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Balow Jr. J.E.,National Human Genome Research Institute NHGRI | Ryan J.G.,National Human Genome Research Institute NHGRI | Chae J.J.,National Human Genome Research Institute NHGRI | Booty M.G.,National Human Genome Research Institute NHGRI | And 8 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objective: To analyse gene expression patterns and to define a specific gene expression signature in patients with the severe end of the spectrum of cryopyrin-associated periodic syndromes (CAPS). The molecular consequences of interleukin 1 inhibition were examined by comparing gene expression patterns in 16 CAPS patients before and after treatment with anakinra. Methods: We collected peripheral blood mononuclear cells from 22 CAPS patients with active disease and from 14 healthy children. Transcripts that passed stringent filtering criteria (p values ≤ false discovery rate 1%) were considered as differentially expressed genes (DEG). A set of DEG was validated by quantitative reverse transcription PCR and functional studies with primary cells from CAPS patients and healthy controls. We used 17 CAPS and 66 non-CAPS patient samples to create a set of gene expression models that differentiates CAPS patients from controls and from patients with other autoinflammatory conditions. Results: Many DEG include transcripts related to the regulation of innate and adaptive immune responses, oxidative stress, cell death, cell adhesion and motility. A set of gene expression-based models comprising the CAPS-specific gene expression signature correctly classified all 17 samples from an independent dataset. This classifier also correctly identified 15 of 16 postanakinra CAPS samples despite the fact that these CAPS patients were in clinical remission. Conclusions: We identified a gene expression signature that clearly distinguished CAPS patients from controls. A number of DEG were in common with other systemic inflammatory diseases such as systemic onset juvenile idiopathic arthritis. The CAPS-specific gene expression classifiers also suggest incomplete suppression of inflammation at low doses of anakinra.


Yang J.,Queensland Institute of Medical Research | Manolio T.A.,National Human Genome Research Institute NHGRI | Pasquale L.R.,Harvard University | Boerwinkle E.,University of Texas Health Science Center at Houston | And 21 more authors.
Nature Genetics | Year: 2011

We estimate and partition genetic variation for height, body mass index (BMI), von Willebrand factor and QT interval (QTi) using 586,898 SNPs genotyped on 11,586 unrelated individuals. We estimate that ̃45%, ̃17%, ̃25% and ̃21% of the variance in height, BMI, von Willebrand factor and QTi, respectively, can be explained by all autosomal SNPs and a further ̃0.5-1% can be explained by X chromosome SNPs. We show that the variance explained by each chromosome is proportional to its length, and that SNPs in or near genes explain more variation than SNPs between genes. We propose a new approach to estimate variation due to cryptic relatedness and population stratification. Our results provide further evidence that a substantial proportion of heritability is captured by common SNPs, that height, BMI and QTi are highly polygenic traits, and that the additive variation explained by a part of the genome is approximately proportional to the total length of DNA contained within genes therein. © 2011 Nature America, Inc. All rights reserved.


Kullo I.J.,Mayo Medical School | Ding K.,Mayo Medical School | Shameer K.,Mayo Medical School | McCarty C.A.,Center for Human Genetics | And 8 more authors.
American Journal of Human Genetics | Year: 2011

The erythrocyte sedimentation rate (ESR), a commonly performed test of the acute phase response, is the rate at which erythrocytes sediment in vitro in 1 hr. The molecular basis of erythrocyte sedimentation is unknown. To identify genetic variants associated with ESR, we carried out a genome-wide association study of 7607 patients in the Electronic Medical Records and Genomics (eMERGE) network. The discovery cohort consisted of 1979 individuals from the Mayo Clinic, and the replication cohort consisted of 5628 individuals from the remaining four eMERGE sites. A nonsynonymous SNP, rs6691117 (Val→IIe), in the complement receptor 1 gene (CR1) was associated with ESR (discovery cohort p = 7 × 10-12, replication cohort p = × 3 10 -14, combined cohort p = 9 × 10-24). We imputed 61 SNPs in CR1, and a ''possibly damaging'' SNP (rs2274567, His→Arg) in linkage disequilibrium (r2 = 0.74) with rs6691117 was also associated with ESR (discovery p = 5 × 10-11, replication p = 7 × 10-17, and combined cohort p = 2 × 10-25). The two nonsynonymous SNPs in CR1 are near the C3b/C4b binding site, suggesting a possible mechanism by which the variants may influence ESR. In conclusion, genetic variation in CR1, which encodes a protein that clears complement-tagged inflammatory particles from the circulation, influences interindividual variation in ESR, highlighting an association between the innate immunity pathway and erythrocyte interactions. © 2011 by The American Society of Human Genetics. All rights reserved.


