👤 Shaun G Goodman

Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) reflect pro-inflammatory properties of Lp(a) (lipoprotein(a)). The effect of OxPL-apoB on major adverse cardiovascular events (MACE) in patients with acute coronary syndrome in recent the era is not known. OxPL-apoB levels and Lp(a) were measured in 11 630 participants before and 5185 participants 4 months after randomization to alirocumab or placebo in the ODYSSEY OUTCOMES trial. Proportional hazards models adjusted for baseline covariates evaluated associations between log Participants were followed for a median 2.9 years; the median age was 58 years, and 23.9% were female. Alirocumab reduced median placebo-adjusted OxPL-apoB by 13.0% and Lp(a) by 26.2% (both In patients with recent acute coronary syndrome receiving optimized statin treatment, elevated OxPL-apoB levels predicted MACEs, a relationship abrogated by alirocumab. The interaction of OxPL-apoB and Lp(a) in the placebo group indicates that OxPL-apoB independently predicts MACEs when Lp(a) levels are relatively low. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT001747 and NCT01663402. Show less

Residual cardiovascular risk remains, despite achieving low-density lipoprotein cholesterol targets with high-intensity statins. Traditional risk scores are suboptimal. This study evaluated the prognostic utility of a 9-plex apolipoprotein panel in recent patients with acute coronary syndrome on statins and its role in predicting treatment benefit by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, enabling precision medicine. Baseline serum samples from 11 843 participants in the ODYSSEY OUTCOMES trial (https://www.clinicaltrials.gov; Unique identifier: NCT01663402) were analyzed using mass spectrometry to measure Apo(a), ApoA-I, ApoA-II, ApoA-IV, ApoB, ApoC-I, ApoC-II, ApoC-III, and ApoE. Using logistic regression, probabilities of major adverse cardiovascular events (MACE) and all-cause death over a median follow-up of 2.9 years were estimated based on baseline apolipoproteins and lipid concentrations. Clinical performance was assessed by comparing the area under the curve (AUC) of 3 models: the apolipoprotein panel, the lipid panel (total cholesterol, high-density lipoprotein cholesterol, and triglycerides), and a combination. In addition, prediction models estimating the treatment benefit of alirocumab by the apolipoprotein panel were developed. The prognostic performance of the apolipoprotein panel for MACE showed an AUC (95% CI) of 0.648 (0.626-0.670), compared with 0.579 (0.557-0.602) for the lipid panel. For all-cause death, the apolipoprotein panel had an AUC of 0.699 (0.664-0.733), while the lipid panel had an AUC of 0.599 (0.564-0.635). Adding the apolipoprotein panel significantly improved the performance of the conventional lipid panel ( A multiplex apolipoprotein panel led to better prediction of MACE and all-cause death, beyond lipids, in patients with postacute coronary syndrome on optimized statin therapy. The panel also predicts the treatment benefit of alirocumab. Further validation of this approach is now needed, and if confirmed and improved, it could lead to better disease prediction and management in the future. Show less

Apolipoprotein (Apo) C3 has been associated with incident coronary heart disease and major adverse cardiovascular events (MACE). Whether ApoC3 levels predict risk in patients with acute coronary syndrome (ACS) on optimized statin treatment is unknown. ApoC3 was measured by mass spectrometry at baseline (n=11,956) and after 4 months' treatment (M4; n=11 176) with alirocumab or placebo in the ODYSSEY OUTCOMES trial. Patients with fasting triglycerides >400 mg/dL were excluded. The association of baseline ApoC3 with risk of MACE or death was assessed in post hoc adjusted Cox regression models and spline analyses adjusted for treatment and ApoB. In adjusted models in the alirocumab group we determined association of ApoC3 change from baseline to M4 with subsequent risk of MACE and death. Median (Q1, Q3) baseline ApoC3 concentration was 85 (65, 113) mg/L. With adjustment for ApoB, baseline ApoC3 showed no clinically meaningful relationship to risk of MACE or death in spline analyses and no association with MACE (P=0.89) or death (P=0.70) in Cox regression analyses. Alirocumab reduced ApoC3 modestly by median -10 (-27, -5) mg/L (P<0.0001) and reduced MACE (10.1% vs 12.1%; P=0.0006) and death (3.5% vs 4.2%; P=0.045) versus placebo. However, the change in ApoC3 on alirocumab did not predict subsequent MACE or death. In patients with recent ACS on optimized statins without severe hypertriglyceridemia, neither baseline ApoC3 (accounting for ApoB) nor ApoC3 change with alirocumab predicted MACE or death. It is uncertain whether targeted therapies producing larger reductions in ApoC3 from higher baseline levels will affect cardiovascular risk. Show less

