2 or more of the following on admission: (1) body temperature <36°C or >38°C, (2) heart rate >90 beats per minute, (3) respiratory rate >20 breaths per minute, or (4) white blood cell count <4,000/mm 3 or >12,000/mm 3 . The relationship among SIRS, infection, and poor outcome (modified Rankin Scale [mRS] 3-6) at discharge and 3 months was assessed., Results: Of 2,441 patients included, 343 (14%) met SIRS criteria at admission. Patients with SIRS were younger (58.2 vs 62.7 years; p < 0.0001) and more likely to have intraventricular hemorrhage (IVH; 53.6% vs 36.7%; p < 0.0001), higher admission hematoma volume (25.4 vs 17.5 mL; p < 0.0001), and lower admission Glasgow Coma Scale (GCS; 10.7 vs 13.1; p < 0.0001). SIRS on admission was significantly related to infections during hospitalization (adjusted odds ratio [OR] 1.36, 95% confidence interval [CI] 1.04-1.78). In unadjusted analyses, SIRS was associated with poor outcomes at discharge (OR 1.96, 95% CI 1.42-2.70) and 3 months (OR 1.75, 95% CI 1.35-2.33) after ICH. In analyses adjusted for infection, age, IVH, hematoma location, admission GCS, and premorbid mRS, SIRS was no longer associated with poor outcomes., Conclusions: SIRS on admission is associated with ICH score on admission and infection, but it was not an independent predictor of poor functional outcomes after ICH.

Background: The early subjective clinical judgment of clinicians outperforms formal prognostic scales for accurate determination of outcome after intracerebral hemorrhage (ICH), with the judgment of physicians and nurses having equivalent accuracy. This study assessed specific decisional factors that physicians and nurses incorporate into early predictions of functional outcome., Methods: This prospective observational study enrolled 121 ICH patients at five US centers. Within 24 h of each patient's admission, one physician and one nurse on the clinical team were each surveyed to predict the patient's modified Rankin Scale (mRS) at 3 months and to list up to 10 subjective factors used in prognostication. Factors were coded and compared between (1) physician and nurse and (2) accurate and inaccurate surveys, with accuracy defined as an exact prediction of mRS., Results: Aside from factors that are components of the ICH or FUNC scores, surveys reported pre-existing comorbidities (40.0%), other clinical or radiographic factors not in clinical scales (43.0%), and non-clinical/radiographic factors (21.9%) as important. Compared to physicians, nurses more frequently listed neurologic examination components (Glasgow Coma Scale motor, 27.3 vs. 5.8%, p < 0.0001; GCS verbal, 12.4 vs. 0.0%, p < 0.0001) and non-clinical/radiographic factors (31.4 vs. 12.4%, p = 0.0005). Physicians more frequently listed neuroimaging factors (ICH location, 33.9 vs. 7.4%, p < 0.0001; intraventricular hemorrhage, 13.2 vs. 2.5%, p = 0.003). There was no difference in listed factors between accurate versus inaccurate surveys., Conclusions: Clinicians frequently utilize factors outside of the components of clinical scales for prognostication, with physician and nurses focusing on different factors despite having similar accuracy.

