Biomedical subjects

Jennifer A Smith

Publications and source records attributed to Jennifer A Smith.

At least 19 recordsLinked to original sources

PubMed2025

Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants.

BACKGROUND AND AIMS: Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. METHODS: We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 % of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels. RESULTS: The one-degree of freedom variant-sleep interaction test identified 10 novel loci (Pint<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature. CONCLUSIONS: Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.

Humans↗

PubMed2025

Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.

BACKGROUND: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability. RESULTS: Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246 K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86 K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate. CONCLUSIONS: This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.

Humans↗

PubMed2025

Epigenetic mechanisms underlying variation of IL-6, a well-established inflammation biomarker and risk factor for cardiovascular disease.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, yet the underlying molecular mechanisms remain less understood. Chronic low-grade inflammation is a complex immune response contributing to the pathophysiology of cardiovascular disease. This response is signaled in part by interleukin-6 (IL-6), a pleiotropic, pro-inflammatory cytokine. Phenotypic variance in circulating IL-6 level may be explained in part by DNA methylation which is increasingly being associated with cardiovascular effects. METHODS: In this study we evaluated methylated DNA (CpG sites) associated with blood IL-6 levels across ∼4,400 ancestrally diverse individuals (81 % self-reported White; 9 % Black or African American, 8 % Hispanic or Latino/a, and 2 % Chinese American). RESULTS: We identified 178 CpG sites associated with IL-6 (p<0.05/∼395,000). Among the sites, cg04437762 is located within the transcription unit of IL6R, a current therapeutic target for inflammatory disease, and cg26692003 and cg00464927 were significant for IL6 and IL6ST trans-CpG-gene transcripts. Functional gene expression downstream of methylation identified cellular response to IL-6 and B-cell regulation and activation pathways. Four genes were linked with both a genetic component of cardiovascular disease and an IL-6 associated CpG site. Three CpG sites identified through Mendelian randomization analyses supported inference of a causal effect on IL-6 levels, including the LYN gene that regulates immune cell signaling and has been previously associated with atherosclerosis. CONCLUSIONS: Overall, we identified several novel IL-6-CpG sites and downstream pathways affected by methylation. Follow-up functional studies including the regulation of IL-6 would complement current knowledge of CVD pathophysiology and potential therapeutic targets.

Humans↗

PubMed2025

Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.

BACKGROUND: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear. METHOD AND RESULTS: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome-wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E-09, odds ratio=1.34). The sliding window-based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E-10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits. CONCLUSIONS: Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.

Humans↗

PubMed2024

The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.

Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called "expected PRS" (ePRS), the expected value of a PRS based on one's global or local admixture patterns. We further define the "residual PRS" (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. Similarly, we applied the ePRS framework to six cardiovascular-related traits in the All of Us dataset, and the results are consistent with those from the TOPMed analysis. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.

Journal Article↗

PubMed2024

Association analysis between an epigenetic alcohol risk score and blood pressure.

BACKGROUND: Epigenome-wide association studies have identified multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. This study aimed to test the hypothesis that an alcohol consumption epigenetic risk score (ERS) is associated with blood pressure (BP) traits. RESULTS: We implemented an ERS based on a previously reported epigenetic signature of 144 alcohol-associated CpGs in meta-analysis of participants of European ancestry. We found a one-unit increment of ERS was associated with eleven drinks of alcohol consumed per day, on average, across several cohorts (p < 0.0001). We examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with BP levels, i.e., a one-unit increase in ERS was associated with 0.74 mm Hg (p = 0.002) higher SBP and 0.50 mm Hg (p = 0.0006) higher DBP, but not with HTN. Longitudinal analyses in FHS (n = 3260) and five independent external cohorts (n = 4021) showed that the baseline ERS was not associated with a change in BP over time or with incident HTN. CONCLUSIONS: Our findings demonstrate that the ERS has potential clinical utility in assessing lifestyle factors related to cardiovascular risk, especially when self-reported behavioral data (e.g., alcohol consumption) are unreliable or unavailable.

Humans↗

PubMed2024

Rare variant contribution to the heritability of coronary artery disease.

