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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.
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Doenças de Pequenos Vasos Cerebrais , Semaforinas , Acidente Vascular Cerebral Lacunar , Humanos , Estudo de Associação Genômica Ampla , Hemorragia Cerebral/genética , Hemorragia Cerebral/complicações , Doenças de Pequenos Vasos Cerebrais/genética , Doenças de Pequenos Vasos Cerebrais/complicações , Acidente Vascular Cerebral Lacunar/complicações , Cromatina , Semaforinas/genéticaRESUMO
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.
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Doenças Autoimunes , COVID-19 , Lúpus Eritematoso Sistêmico , Humanos , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , COVID-19/genética , Lúpus Eritematoso Sistêmico/genética , Doenças Autoimunes/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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 (PFDR < 0.05, for BMI, SI, 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 (ß = 1.87, P = 1.9 × 10-16) and SI (ß = -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.
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Metilação de DNA , Epigênese Genética , Resistência à Insulina , Obesidade , Humanos , Resistência à Insulina/genética , Obesidade/metabolismo , Obesidade/genética , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Regulação da Expressão Gênica , Tecido Adiposo/metabolismo , MetabolômicaRESUMO
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.
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Fibrinolíticos , Estudo de Associação Genômica Ampla , Humanos , Fatores de Risco , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/genética , GenômicaRESUMO
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 â¼3000 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.
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Adipogenia/genética , Tecido Adiposo/metabolismo , Regulação da Expressão Gênica , Caracteres Sexuais , Dessaturase de Ácido Graxo Delta-5 , Feminino , Genótipo , Humanos , Masculino , Fosforilação Oxidativa , Fatores de Transcrição/metabolismoRESUMO
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.
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Redes Reguladoras de Genes , Obesidade , Transcriptoma , Tecido Adiposo/metabolismo , Adiposidade/genética , Animais , Perfilação da Expressão Gênica , Humanos , Masculino , Obesidade/genética , RatosRESUMO
OBJECTIVES: To determine if the polymorphism encoding the Arg206Cys substitution in DNASE1L3 explains the association of the DNASE1L3/PXK gene locus with systemic lupus erythematosus (SLE) and to examine the effect of the Arg206Cys sequence change on DNASE1L3 protein function. METHODS: Conditional analysis for rs35677470 was performed on cases and controls with European ancestry from the SLE Immunochip study, and genotype and haplotype frequencies were compared. DNASE1L3 protein levels were measured in cells and supernatants of HEK293 cells and monocyte-derived dendritic cells expressing recombinant and endogenous 206Arg and 206Cys protein variants. RESULTS: Conditional analysis on rs35677470 eliminated the SLE risk association signal for lead single-nucleotide polymorphisms (SNPs) rs180977001 and rs73081554, which are found to tag the same risk haplotype as rs35677470. The modest effect sizes of the SLE risk genotypes (heterozygous risk OR=1.14 and homozygous risk allele OR=1.68) suggest some DNASE1L3 endonuclease enzyme function is retained. An SLE protective signal in PXK (lead SNP rs11130643) remained following conditioning on rs35677470. The DNASE1L3 206Cys risk variant maintained enzymatic activity, but secretion of the artificial and endogenous DNASE1L3 206Cys protein was substantially reduced. CONCLUSIONS: SLE risk association in the DNASE1L3 locus is dependent on the missense SNP rs35677470, which confers a reduction in DNASE1L3 protein secretion but does not eliminate its DNase enzyme function.
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Endodesoxirribonucleases/genética , Lúpus Eritematoso Sistêmico , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Células HEK293 , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.
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Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Complexo Principal de Histocompatibilidade/genética , Polimorfismo de Nucleotídeo Único , Negro ou Afro-Americano/genética , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Masculino , Modelos Genéticos , População Branca/genéticaRESUMO
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.