Craig D.W.,Translational Genomics Research Institute TGen | Goor R.M.,U.S. National Center for Biotechnology Information | Wang Z.,U.S. National Center for Biotechnology Information | Paschall J.,U.S. National Center for Biotechnology Information | And 4 more authors.
Nature Reviews Genetics | Year: 2011

Access to genetic data across studies is an important aspect of identifying new genetic associations through genome-wide association studies (GWASs). Meta-analysis across multiple GWASs with combined cohort sizes of tens of thousands of individuals often uncovers many more genome-wide associated loci than the original individual studies; this emphasizes the importance of tools and mechanisms for data sharing. However, even sharing summary-level data, such as allele frequencies, inherently carries some degree of privacy risk to study participants. Here we discuss mechanisms and resources for sharing data from GWASs, particularly focusing on approaches for assessing and quantifying the privacy risks to participants that result from the sharing of summary-level data. © 2011 Macmillan Publishers Limited. All rights reserved.


PubMed | University of Arkansas for Medical Sciences, Morehouse School of Medicine, National Human Genome Research Institute NHGRI, University of Michigan and 4 more.
Type: Journal Article | Journal: Journal of epidemiology and community health | Year: 2016

Using Jackson Heart Study data, we examined associations of multiple measures of perceived discrimination with health behaviours among African-Americans (AA).The cross-sectional associations of everyday, lifetime and burden of discrimination with odds of smoking and mean differences in physical activity, dietary fat and sleep were examined among 4925 participants aged 35-84 years after adjustment for age and socioeconomic status (SES).Men reported slightly higher levels of everyday and lifetime discrimination than women and similar levels of burden of discrimination as women. After adjustment for age and SES, everyday discrimination was associated with more smoking and a greater percentage of dietary fat in men and women (OR for smoking: 1.13, 95% CI 1.00 to 1.28 and 1.19, 95% CI 1.05 to 1.34; mean difference in dietary fat: 0.37, p<0.05 and 0.43, p<0.01, in men and women, respectively). Everyday and lifetime discrimination were associated with fewer hours of sleep in men and women (mean difference for everyday discrimination: -0.08, p<0.05 and -0.18, p<0.001, respectively; and mean difference for lifetime discrimination: -0.08, p<0.05 and -0.24, p<0.001, respectively). Burden of discrimination was associated with more smoking and fewer hours of sleep in women only.Higher levels of perceived discrimination were associated with select health behaviours among men and women. Health behaviours offer a potential mechanism through which perceived discrimination affects health in AA.


McBride C.M.,National Human Genome Research Institute NHGRI | Persky S.,National Human Genome Research Institute NHGRI | Wagner L.K.,National Human Genome Research Institute NHGRI | Faith M.S.,University of North Carolina at Chapel Hill | Ward D.S.,University of North Carolina at Chapel Hill
International Journal of Obesity | Year: 2013

Background:Providing personalized genetic-risk feedback of a child's susceptibility to adult-onset health conditions is a topic of considerable debate. Family health history (FHH), specifically parental overweight/obesity status, is a useful assessment for evaluating a child's genetic and environmental risk of becoming obese. It is unclear whether such risk information may influence parents' efforts to reduce their child's risk of obesity.Purpose:To evaluate whether telling mothers the magnitude of their child's risk of becoming obese based on personal FHH influenced food choices for their young child from a virtual reality-based buffet restaurant.Methods: Overweight/obese mothers of a child aged 4-5 years who met eligibility criteria (N=221) were randomly assigned to one of three experimental arms, which emphasized different health information: arm 1, food safety control (Control); arm 2, behavioral-risk information (BRI) alone or arm 3, behavioral-risk information plus personal FHH-based risk assessment (BRI+FHH). Mothers donned a head-mounted display to be immersed in a virtual restaurant buffet, where they selected virtual food and beverages as a lunch for their child.Results:Mothers who were randomized to BRI+FHH filled the index child's plate with an average of 45 fewer calories than those in the Control arm (P<0.05); those in the BRI arm filled the plate with 35 fewer calories than the Control arm, a non-significant difference. Calorie restriction was greatest among mothers in the BRI+FHH arm who received the weaker-risk message (that is, only one overweight parent).Conclusions:The influence of communicating a child's inherited risk of obesity on mothers' feeding practices may vary by the risk level conveyed. High-risk messages may best be coupled with strategies to increase mother's perceptions that efforts can be undertaken to reduce risk and build requisite behavioral skills to reduce risk. © 2013 Macmillan Publishers Limited.