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Humans↗

PubMed2024

The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1), and one locus associated with a sex-associated mutation pathway (SRGAP2C). We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

Journal Article↗

PubMed2024

Aire mediates tolerance to insulin through thymic trimming of high-affinity T cell clones.

Insulin is a central autoantigen in the pathogenesis of T1D, and thymic epithelial cell expression of insulin under the control of the Autoimmune Regulator (Aire) is thought to be a key component of maintaining tolerance to insulin. In spite of this general working model, direct detection of this thymic selection on insulin-specific T cells has been somewhat elusive. Here, we used a combination of highly sensitive T cell receptor transgenic models for detecting thymic selection and sorting and sequencing of Insulin-specific CD4+ T cells from Aire-deficient mice as a strategy to further define their selection. This analysis revealed a number of unique t cell receptor (TCR) clones in Aire-deficient hosts with high affinity for insulin/major histocompatibility complex (MHC) ligands. We then modeled the thymic selection of one of these clones in Aire-deficient versus wild-type hosts and found that this model clone could escape thymic negative selection in the absence of thymic Aire. Together, these results suggest that thymic expression of insulin plays a key role in trimming and removing high-affinity insulin-specific T cells from the repertoire to help promote tolerance.

Animals↗

PubMed2006

The cellular protein P58IPK regulates influenza virus mRNA translation and replication through a PKR-mediated mechanism.

We previously hypothesized that efficient translation of influenza virus mRNA requires the recruitment of P58(IPK), the cellular inhibitor of PKR, an interferon-induced kinase that targets the eukaryotic translation initiation factor eIF2alpha. P58(IPK) also inhibits PERK, an eIF2alpha kinase that is localized in the endoplasmic reticulum (ER) and induced during ER stress. The ability of P58(IPK) to interact with and inhibit multiple eIF2alpha kinases suggests it is a critical regulator of both cellular and viral mRNA translation. In this study, we sought to definitively define the role of P58(IPK) during viral infection of mammalian cells. Using mouse embryo fibroblasts from P58(IPK-/-) mice, we demonstrated that the absence of P58(IPK) led to an increase in eIF2alpha phosphorylation and decreased influenza virus mRNA translation. The absence of P58(IPK) also resulted in decreased vesicular stomatitis virus replication but enhanced reovirus yields. In cells lacking the P58(IPK) target, PKR, the trends were reversed-eIF2alpha phosphorylation was decreased, and influenza virus mRNA translation was increased. Although P58(IPK) also inhibits PERK, the presence or absence of this kinase had little effect on influenza virus mRNA translation, despite reduced levels of eIF2alpha phosphorylation in cells lacking PERK. Finally, we showed that influenza virus protein synthesis and viral mRNA levels decrease in cells that express a constitutively active, nonphosphorylatable eIF2alpha. Taken together, our results support a model in which P58(IPK) regulates influenza virus mRNA translation and infection through a PKR-mediated mechanism which is independent of PERK.

Animals↗

PubMed2006

KGraph: a system for visualizing and evaluating complex genetic associations.

UNLABELLED: The KGraph is a data visualization system that has been developed to display the complex relationships between the univariate and bivariate associations among an outcome of interest, a set of covariates, and a set of genetic factors, such as single nucleotide polymorphisms (SNPs). It allows for easy viewing and interpretation of genetic associations, correlations among covariates and SNPs, and information about the replication and cross-validation of the associations. The KGraph allows the user to more easily investigate multicollinearity and confounding through visualization of the multidimensional correlation structure underlying genetic associations. It emphasizes gene-environment and gene-gene interaction, both important components of any genetic system that are often overlooked in association frameworks. AVAILABILITY: http://www.epidkardia.sph.umich.edu/software/kgrapher

Algorithms↗

PubMed2006

Reovirus induces and benefits from an integrated cellular stress response.