Objective: Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)-negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes., Methods: Three cohorts comprising 2,751 patients with oligoarticular or RF-negative polyarticular JIA were genotyped using the Affymetrix Genome-Wide SNP Array 6.0 or the Illumina HumanCoreExome-12+ Array. Overall, 15,886 local and out-of-study controls, typed on these platforms or the Illumina HumanOmni2.5, were used for association analyses. High-quality single-nucleotide polymorphisms (SNPs) were used for imputation to 1000 Genomes prior to SNP association analysis., Results: Meta-analysis showed evidence of association (P < 1 × 10 -6 ) at 9 regions: PRR9&#95;LOR (P = 5.12 × 10 -8 ), ILDR1&#95;CD86 (P = 6.73 × 10 -8 ), WDFY4 (P = 1.79 × 10 -7 ), PTH1R (P = 1.87 × 10 -7 ), RNF215 (P = 3.09 × 10 -7 ), AHI1&#95;LINC00271 (P = 3.48 × 10 -7 ), JAK1 (P = 4.18 × 10 -7 ), LINC00951 (P = 5.80 × 10 -7 ), and HBP1 (P = 7.29 × 10 -7 ). Of these, PRR9&#95;LOR, ILDR1&#95;CD86, RNF215, LINC00951, and HBP1 were shown, for the first time, to be autoimmune disease susceptibility loci. Furthermore, associated SNPs included cis expression quantitative trait loci for WDFY4, CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22., Conclusion: This study provides evidence of both unique JIA risk loci and risk loci overlapping between JIA and other autoimmune diseases. These newly associated SNPs are shown to influence gene expression, and their bounding regions tie into molecular pathways of immunologic relevance. Thus, they likely represent regions that contribute to the pathology of oligoarticular JIA and RF-negative polyarticular JIA., (© 2017, American College of Rheumatology.)

Dyslipidemia is a major contributor to the increased cardiovascular disease and mortality associated with obesity and type 2 diabetes. We hypothesized that variation in expression of adipose tissue transcripts is associated with serum lipid concentrations in African Americans (AAs), and common genetic variants regulate expression levels of these transcripts. Fasting serum lipid levels, genome-wide transcript expression profiles of subcutaneous adipose tissue, and genome-wide SNP genotypes were analyzed in a cohort of non-diabetic AAs (N=250). Serum triglyceride (TRIG) and high density lipoprotein-cholesterol (HDL-C) levels were associated (FDR<0.01) with expression level of 1021 and 1875 adipose tissue transcripts, respectively, but none associated with total cholesterol or LDL-C levels. Serum HDL-C-associated transcripts were enriched for salient biological pathways, including branched-chain amino acid degradation, and oxidative phosphorylation. Genes in immuno-inflammatory pathways were activated among individuals with higher serum TRIG levels. We identified significant cis-regulatory SNPs (cis-eSNPs) for 449 serum lipid-associated transcripts in adipose tissue. The cis-eSNPs of 12 genes were nominally associated (p<0.001) with serum lipid level in genome wide association studies in Global Lipids Genetics Consortium (GLGC) cohorts. Allelic effect direction of cis-eSNPs on expression of MARCH2, BEST1 and TMEM258 matched with effect direction of these SNP alleles on serum TRIG or HDL-C levels in GLGC cohorts. These data suggest that expressions of serum lipid-associated transcripts in adipose tissue are dependent on common cis-eSNPs in African Americans. Thus, genetically-mediated transcriptional regulation in adipose tissue may play a role in reducing HDL-C and increasing TRIG in serum., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background : Children's health is a current concern and data suggests that poor fundamental movement skills (FMS) could be associated with poor health, which may or may not be mediated by low physical activity level. However, tools to assess FMS have not been standardized, and could consequently lead to different associations between FMS and health indicators. Objective : The primary objective of this study was to evaluate the associations between FMS and health indicators using two different FMS measurement tools often used in Canada. Methods : A total of 145 children between the ages of 9 to 12 were recruited from schools, after school programs, and summer camps in 2016. FMS were evaluated using the Passport for Life (bound, plank, run, kick, throw) and the PLAYbasic (run, hop, throw, kick, and balance). The association between each test and an average score for each tool were tests with health indicators including anthropometric measures, grip strength, cardiorespiratory fitness, and percent body fat. Results : Participants were composed of 54.2% boys aged 10.4 ± 1.2 years with an average body mass index of 18.8 ± 3.8 kg/m². The association between the average score of both tools was 0.77 ( p < 0.01), body mass index was significantly associated with 67% of FMS elements using the Passport for Life ( r ranging from -0.18 to -0.32; p < 0.05), and 60% of FMS using the PLAYbasic ( r ranging from -0.15 to -0.30; p < 0.05). There were no significant differences between the associations of the health indicators with FMS and either FMS assessment tool (Passport for Life and PLAYbasic) ( p = 0.05). Average score of FMS was significantly associated with all health indicators using both PLAYbasic and Passport for Life (all p < 0.05). Conclusions : Health indicators in children are associated with FMS regardless of whether the Passport for Life or the PLAYbasic was used as the assessment tool. It is worth investigating if interventions that improve FMS lead to improvements in these health indicators., Competing Interests: The authors have no conflict of interests to declare.

