Citations

Abstract With aging, somatic mutations in hematopoietic stem and progenitor cells (HSPC) can give rise to clonal hematopoiesis of indeterminate potential (CHIP), a premalignant state associated with diverse age-related diseases. Here we report the largest multi-ancestry genome-wide analysis of CHIP to date (N = 1,018,305), including individuals of African (N = 85,978), Admixed American (N = 191,371), East Asian (N = 13,532), European (N = 694,015), and South Asian (N = 13,193) ancestry. Multi-ancestry meta-analyses identified 72 genome-wide significant loci, including 44 novel associations implicating genes such as AFF1 , ATF7IP , ATP8B4 , BCL2 , CEBPA , CYRIA , DNM2 , ELF1 , NKX2-3 , PIK3CB , PRDM16 , RPN1 , TERC , and TRIM4 . Notably, variants at MECOM and PHF20L1 showed opposite allelic effects between DNMT3A - and non- DNMT3A -driven CHIP, highlighting driver-specific germline influences. Implicated loci converge on pathways regulating telomere maintenance, cell-cycle control, hematopoietic transcription, DNA damage response and immune signaling. These findings support a model in which germline variation both expands the HSPC pool and biases clonal selection in a driver-dependent manner, providing a mechanistic basis for inter-individual heterogeneity in CHIP. Phenome-wide association analyses further linked CHIP to hematologic, neoplastic, and circulatory traits, with enrichment across hematopoietic and non-hematopoietic cell types. Together, this work expands the genomic and phenomic landscape of CHIP and reveals germline–somatic interactions that shape clonal evolution during aging.

AbstractPeripheral nerve injury‐induced spinal microglial proliferation plays a pivotal role in neuropathic pain. So far, key intracellular druggable molecules involved in this process are not identified. The nuclear factor of activated T‐cells (NFAT1) is a master regulator of immune cell proliferation. Whether and how NFAT1 modulates spinal microglial proliferation during neuropathic pain remain unknown. Here it is reported that NFAT1 is persistently upregulated in microglia after spinal nerve ligation (SNL), which is regulated by TET2‐mediated DNA demethylation. Global or microglia‐specific deletion of Nfat1 attenuates SNL‐induced pain and decreases excitatory synaptic transmission of lamina II neurons. Furthermore, deletion of Nfat1 decreases microglial proliferation and the expression of multiple microglia‐related genes, such as cytokines, transmembrane signaling receptors, and transcription factors. Particularly, SNL increases the binding of NFAT1 with the promoter of Itgam, Tnf, Il‐1b, and c‐Myc in the spinal cord. Microglia‐specific overexpression of c‐MYC induces pain hypersensitivity and microglial proliferation. Finally, inhibiting NFAT1 and c‐MYC by intrathecal injection of inhibitor or siRNA alleviates SNL‐induced neuropathic pain. Collectively, NFAT1 is a hub transcription factor that regulates microglial proliferation via c‐MYC and guides the expression of the activated microglia genome. Thus, NFAT1 may be an effective target for treating neuropathic pain.

AbstractBackgroundTwo studies that examined the interaction between HLA‐DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions.ObjectiveTo perform a large‐scale independent replication of the HLA‐DRB1 × smoking interaction.MethodsWe genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA‐DRB1.ResultsAt the amino acid level, a valine at position 11 (V11) in HLA‐DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59–0.93, PInteraction = 0.028). In silico predictions of the influence of V11 and smoking‐induced modifications of α‐synuclein on binding affinity showed findings consistent with this interaction pattern.ConclusionsDespite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

PurposeTo evaluate multicenter repeatability and reproducibility of T1 and T2 maps generated using MR fingerprinting (MRF) in the International Society for Magnetic Resonance in Medicine/National Institute of Standards and Technology MRI system phantom and in prostatic tissues.MethodsMRF experiments were performed on 5 different 3 Tesla MRI scanners at 3 different institutions: University Hospitals Cleveland Medical Center (Cleveland, OH), Brigham and Women's Hospital (Boston, MA) in the United States, and Diagnosticos da America (Rio de Janeiro, RJ) in Brazil. Raw MRF data were reconstructed using a Gadgetron‐based MRF online reconstruction pipeline to yield quantitative T1 and T2 maps. The repeatability of T1 and T2 values over 6 measurements in the International Society for Magnetic Resonance in Medicine/National Institute of Standards and Technology MRI system phantom was assessed to demonstrate intrascanner variation. The reproducibility between the 4 clinical scanners was assessed to demonstrate interscanner variation. The same‐day test–retest normal prostate mean T1 and T2 values from peripheral zone and transitional zone were also compared using the intraclass correlation coefficient and Bland–Altman analysis.ResultsThe intrascanner variation of values measured using MRF was less than 2% for T1 and 4.7% for T2 for relaxation values, within the range of 307.7 to 2360 ms for T1 and 19.1 to 248.5 ms for T2. Interscanner measurements showed that the T1 variation was less than 4.9%, and T2 variation was less than 8.1% between multicenter scanners. Both T1 and T2 values in in vivo prostatic tissue demonstrated high test–retest reliability (intraclass correlation coefficient > 0.92) and strong linear correlation (R2 > 0.840).ConclusionProstate MRF measurements of T1 and T2 are repeatable and reproducible between MRI scanners at different centers on different continents for the above measurement ranges.