Recent introduction of new steatotic liver disease categorizations has necessitated updated epidemiologic studies. Specifically, recognition of (1) "MetALD" defined as where metabolic dysfunction-associated steatotic liver disease (MASLD) overlaps with alcohol use and (2) alcohol-related liver disease (ALD) without cardiometabolic risk factors (CMRFs) creates new clinical phenotypes with undefined prevalence. We conducted a cross-sectional multicenter analysis of liver disease associated with alcohol use (ALD and MetALD). We included adults with an International Classification of Diseases (ICD) diagnosis of ALD or both metabolic dysfunction associated liver disease and alcohol use disorder assigned from 1/1/2000-1/1/2024. Among 4057 patients, only 118 (2.9%) did not have any CMRF ("pure ALD"). Compared to patients with CMRF, patients with pure ALD were more commonly female (56% [0 CRMF] vs. 48%, 45%, 38%, and 42% [1, 2, 3, and 4 CMRFs, respectively]; ALD without diagnosed metabolic disease is uncommon and associated with higher rates of cirrhosis, HCC, and all-cause mortality than ALD with concurrent CMRF. Having a BMI measuring 25-30 kg/m Show less

Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD. Show less

Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD Show less

Pinpointing genetic impacts on DNA methylation can improve our understanding of pathways that underlie gene regulation and disease risk. We report heritability and methylation quantitative trait locus (meQTL) analysis at 724,499 CpGs profiled with the Illumina Infinium MethylationEPIC array in 2358 blood samples from three UK cohorts. Methylation levels at 34.2% of CpGs are affected by SNPs, and 98% of effects are cis-acting or within 1 Mbp of the tested CpG. Our results are consistent with meQTL analyses based on the former Illumina Infinium HumanMethylation450 array. Both SNPs and CpGs with meQTLs are overrepresented in enhancers, which have improved coverage on this platform compared to previous approaches. Co-localisation analyses across genetic effects on DNA methylation and 56 human traits identify 1520 co-localisations across 1325 unique CpGs and 34 phenotypes, including in disease-relevant genes, such as USP1 and DOCK7 (total cholesterol levels), and ICOSLG (inflammatory bowel disease). Enrichment analysis of meQTLs and integration with expression QTLs give insights into mechanisms underlying cis-meQTLs (e.g. through disruption of transcription factor binding sites for CTCF and SMC3) and trans-meQTLs (e.g. through regulating the expression of ACD and SENP7 which can modulate DNA methylation at distal sites). Our findings improve the characterisation of the mechanisms underlying DNA methylation variability and are informative for prioritisation of GWAS variants for functional follow-ups. The MeQTL EPIC Database and viewer are available online at https://epicmeqtl.kcl.ac.uk . Show less

The ε4 allele of the apolipoprotein E (APOE) gene and lower apolipoprotein E (apoE) protein levels in plasma are risk factors for Alzheimer disease, but the underlying biological mechanisms are not fully understood. Half of plasma apoE circulates on high-density lipoproteins (HDLs). Higher apoE levels in plasma HDL were previously found to be associated with lower coronary heart disease risk, but the coexistence of another apolipoprotein, apoC3, modified this lower risk. To investigate associations between the presence of apoE in different lipoproteins with cognitive function, particularly the risk of dementia. This prospective case-cohort study embedded in the Ginkgo Evaluation of Memory Study (2000-2008) analyzed data from 1351 community-dwelling participants 74 years and older. Of this group, 995 participants were free of dementia at baseline (recruited from September 2000 to June 2002) and 521 participants were diagnosed with incident dementia during follow-up until 2008. Data analysis was performed from January 2018 to December 2019. Enzyme-linked immunosorbent assay-measured concentration of apoE in whole plasma, HDL-depleted plasma (non-HDL), HDL, and HDL subspecies that contain or lack apoC3 or apoJ. Adjusted hazard ratios for risk of dementia and Alzheimer disease during follow-up and adjusted differences (β coefficients) in Alzheimer Disease Assessment-Cognitive Subscale (ADAS-cog) and Modified Mini-Mental State Examination scores at baseline. Among 1351 participants, the median (interquartile range) age was 78 (76-81) years; 639 (47.3%) were women. The median (interquartile range) follow-up time was 5.9 (3.7-6.5) years. Higher whole plasma apoE levels and higher apoE levels in HDL were associated with better cognitive function assessed by ADAS-cog (whole plasma, β coefficient, -0.15; 95% CI, -0.24 to -0.06; HDL, β coefficient, -0.20; 95% CI, -0.30 to -0.10) but were unassociated with dementia or Alzheimer disease risk. When separated by apoC3, a higher apoE level in HDL that lacks apoC3 was associated with better cognitive function (ADAS-cog per SD: β coefficient, 0.17; 95% CI, -0.27 to -0.07; Modified Mini-Mental State Examination score per SD: β coefficient, 0.25; 95% CI, 0.07 to 0.42) and lower risk of dementia (hazard ratio per SD, 0.86; 95% CI, 0.76 to 0.99). In contrast, apoE levels in HDL that contains apoC3 were unassociated with any of these outcomes. In a prospective cohort of older adults with rigorous follow-up of dementia, the apoE level in HDL that lacked apoC3 was associated with better cognitive function and lower dementia risk. This finding suggests that the cardioprotective associations of this novel lipoprotein extend to dementia. Show less

