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1.
Circ Genom Precis Med ; 12(7): e002338, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31306060

RESUMO

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.

2.
Stroke ; 50(8): 2044-2049, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31238829

RESUMO

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.

3.
Diabetes ; 68(7): 1508-1522, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31010960

RESUMO

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 Ser473 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.

4.
Hum Mol Genet ; 27(21): 3813-3824, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30085094

RESUMO

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.

5.
Int J Mol Sci ; 19(8)2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30096841

RESUMO

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.

6.
J Clin Endocrinol Metab ; 103(11): 4197-4208, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30099506

RESUMO

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.

7.
Neurosurgery ; 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30011018

RESUMO

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.

8.
Hum Mol Genet ; 2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29912393

RESUMO

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 to 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.

9.
Kidney Int ; 94(3): 599-607, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29885931

RESUMO

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.

10.
Arthritis Rheumatol ; 70(6): 957-962, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29426059

RESUMO

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.

11.
Obesity (Silver Spring) ; 26(3): 559-569, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29377571

RESUMO

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.


Assuntos
Adiposidade/fisiologia , Músculos/metabolismo , Obesidade/metabolismo , Adolescente , Adulto , Humanos , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
12.
Neurol Neuroimmunol Neuroinflamm ; 5(2): e428, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29318180

RESUMO

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/mm3 or >12,000/mm3. 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.

13.
Hemodial Int ; 22(2): 270-278, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28643378

RESUMO

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.

14.
Gene ; 632: 50-58, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-28844666

RESUMO

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.


Assuntos
Tecido Adiposo/metabolismo , HDL-Colesterol/sangue , Transcriptoma , Triglicerídeos/sangue , Adolescente , Adulto , Afro-Americanos/genética , HDL-Colesterol/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Triglicerídeos/genética
15.
Stroke ; 48(8): 2098-2104, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28663510

RESUMO

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.


Assuntos
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 Tratamento
16.
Neurocrit Care ; 27(3): 316-325, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28744847

RESUMO

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 no Hospital , Avaliação de Resultados (Cuidados de Saúde)/métodos , Índice de Gravidade de Doença , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados (Cuidados de Saúde)/normas , Prognóstico , Estudos Prospectivos
17.
Arthritis Rheumatol ; 69(11): 2222-2232, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28719732

RESUMO

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_LOR (P = 5.12 × 10-8 ), ILDR1_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_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_LOR, ILDR1_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.


Assuntos
Artrite Juvenil/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Antígeno B7-2/genética , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas de Grupo de Alta Mobilidade/genética , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Janus Quinase 1/genética , Masculino , Proteínas Mitocondriais/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Locos de Características Quantitativas/genética , Fatores de Processamento de RNA/genética , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas-G/genética , Proteínas Repressoras/genética
18.
Nat Commun ; 8: 16021, 2017 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-28714469

RESUMO

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.

19.
Obesity (Silver Spring) ; 24(8): 1810-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27356020

RESUMO

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.


Assuntos
Afro-Americanos/estatística & dados numéricos , Aterosclerose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Obesidade/metabolismo , Gordura Subcutânea/metabolismo , Idoso , Aterosclerose/complicações , Aterosclerose/etnologia , Vasos Coronários , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/etnologia , Fatores de Risco
20.
Hum Genet ; 135(8): 869-80, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27193597

RESUMO

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.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/genética , Músculos/metabolismo , Obesidade/genética , Locos de Características Quantitativas/genética , Tecido Adiposo/patologia , Adolescente , Adulto , Afro-Americanos/genética , Mapeamento Cromossômico , Diabetes Mellitus Tipo 2/patologia , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Obesidade/patologia
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