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"Floyd, James"
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Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis
Carl Anderson and colleagues report a genome-wide association study identifying 13 new susceptibility loci for primary biliary cirrhosis, a chronic autoimmune liver disease.
In addition to the
HLA
locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of
P
< 5 × 10
−8
) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include
STAT4
,
DENND1B
,
CD80
,
IL7R
,
CXCR5
,
TNFRSF1A
,
CLEC16A
and
NFKB1
. This study has considerably expanded our knowledge of the genetic architecture of PBC.
Journal Article
Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease
Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators
DNMT3A
and
TET2
are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that
DNMT3A
and
TET2
CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.
Clonal hematopoiesis, often caused by mutations in
DNMT3A
and
TET2,
is associated with blood cancer and coronary artery disease. Here, the authors conduct an epigenome-wide association study, finding that clonal hematopoiesis caused by
DNMT3A
vs.
TET2
mutations has directionally opposing changes in DNA methylation profiles, with both promoting stem cell self-renewal.
Journal Article
Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs
Background
Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.
Methods
To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (
N
= 533) and Framingham Heart Study (FHS) (
N
= 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of
TFAM
, a regulator of mtDNA replication, via CRISPR-Cas9.
Results
Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (
P
< 5 × 10
− 8
). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (
P
< 5 × 10
− 8
). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the “neuroactive ligand receptor interaction” KEGG pathway was found to be highly overrepresented in the ARIC cohort (
P
= 5.24 × 10
− 12
), as well as the
TFAM
knockout methylation (
P =
4.41 × 10
− 4
) and expression (
P =
4.30 × 10
− 4
) studies.
Conclusions
These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.
Journal Article
Centerbrook. 4
\"In these pages we partners of Centerbrook (Jeff Riley, Mark Simon, Chad Floyd, and Jim Childress) show our work of the last 15 years ... Our first three books presented us more or less as a collective, but here we present material by partner, each of us devoting 96 pages to photographs and drawings of projects accompanied by candid explanations of our inspirations, references, and design goals.\"--Page vi.
Book
Metformin and Sulfonylurea Use and Risk of Incident Dementia
To compare incident dementia risk among patients who initiated treatment with metformin or sulfonylurea in Veterans Health Affairs (VHA) patients with replication in Kaiser Permanente Washington (KPW) patients to determine whether first-choice antidiabetic medications are associated with reduced risk of dementia.
Cohorts contained 75,187 VHA patients and 10,866 KPW patients, 50 years and older, who initiated monotherapy with metformin or sulfonylurea. Patients were free of dementia diagnoses and any diabetes treatment for 2 years before cohort entry. Variables were extracted from electronic health data from VHA (1999-2015) and KPW (1996-2015), which included diagnosis codes, pharmacy data, laboratory values, and demographic characteristics. Propensity scores and inverse probability of treatment weighting controlled for confounding.
Veterans Health Affairs patients were 60.8±6.8 years of age on average, and KPW patients were 63.1±9.5 years of age. In the VHA sample, 72,769 (96.8%) were male; and in the KPW sample, 5480 (50.4%). After adjusting for confounding, metformin initiation was associated with a significantly (P=.02) lower risk of dementia in VHA (hazard ratio, 0.9; 95% CI, 0.9-1.0), with a similar point estimate in KPW (hazard ratio, 0.9; 95% CI, 0.7-1.1). Metformin was not associated with dementia risk in patients 75 years and older.
Existing epidemiological studies of metformin and incident dementia have been inconsistent. Using a similar study design in 2 patient populations that differed in clinical and demographic characteristics, our results provide robust evidence that metformin use is associated with a modestly lower risk of incident dementia.
Journal Article
Enhancing Obstetric Healthcare Providers’ Knowledge of Black Maternal Mental Health: A Feasibility Study
Despite guidelines for screening and treating perinatal mood and anxiety disorders (PMADs), systemic issues and clinician biases often result in unmet mental health needs in Black women. This study assessed the feasibility and impact of comprehensive PMAD training on obstetric healthcare providers’ attitudes, knowledge, and implicit racial biases. We conducted a feasibility study with two cohorts of healthcare providers who received either in-person or virtual training. The training focused on PMADs, implicit bias, and culturally responsive care. Participants completed pre- and post-training assessments measuring attitudes, knowledge, empathy, and implicit racial biases. Both training modalities showed trends towards improved PMAD screening attitudes and empathy, with significant increases in beliefs about treatment efficacy. Implicit bias scores approached significance, showing a shift toward fewer participants with racial preferences. However, there was an unexplained increase in preference for White over Black post training. The training improved healthcare providers’ readiness to screen for PMADs and enhanced their understanding of PMADs. However, the persistence of implicit biases highlights the need for ongoing, sustained interventions to address deeply rooted biases. Future research should incorporate continuous learning strategies and link training to healthcare outcomes for minoritized communities.
Journal Article
Association of liver related biomarkers with incident cardiovascular disease and all-cause mortality in the Hispanic community health study/study of Latinos (HCHS/SOL), a population-based cohort study
Background
Metabolic dysfunction-associated steatotic liver disease (MASLD) increases risk of cardiovascular disease (CVD). Despite the high prevalence of MASLD among Hispanic populations, there is a scarcity of research on the associations between non-invasive markers of liver disease and incident CVD and all-cause mortality. In this study we investigated the association of liver related biomarkers with CVD events and all-cause mortality in a population based Hispanic/Latino cohort.
Methods
We included 15,216 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18–74 years with no pre-existing CVD. The composite outcome combined incident CVD and all-cause mortality. Having “elevated ALT/AST” was defined as ALT > 40 IU/mL or AST > 37 IU/mL for males, and ALT or AST > 31 IU/mL for females. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) relating our composite outcome to elevated ALT/AST, FIB-4 and MASLD. Using interaction terms, we assessed whether the relationship between elevated ALT/AST and the composite outcome differed by MASLD status.
Results
The study population was 40 years old on average, 52.7% female and had 740 CVD or all-cause mortality events. Elevated FIB-4 had the strongest association with incident CVD or all-cause mortality (comparing FIB-4 > 2.67 versus ≤ 2.67, HR:3.47; CI:2.34–5.14). Elevated AST was found to be associated with incident CVD or all-cause mortality (HR:1.53; CI:1.14–2.05). MASLD was not associated with incident CVD or all-cause mortality (HR:1.14; CI: 0.94–1.40), but it was associated with incident CVD alone (HR:1.69; CI:1.19–2.39). The relationship between elevated ALT/AST and incident or all-cause mortality was modified by MASLD, such that the strongest association between elevated ALT/AST and incident CVD or all-cause mortality was in the absence of MASLD (HR:1.95; CI:1.20–3.18).
Conclusions
Among Hispanic adults FIB-4 was strongly associated with CVD or all-cause mortality and among persons without MASLD, elevated ALT/AST were associated with CVD or all-cause mortality.
Journal Article