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Alelos , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Locos de Características Quantitativas , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT4/genética , Feminino , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Fatores de RiscoRESUMO
Background and Purpose- Clinical trials in spontaneous intracerebral hemorrhage (ICH) have used volume cutoffs as inclusion criteria to select populations in which the effects of interventions are likely to be the greatest. However, optimal volume cutoffs for predicting poor outcome in deep locations (thalamus versus basal ganglia) are unknown. Methods- We conducted a 2-phase study to determine ICH volume cutoffs for poor outcome (modified Rankin Scale score of 4-6) in the thalamus and basal ganglia. Cutoffs with optimal sensitivity and specificity for poor outcome were identified in the ERICH ([Ethnic/Racial Variations of ICH] study; derivation cohort) using receiver operating characteristic curves. The cutoffs were then validated in the ATACH-2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) by comparing the c-statistic of regression models for outcome (including dichotomized volume) in the validation cohort. Results- Of the 3000 patients enrolled in ERICH, 1564 (52%) had deep ICH, of whom 1305 (84%) had complete neuroimaging and outcome data (660 thalamic and 645 basal ganglia hemorrhages). Receiver operating characteristic curve analysis identified 8 mL in thalamic (area under the curve, 0.79; sensitivity, 73%; specificity, 78%) and 18 mL in basal ganglia ICH (area under the curve, 0.79; sensitivity, 70%; specificity, 83%) as optimal cutoffs for predicting poor outcome. The validation cohort included 834 (84%) patients with deep ICH and complete neuroimaging data enrolled in ATACH-2 (353 thalamic and 431 basal ganglia hemorrhages). In thalamic ICH, the c-statistic of the multivariable outcome model including dichotomized ICH volume was 0.80 (95% CI, 0.75-0.85) in the validation cohort. For basal ganglia ICH, the c-statistic was 0.81 (95% CI, 0.76-0.85) in the validation cohort. Conclusions- Optimal hematoma volume cutoffs for predicting poor outcome in deep ICH vary by the specific deep brain nucleus involved. Utilization of location-specific volume cutoffs may improve clinical trial design by targeting deep ICH patients that will obtain maximal benefit from candidate therapies.
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Hemorragia Cerebral/patologia , Hematoma/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Prognóstico , Valores de ReferênciaRESUMO
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.
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Apolipoproteína L1/genética , Negro ou Afro-Americano/genética , Interação Gene-Ambiente , Falência Renal Crônica/genética , Nefrite Lúpica/genética , Estudos de Casos e Controles , Progressão da Doença , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Falência Renal Crônica/patologia , Nefrite Lúpica/patologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.
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Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteína Proto-Oncogênica c-ets-1/genética , Fator de Transcrição STAT1/genética , Alelos , Animais , Povo Asiático , Teorema de Bayes , Genótipo , Haplótipos , Humanos , Camundongos , Ligação Proteica , Proteína Proto-Oncogênica c-ets-1/metabolismo , Fator de Transcrição STAT1/metabolismoRESUMO
Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.
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Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Negro ou Afro-Americano/genética , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etnologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Humanos , Indígenas Norte-Americanos/genética , Proteínas de Ligação a RNA/genética , Estados Unidos , População Branca/genéticaRESUMO
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.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Doenças Autoimunes/genética , Epigênese Genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Doenças Autoimunes/patologia , Sítios de Ligação , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação da Expressão Gênica/genética , Ligação Genética , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Íntrons/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Fatores de Risco , População BrancaRESUMO
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.
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Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Estudos Prospectivos , Tomografia Computadorizada por Raios X/mortalidade , Tomografia Computadorizada por Raios X/tendências , Resultado do TratamentoRESUMO
Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.
Assuntos
Hemorragia Cerebral/genética , Cromossomos Humanos Par 1 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Humanos , Locos de Características QuantitativasRESUMO
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)
Assuntos
Diabetes Mellitus Tipo 2/genética , Antígeno HLA-B27/genética , Proteína HMGA2/genética , Canal de Potássio KCNQ1/genética , Proteínas Mutantes Quiméricas/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Negro ou Afro-Americano/genética , Diabetes Mellitus Tipo 2/patologia , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
Assuntos
Hemorragia Cerebral/diagnóstico , Corpo Clínico Hospitalar , Recursos Humanos de Enfermagem Hospitalar , Avaliação de Resultados em Cuidados de Saúde/métodos , Índice de Gravidade de Doença , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/normas , Prognóstico , Estudos ProspectivosRESUMO
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.
Assuntos
Apolipoproteínas/genética , Negro ou Afro-Americano/genética , Nefropatias Diabéticas/mortalidade , Falência Renal Crônica/mortalidade , Lipoproteínas HDL/genética , Diálise Renal , Idoso , Apolipoproteína L1 , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/terapia , Feminino , Genótipo , Humanos , Falência Renal Crônica/genética , Falência Renal Crônica/terapia , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Análise de Sobrevida , População Branca/genéticaRESUMO
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.