Background and Purpose: Statin use may be associated with improved outcome in intracerebral hemorrhage patients. However, the topic remains controversial. Our analysis examined the effect of prior, continued, or new statin use on intracerebral hemorrhage outcomes using the ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage) data set., Methods: We analyzed ERICH (a multicenter study designed to examine ethnic variations in the risk, presentation, and outcomes of intracerebral hemorrhage) to explore the association of statin use and hematoma growth, mortality, and 3-month disability. We computed subset analyses with respect to 3 statin categories (prior, continued, or new use)., Results: Two thousand four hundred and fifty-seven enrolled cases (mean age, 62 years; 42% females) had complete data on mortality and 3-month disability (modified Rankin Scale). Among those, 1093 cases were on statins (prior, n=268; continued, n=423; new, n=402). Overall, statin use was associated with reduced mortality and disability without any effect on hematoma growth. This association was primarily driven by continued/new statin use. A multivariate analysis adjusted for age and major predictors for poor outcome showed that continued/new statins users had good outcomes compared with prior users. However, statins may have been continued/started more frequently among less severe patients. When a propensity score was developed based on factors that could influence a physician's decision in prescribing statins and used as a covariate, continued/new statin use was no longer a significant predictor of good outcome., Conclusions: Although statin use, especially continued/new use, was associated with improved intracerebral hemorrhage outcomes, this effect may merely reflect the physician's view of a patient's prognosis rather than a predictor of survival., (© 2017 American Heart Association, Inc.)

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10 -8 ), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation., Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases., Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015., Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available., Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population., Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation., Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15])., Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Objectives: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides., Methods: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed., Results: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA., Conclusions: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Relative to European Americans, evidence supports that African Americans with end-stage renal disease (ESRD) survive longer on dialysis. Renal-risk variants in the apolipoprotein L1 gene (APOL1), associated with nondiabetic nephropathy and less subclinical atherosclerosis, may contribute to dialysis outcomes. Here, APOL1 renal-risk variants were assessed for association with dialytic survival in 450 diabetic and 275 nondiabetic African American hemodialysis patients from Wake Forest and Emory School of Medicine outpatient facilities. Outcomes were provided by the ESRD Network 6-Southeastern Kidney Council Standardized Information Management System. Dates of death, receipt of a kidney transplant, and loss to follow-up were recorded. Outcomes were censored at the date of transplantation or through 1 July 2015. Multivariable Cox proportional hazards models were computed separately in patients with nondiabetic and diabetic ESRD, adjusting for the covariates age, gender, comorbidities, ancestry, and presence of an arteriovenous fistula or graft at dialysis initiation. In nondiabetic ESRD, patients with 2 (vs. 0/1) APOL1 renal-risk variants had significantly longer dialysis survival (hazard ratio 0.57), a pattern not observed in patients with diabetes-associated ESRD (hazard ratio 1.29). Thus, 2 APOL1 renal-risk variants are associated with longer dialysis survival in African Americans without diabetes, potentially relating to presence of renal-limited disease or less atherosclerosis., (Copyright © 2016 International Society of Nephrology. All rights reserved.)