Following infection with most reovirus strains, viral protein synthesis is robust, even when cellular translation is inhibited. To gain further insight into pathways that regulate translation in reovirus-infected cells, we performed a comparative microarray analysis of cellular gene expression following infection with two strains of reovirus that inhibit host translation (clone 8 and clone 87) and one strain that does not (Dearing). Infection with clone 8 and clone 87 significantly increased the expression of cellular genes characteristic of stress responses, including the integrated stress response. Infection with these same strains decreased transcript and protein levels of P58(IPK), the cellular inhibitor of the eukaryotic initiation factor 2alpha (eIF2alpha) kinases PKR and PERK. Since infection with host shutoff-inducing strains of reovirus impacted cellular pathways that control eIF2alpha phosphorylation and unphosphorylated eIF2alpha is required for translation initiation, we examined reovirus replication in a variety of cell lines with mutations that impact eIF2alpha phosphorylation. Our results revealed that reovirus replication is more efficient in the presence of eIF2alpha kinases and phosphorylatable eIF2alpha. When eIF2alpha is phosphorylated, it promotes the synthesis of ATF4, a transcription factor that controls cellular recovery from stress. We found that the presence of this transcription factor increased reovirus yields 10- to 100-fold. eIF2alpha phosphorylation also led to the formation of stress granules in reovirus-infected cells. Based on these results, we hypothesize that eIF2alpha phosphorylation facilitates reovirus replication in two ways-first, by inducing ATF4 synthesis, and second, by creating an environment that places abundant reovirus transcripts at a competitive advantage for limited translational components.

Activating Transcription Factor 4↗

PubMed2005

Expression of a dromedary heavy chain-only antibody and B cell development in the mouse.

In mature B cells of mice and most mammals, cellular release of single H chain Abs without L chains is prevented by H chain association with Ig-specific chaperons in the endoplasmic reticulum. In precursor B cells, however, surface expression of mu-H chain in the absence of surrogate and conventional L chain has been identified. Despite this, Ag-specific single H chain Ig repertoires, using mu-, gamma-, epsilon-, or alpha-H chains found in conventional Abs, are not produced. Moreover, removal of H chain or, separately, L chain (kappa/lambda) locus core sequences by gene targeting has prevented B cell development. In contrast, H chain-only Abs are produced abundantly in Camelidae as H2 IgG without the C(H)1 domain. To test whether H chain Abs can be produced in mice, and to investigate how their expression affects B cell development, we introduced a rearranged dromedary gamma2a H chain into the mouse germline. The dromedary transgene was expressed as a naturally occurring Ag-specific disulphide-linked homodimer, which showed that B cell development can be instigated by expression of single H chains without L chains. Lymphocyte development and B cell proliferation was accomplished despite the absence of L chain from the BCR complex. Endogenous Ig could not be detected, although V(D)J recombination and IgH/L transcription was unaltered. Furthermore, crossing the dromedary H chain mice with mice devoid of all C genes demonstrated without a doubt that a H chain-only Ab can facilitate B cell development independent of endogenous Ig expression, such as mu- or delta-H chain, at early developmental stages.

Animals↗

PubMed2005

Terminating the provider-patient relationship.

Explore the source record for details and available documents.

Humans↗

PubMed2005

Involvement of the interferon-regulated antiviral proteins PKR and RNase L in reovirus-induced shutoff of cellular translation.

Cellular translation is inhibited following infection with most strains of reovirus, but the mechanisms responsible for this phenomenon remain to be elucidated. The extent of host shutoff varies in a strain-dependent manner; infection with the majority of strains leads to strong host shutoff, while infection with strain Dearing results in minimal inhibition of cellular translation. A genetic study with reassortant viruses and subsequent biochemical analyses led to the hypothesis that the interferon-induced, double-stranded RNA-activated protein kinase, PKR, is responsible for reovirus-induced host shutoff. To directly determine whether PKR is responsible for reovirus-induced host shutoff, we used a panel of reovirus strains and mouse embryo fibroblasts derived from knockout mice. This approach revealed that PKR contributes to but is not wholly responsible for reovirus-induced host shutoff. Studies with cells lacking RNase L, the endoribonuclease component of the interferon-regulated 2',5'-oligoadenylate synthetase-RNase L system, demonstrated that RNase L also down-regulates cellular protein synthesis in reovirus-infected cells. In many viral systems, PKR and RNase L have well-characterized antiviral functions. An analysis of reovirus replication in cells lacking these molecules indicated that, while they contributed to host shutoff, neither PKR nor RNase L exerted an antiviral effect on reovirus growth. In fact, some strains of reovirus replicated more efficiently in the presence of PKR and RNase L than in their absence. Data presented in this report illustrate that the inhibition of cellular translation following reovirus infection is complex and involves multiple interferon-regulated gene products. In addition, our results suggest that reovirus has evolved effective mechanisms to avoid the actions of the interferon-stimulated antiviral pathways that include PKR and RNase L and may even benefit from their expression.