Integrating vectors based on γ-retroviruses and containing full-length long terminal repeats (LTRs) have been associated with activation of oncogene expression and leukemogenesis in human gene therapy trials. Identification of the specific molecular elements of the LTRs that have a role in insertional oncogenesis events is important as it can lead to the development of safer gene transfer vectors. The negative control region (NCR) of the LTR is a particularly well-conserved sequence among mammalian γ-retroviruses with demonstrated regulatory activity of gene transcription in hematopoietic cells, which led us to hypothesize that this region may have a role in insertional oncogenesis after γ-retroviral vector (GV)-mediated gene transfer into hematopoietic progenitors. We used an in vitro assay of murine bone marrow cell immortalization to compare the immortalization capabilities of a series of GVs carrying murine leukemia virus (MLV) LTR deletion mutants. Compared with GV carrying the full-length MLV LTR, deletion of the complete LTR enhancer sequence showed significant reduction of immortalization rates. However, the use of a mutant LTR deleted of the enhancer sequence, with exception of the NCR, did not affect immortalization. Importantly, the inclusion of an LTR mutant devoid only of the NCR did show significant reduction of immortalization rates compared with the full LTR sequence. Therefore, our data point to the NCR as a key element for immortalization and justify additional studies to evaluate its specific role in MLV-mediated insertional oncogenesis.Gene Therapy advance online publication, 4 August 2016; doi:10.1038/gt.2016.51. © 2016 Macmillan Publishers Limited, part of Springer Nature.


Wise A.L.,National Human Genome Research Institute NHGRI | Gyi L.,National Human Genome Research Institute NHGRI | Manolio T.A.,National Human Genome Research Institute NHGRI
American Journal of Human Genetics | Year: 2013

The X chromosome lags behind autosomal chromosomes in genome-wide association study (GWAS) findings. Indeed, the X chromosome is commonly excluded from GWAS analyses despite being assayed on all current GWAS microarray platforms. This raises the question: why are so few hits reported on the X chromosome? This commentary aims to examine this question through review of the current X chromosome results in the National Human Genome Research Institute Catalog of Published Genome-Wide Association Studies (NHGRI GWAS Catalog). It will also investigate commonly cited reasons for exclusion of the X chromosome from GWAS and review the tools currently available for X chromosome analysis. It will conclude with recommendations for incorporating X chromosome analyses in future studies. © 2013 The American Society of Human Genetics.


Peay H.L.,National Human Genome Research Institute NHGRI | Rosenstein D.L.,University of North Carolina at Chapel Hill | Biesecker B.B.,National Human Genome Research Institute NHGRI
BMC Psychiatry | Year: 2013

Background: Bipolar disorder (BPD) is a common condition associated with significant morbidity and reduced quality of life. In addition to challenges caused by their mood symptoms, parents affected with BPD harbor concerns about the mental health of their children. Among adult parents who perceive themselves to have BPD, this study aims to examine participants' coping methods; identify predictors of adaptation; assess parental perceptions of risks for mood disorders among their children; and describe the relationships among illness appraisals, coping, adaptation to one's own illness, and perceived risk to one's children. Methods: Parents who self-identified as having BPD completed a web-based survey that assessed dispositional optimism, coping, perceived illness severity, perceived etiology of BPD, perceived risk to offspring, and adaptation to BPD. Participants had at least one unaffected child who was 30 years of age or below. Results: 266 parents were included in the analysis. 87% of parents endorsed a " somewhat greater" or " much greater" risk for mood disorders in one's child(ren) than someone without a family history. Endorsing a genetic/familial etiology to BPD was positively correlated with perceived risk for mood disorders in children (rs = .3, p < 0.01) and active coping with BDP (r = .2, p < 0.01). Increased active coping (β = 0.4, p < 0.001) and dispositional optimism (β = 0.3, p < 0.001) were positively associated with better adaptation, while using denial coping was negatively associated with adaptation (β = -0.3, p < 0.001). The variables explained 55.2% of the variance in adaptation (F = 73.2, p < 0.001). Coping mediated the effect of perceived illness severity on adaptation.Conclusions: These data inform studies of interventions that extend beyond symptom management and aim to improve the psychological wellbeing of parents with BPD. Interventions targeted at illness perceptions and those aimed at enhancing coping should be studied for positive effects on adaptation. Parents with BPD may benefit from genetic counseling to promote active coping with their condition, and manage worry about perceived risk to their children. © 2013 Peay et al.; licensee BioMed Central Ltd.


PubMed | Korea University and National Human Genome Research Institute NHGRI
Type: Journal Article | Journal: Korean journal of pediatrics | Year: 2016

Familial Mediterranean fever (FMF) is the most common Mendelian autoinflammatory disease, characterized by uncontrolled activation of the innate immune system that manifests as recurrent brief fever and polyserositis (e.g., peritonitis, pleuritic, and arthritis). FMF is caused by autosomal recessive mutations of the Mediterranean fever gene,

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