Abstract Introduction Late‐onset Alzheimer's disease (LOAD) is a complex neurodegenerative disease characterized by multiple progressive stages, glucose metabolic dysregulation, Alzheimer's disease (AD) pathology, and inexorable cognitive decline. Discovery of metabolic profiles unique to sex, apolipoprotein E ( APOE ) genotype, and stage of disease progression could provide critical insights for personalized LOAD medicine. Methods Sex‐ and APOE ‐specific metabolic networks were constructed based on changes in 127 metabolites of 656 serum samples from the Alzheimer's Disease Neuroimaging Initiative cohort. Results Application of an advanced analytical platform identified metabolic drivers and signatures clustered with sex and/or APOE ɛ4, establishing patient‐specific biomarkers predictive of disease state that significantly associated with cognitive function. Presence of the APOE ɛ4 shifts metabolic signatures to a phosphatidylcholine‐focused profile overriding sex‐specific differences in serum metabolites of AD patients. Discussion These findings provide an initial but critical step in developing a diagnostic platform for personalized medicine by integrating metabolomic profiling and cognitive assessments to identify targeted precision therapeutics for AD patient subgroups through computational network modeling.

Abstract Study Objectives Objective excessive daytime sleepiness (EDS) is associated with systemic inflammation and a higher risk of cardiometabolic morbidity in obstructive sleep apnea (OSA). We hypothesized that OSA with objective EDS is associated with higher levels of sympathetic nerve activity (SNA) when compared with self-reported EDS. We, therefore, examined the associations between objective and self-reported EDS with SNA in patients with OSA. Methods We studied 147 consecutive male patients with OSA from the institutional sleep clinic. Objective EDS and self-reported EDS were defined based on Multiple Sleep Latency Test (MSLT) latency ≤ 8 minutes and Epworth Sleepiness Scale (ESS) > 10, respectively. Twenty-four-hour urinary norepinephrine was used for assessing SNA. Blood pressure (BP) was measured both in the evening and in the morning. Results Twenty-four-hour urinary norepinephrine was significantly higher in patients with OSA with objective EDS compared with those without objective EDS (p = 0.034), whereas it was lower in patients with OSA with self-reported EDS compared with those without self-reported EDS (p = 0.038) after adjusting for confounders. Differences in the sympathetic drive were most striking in those with an objective but not self-reported EDS versus those with self-reported but not objective EDS (p = 0.002). Moreover, shorter MSLT latency was significantly associated with higher diastolic BP (β = −0.156, p = 0.049) but not systolic BP. No significant association between ESS scores and BP was observed. Conclusions Objective, but not self-reported EDS, is associated with increased SNA and diastolic BP among males with OSA, suggesting that objective EDS is a more severe phenotype of OSA that is accompanied by higher sympathetic drive, higher BP, and possibly greater cardiovascular morbidity and mortality.

Abstract Background and Aims Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. Approach and Results By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta‐Catenin with high Male predominance) is characterized by prominent β‐catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient‐derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. Conclusions Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.

Background: Over 9 million dual-eligible beneficiaries rely on both Medicare and Medicaid to obtain critical medical services. Medicaid serves as a safety net for low-income Medicare beneficiaries with limited assets; however, it is unknown whether dual-eligible patients have comparable outcomes for procedures to non-dual-eligible Medicare beneficiaries. We compared outcomes by dual-eligible status for patients undergoing carotid endarterectomy (CEA). Methods: We identified Medicare fee-for-service beneficiaries aged ≥65y who underwent CEA (ICD-9 38.12) from 2003-2010. Beneficiaries with ≥1m of Medicaid coverage were considered dual eligible. We fit mixed models with a random intercept for state and adjustment for demographics, comorbidities, and symptomatic status to assess the relationship between dual-eligible status and outcomes. Results: A total of 35,832 dual-eligible and 470,134 non-dual-eligible beneficiaries were hospitalized for CEA during the study period. The percentage of dual-eligible CEA patients decreased from 7.9% in 2003 to 6.7% in 2010. Dual eligibles were more likely to be younger, female, of nonwhite race, and living with comorbid conditions (e.g., heart failure, renal failure, diabetes) and symptomatic carotid disease. Dual eligibles had higher 30d composite outcomes including stroke (Table), but the associations with 1y stroke became nonsignificant from 2003-2010. Dual-eligible status was associated with higher 30d and 1y mortality after CEA throughout the study period. Conclusions: Dual-eligible Medicare-Medicaid beneficiaries had worse short-term stroke and mortality outcomes than other beneficiaries, even after adjustment for comorbidities. Our results indicate a need to understand factors contributing to poorer outcomes. Challenges include the split accountability between the two programs and the diverse sociodemographics, clinical characteristics, and generally poorer health of the patients.