Objective: Assess cross-sectional relationships between body mass index (BMI), waist circumference (WC), pericardial (PAT), visceral (VAT), and subcutaneous adipose tissue (SAT) volumes with calcified plaque (CP) in African Americans (AAs) and European Americans (EAs) with type 2 diabetes., Methods: Computed tomography measured PAT, VAT, SAT, and CP in coronary arteries (CAC), carotid arteries, and aorta. Generalized estimating equations models were fitted to test for associations between adiposity and CP, stratified by ethnicity while accounting for familial correlations., Results: AAs (N = 753) vs. EAs (N = 562) had significantly lower PAT and VAT, despite equal or higher BMI. In multivariable models adjusting for age, gender, education, HbA1c, statins, smoking, cardiovascular disease, hypertension, nephropathy, and C-reactive protein, PAT positively associated with presence of CAC in AAs (P < 0.001), not EAs (P = 0.68; ethnicity interaction P < 0.01). Inverse associations were detected between SAT and severity of aorta CP (P < 0.01) in AAs and between BMI, WC, and SAT with severity of aorta CP in all participants., Conclusions: Ethnic- and gender-specific differences in BMI, WC, PAT, SAT, and VAT were present in AAs and EAs with diabetes. Only PAT was positively associated with CAC in AAs; paradoxical inverse associations were seen between several other adiposity measures and subclinical cardiovascular disease., (© 2016 The Obesity Society.)

Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet, published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits. Quantitative measures of adipose and muscle gene expression, and genotypic data were integrated in 260 non-diabetic AAs to identify expression regulatory variants. Their roles in genetic susceptibility to T2D, and related metabolic phenotypes, were evaluated by mining GWAS datasets. eQTL analysis identified 1971 and 2078 cis-eGenes in adipose and muscle, respectively. Cis-eQTLs for 885 transcripts including top cis-eGenes CHURC1, USMG5, and ERAP2 were identified in both tissues. 62.1 % of top cis-eSNPs were within ±50 kb of transcription start sites and cis-eGenes were enriched for mitochondrial transcripts. Mining GWAS databases revealed association of cis-eSNPs for more than 50 genes with T2D (e.g. PIK3C2A, RBMS1, UFSP1), gluco-metabolic phenotypes (e.g. INPP5E, SNX17, ERAP2, FN3KRP), and obesity (e.g. POMC, CPEB4). Integration of GWAS meta-analysis data from AA cohorts revealed the most significant association for cis-eSNPs of ATP5SL and MCCC1 genes, with T2D and BMI, respectively. This study developed the first comprehensive map of adipose and muscle tissue eQTLs in AAs (publically accessible at https://mdsetaa.phs.wakehealth.edu ) and identified genetically regulated transcripts for delineating genetic causes of T2D, and related metabolic phenotypes.

Integrative multiomics analyses of adipose and muscle tissue transcripts, S, and genotypes revealed novel genetic regulatory mechanisms of insulin resistance in African Americans.

Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. We undertook the present work to perform the first genome-wide association study on individuals from the Americas who are enriched for Native American heritage., Methods: We analyzed 3,710 individuals from the US and 4 countries of Latin America who were diagnosed as having SLE, and healthy controls. Samples were genotyped with HumanOmni1 BeadChip. Data on out-of-study controls genotyped with HumanOmni2.5 were also included. Statistical analyses were performed using SNPtest and SNPGWA. Data were adjusted for genomic control and false discovery rate. Imputation was performed using Impute2 and, for classic HLA alleles, HiBag. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated., Results: The IRF5-TNPO3 region showed the strongest association and largest OR for SLE (rs10488631: genomic control-adjusted P [Pgcadj ] = 2.61 × 10(-29), OR 2.12 [95% CI 1.88-2.39]), followed by HLA class II on the DQA2-DQB1 loci (rs9275572: Pgcadj  = 1.11 × 10(-16), OR 1.62 [95% CI 1.46-1.80] and rs9271366: Pgcadj  = 6.46 × 10(-12), OR 2.06 [95% CI 1.71-2.50]). Other known SLE loci found to be associated in this population were ITGAM, STAT4, TNIP1, NCF2, and IRAK1. We identified a novel locus on 10q24.33 (rs4917385: Pgcadj  = 1.39 × 10(-8)) with an expression quantitative trait locus (eQTL) effect (Peqtl  = 8.0 × 10(-37) at USMG5/miR1307), and several new suggestive loci. SLE risk loci previously identified in Europeans and Asians were corroborated. Local ancestry estimation showed that the HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection against development of SLE., Conclusion: Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases., (© 2016, American College of Rheumatology.)