Animals↗

PubMed2005

Population pharmacokinetics of motexafin gadolinium in adults with brain metastases or glioblastoma multiforme.

The purpose of this study was to determine clinical variables affecting motexafin gadolinium (MGd) pharmacokinetics. Motexafin gadolinium (4-5.3 mg/kg/d) was administered intravenously for 2 to 6.5 weeks. Plasma samples from 3 clinical trials were analyzed for MGd using liquid chromatography/mass spectroscopy. The pooled data were analyzed using population pharmacokinetic (POP-PK) methods. The POP-PK model included 243 patients (1575 samples). Clearance (CL) was 14% lower in women, but weight-normalized clearance was only 5% lower in women. Clearance decreased with increasing alkaline phosphatase, increasing age, and decreasing hemoglobin. Administration of phenytoin increased CL by approximately 30%. Central compartment volume (V1) was 21% lower in women and increased with increasing serum creatinine. For all covariates, except sex and phenytoin, the predicted change in CL or V1 (5th and 95th percentiles) varied < or =13% from the population mean CL or V1 estimate. It was concluded that a 3-compartment, open, POP-PK model predicts small but significant effects of age, sex, alkaline phosphatase, hemoglobin, serum creatinine, and phenytoin on MGd pharmacokinetics.

Adult↗

PubMed2004

Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial.

PURPOSE: To report the neurocognitive findings in a phase III randomized trial evaluating survival and neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). PATIENTS AND METHODS: Patients were randomly assigned to receive WBRT 30 Gy in 10 fractions with or without MGd 5 mg/kg/d. Monthly neurocognitive testing for memory, executive function, and fine motor skill was performed. RESULTS: Four hundred one patients were enrolled (251 with non-small-cell lung cancer, 75 with breast cancer, and 75 with other cancers); 90.5% patients had impairment of one or more neurocognitive tests at baseline. Neurocognitive test scores of memory, fine motor speed, executive function, and global neurocognitive impairment at baseline were correlated with brain tumor volume and predictive of survival. There was no statistically significant difference between treatment arms in time to neurocognitive progression. Patients with lung cancer (but not other types of cancer) who were treated with MGd tended to have improved memory and executive function (P =.062) and improved neurologic function as assessed by a blinded events review committee (P =.048). CONCLUSION: Neurocognitive tests are a relatively sensitive measure of brain functioning; a combination of tumor prognostic variables and brain function assessments seems to predict survival better than tumor variables alone. Although the addition of MGd to WBRT did not produce a significant overall improvement between treatment arms, MGd may improve memory and executive function and prolong time to neurocognitive and neurologic progression in patients with brain metastases from lung cancer.

Adult↗

PubMed2004

Silencing of the immunoglobulin heavy chain locus by removal of all eight constant-region genes in a 200-kb region.

Silencing or removal of individual C (constant)-region genes and/or adjacent control sequences did not generate fully deficient Ig (immunoglobulin)- mice. A reason is that different C genes share many functional tasks and most importantly are individually capable of ensuring lymphocyte differentiation. Nevertheless, incomplete arrests in B-cell development were found, most pronounced at the onset of H-chain expression. Here we show that removal of 200 kb accommodating all C genes, Cmu-Cdelta-Cgamma3-Cgamma1-Cgamma2b-Cgamma2a-Cepsilon-Calpha, stops antibody production. For this two loxP targeting constructs were introduced into the most 5' C gene and the distal alpha 3' enhancer. Cre-loxP-mediated in vivo deletion was accompanied by extensive germ-line mosaicism, which could be separated by breeding. Homozygous C-gene deletion mice did not express Ig H or L chains and flow cytometry revealed a complete block in B-cell development. However, C-gene removal did not affect DNA rearrangement processes following locus activation, as recombination efficacy appears to be similar to what is found in normal mice.

Animals↗