Whether HDL is associated with dementia risk is unclear. In addition to apoA1, other apolipoproteins are found in HDL, creating subspecies of HDL that may have distinct metabolic properties. We measured apoA1, apoC3, and apoJ levels in plasma and apoA1 levels in HDL that contains or lacks apoE, apoJ, or apoC3 using a modified sandwich ELISA in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 995 randomly selected participants and 521 participants who developed dementia during a mean of 5.1 years of follow-up. The level of total apoA1 was not significantly related to dementia risk, regardless of the coexistence of apoC3, apoJ, or apoE. Higher levels of total plasma apoC3 were associated with better cognitive function at baseline (difference in Modified Mini-Mental State Examination scores tertile 3 vs. tertile 1: 0.60; 95% CI: 0.23, 0.98) and a lower dementia risk (adjusted hazard ratio tertile 3 vs. tertile 1: 0.73; 95% CI: 0.55, 0.96). Plasma concentrations of apoA1 in HDL and its apolipoprotein-defined subspecies were not associated with cognitive function at baseline or with the risk of dementia during follow-up. Similar studies in other populations are required to better understand the association between apoC3 and Alzheimer's disease pathology. Show less

To evaluate cardiovascular (CV) outcomes in outpatients with coronary artery disease (CAD) living alone compared with those living with others. The prospeCtive observational LongitudinAl RegIstry oF patients with stable coronarY artery disease (CLARIFY) included outpatients with stable CAD. CLARIFY enrolled participants in 45 countries from November 2009 to July 2010, with 5 years of follow-up. Living arrangement was documented at baseline. The primary outcome was a composite of major adverse cardiovascular events (MACEs) defined as CV death, myocardial infarction (MI) and stroke. Among 32 367 patients, 3648 patients were living alone (11.3%). After multivariate adjustment, there were no residual differences in MACE among patients living alone compared with those living with others (HR 1.04, 95% CI 0.92 to 1.18, p=0.52); however, there was significant heterogeneity in the exposure effect by sex (P Living alone was not associated with an independent increase in MACE, although significant sex-based differences were apparent. Men living alone may have a worse prognosis from CV disease than women; further analyses are needed to elucidate the mechanisms underlying this difference. ISRCTN43070564. Show less

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations. Show less

Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression. Show less

We report the case of an 11-month-old patient with a clinical diagnosis of infantile acute lymphoblastic leukemia and an MLL (11q23) rearrangement in 69% of nuclei, revealed with interphase fluorescence in situ hybridization (FISH). Routine chromosome analysis of the bone marrow showed a very subtle rearrangement involving the short arm of chromosome 10 and the long arm of chromosome 11 in the abnormal cells. To clarify the nature of this rearrangement, we hybridized the MLL break-apart probe to previously G-banded slides. The rearrangement was interpreted as a small inversion within the band 11q23, separating the 5' MLL from the 3' MLL region. This segment on the long arm of chromosome 11 containing the rearranged MLL locus was either inserted in or translocated to the short arm of chromosome 10 at approximately band 10p12. The inversion affecting MLL may have followed insertion or preceded it. Molecular characterization of this rearrangement was not possible, due to limited sample material. There have been previous reports of rearrangements of MLL with the MLLT10 (alias AF10) gene locus at 10p12, including an interstitial inverted insertion of 11q13q23 in one case and insertion of 11q14q23 at 10p12 in another. These both resulted in a large derivative chromosome 10 and transcription of an MLL/MLLT10 fusion product. To our knowledge, the novel and cryptic rearrangement detected in our patient has not been described previously. A follow-up study of the patient's bone marrow at the end of induction therapy showed no morphologic evidence of residual leukemia and both FISH and chromosome analyses were normal. Show less