Decoding triancestral origins, archaic introgression, and natural selection in the Japanese population by whole-genome sequencing.

We generated Japanese Encyclopedia of Whole-Genome/Exome Sequencing Library (JEWEL), a high-depth whole-genome sequencing dataset comprising 3256 individuals from across Japan. Analysis of JEWEL revealed genetic characteristics of the Japanese population that were not discernible using microarray data. First, rare variant-based analysis revealed an unprecedented fine-scale genetic structure. Together with population genetics analysis, the present-day Japanese can be decomposed into three ancestral components. Second, we identified unreported loss-of-function (LoF) variants and observed that for specific genes, LoF variants appeared to be restricted to a more limited set of transcripts than would be expected by chance, with PTPRD as a notable example. Third, we identified 44 archaic segments linked to complex traits, including a Denisovan-derived segment at NKX6-1 associated with type 2 diabetes. Most of these segments are specific to East Asians. Fourth, we identified candidate genetic loci under recent natural selection. Overall, our work provided insights into genetic characteristics of the Japanese population.

Modification of coronary artery disease clinical risk factors by coronary artery disease polygenic risk score.

BACKGROUND: The extent to which the relationships between clinical risk factors and coronary artery disease (CAD) are altered by CAD polygenic risk score (PRS) is not well understood. Here, we determine whether the interactions between clinical risk factors and CAD PRS further explain risk for incident CAD. METHODS: Participants were of European ancestry from the UK Biobank without prevalent CAD. An externally trained genome-wide CAD PRS was generated and then applied. Clinical risk factors were ascertained at baseline. Cox proportional hazards models were fitted to examine the incident CAD effects of CAD PRS, risk factors, and their interactions. Next, the PRS and risk factors were stratified to investigate the attributable risk of clinical risk factors. FINDINGS: A total of 357,144 individuals of European ancestry without prevalent CAD were included. During a median of 11.1 years of follow-up (interquartile range 10.4-14.1 years), CAD PRS was associated with 1.35-fold (95% confidence interval [CI] 1.332-1.368) risk per SD for incident CAD. The prognostic relevance of the following risk factors was relatively diminished for those with high CAD PRS on a continuous scale: type 2 diabetes (hazard ratio [HR]interaction 0.91, 95% CIinteraction 0.88-0.94), increased body mass index (HRinteraction 0.97, 95% CIinteraction 0.96-0.98), and increased C-reactive protein (HRinteraction 0.98, 95% CIinteraction 0.96-0.99). However, a high CAD PRS yielded joint risk increases with low-density lipoprotein cholesterol (HRinteraction 1.05, 95% CIinteraction 1.04-1.06) and total cholesterol (HRinteraction 1.05, 95% CIinteraction 1.03-1.06). CONCLUSION: The CAD PRS is associated with incident CAD, and its application improves the prognostic relevance of several clinical risk factors. FUNDING: P.N. (R01HL127564, R01HL151152, and U01HG011719) is supported by the National Institutes of Health.

Investigation of biomarkers to predict outcomes in allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Various biomarkers have been developed and evaluated to predict the prognosis and complications of allogeneic hematopoietic cell transplantation (HCT). Most previous studies conducted on different biomarkers evaluated single effects such as those associated with inflammation, immunology, iron metabolism, and nutrition, and only a few studies have comprehensively analyzed markers. OBJECTIVE: The study aimed to survey comprehensive multiple markers prior to HCT and extract those that significantly predict the outcomes. STUDY DESIGN: A prospective multicenter observational study was performed. (UMIN000013506) Patients undergoing HCT for hematologic diseases were consecutively enrolled. Besides the usual clinical biomarkers, serum samples for extra-clinical biomarkers were collected and cryopreserved before starting the conditioning regimen. A total of 32 candidate biomarkers were selected, 23 from hematology, biochemistry, immunology, nutrition, and iron metabolism, and 9 from composite markers. Based on the area under the curve (AUC) values for survival, promising biomarkers was extracted. Internal validation for these markers was applied based on bootstrap methods. Setting the cut-off values for them, log-rank test was applied and outcomes including overall survival (OS), relapse, and non-relapse mortality (NRM) were evaluated using multivariate analyses. Furthermore, detailed analysis including transplant-related complications and external validation were conducted focusing on C-reactive protein (CRP) to platelet (Plt) ratio. RESULTS: A total of 152 patients with hematologic malignancies were enrolled from April 2014 to March 2017. CRP, soluble interleukin-2 receptor (IL2R), CRP to albumin (Alb) ratio, CRP to Plt ratio, Plt to IL2R ratio, and IL2R to Alb ratio were identified as promising markers. Internal validation successfully confirmed their reliability of AUC and multivariate analysis demonstrated the statistical significance between the higher and the lower markers. Above all, a higher CRP to Plt ratio was significantly associated with a lower OS (hazard ratio [HR] 2.77; 95% confidence interval [CI] 1.30-5.91; P = 0.008) and higher non-relapse mortality rates (HR 2.79; 95%CI 1.14-6.80; P = 0.024) at 180 days. Furthermore, univariate analysis showed that a higher CRP to Plt ratio was significantly associated with a higher incidence of sinusoidal obstructive syndrome (P < 0.001) and bloodstream infection (P = 0.027). An external validation test confirmed the significance of the CRP to Plt ratio for these outcomes. CONCLUSION: The multicenter prospective observational study successfully identified significant biomarkers in patients with hematologic malignancies who received HCT. In particular, CRP to Plt ratio was identified as a novel and useful biomarker for predicting transplant outcomes. Further investigations are needed to validate the novel markers, analysis of the pathophysiology, and application to treatment settings other than HCT.

A case of Bloom syndrome manifesting with therapy-related myelodysplastic syndromes harboring a novel BLM gene variant.

Bloom syndrome (BS) is an autosomal recessive genetic disorder caused by variants in the BLM gene. BS is characterized by distinct facial features, elongated limbs, and various dermatological complications including photosensitivity, poikiloderma, and telangiectatic erythema. The BLM gene encodes a RecQ helicase critical for genome maintenance, stability, and repair, and a deficiency in functional BLM protein leads to genomic instability and high predisposition to various types of cancers, particularly hematological and gastrointestinal malignancies. Here, we report a case of BS with a previously unreported variant in the BLM gene. The patient was a 34-year-old woman who presented with short stature, prominent facial features, and a history of malignancies, including lymphoma, breast cancer, and myelodysplastic syndromes (MDS). She was initially treated with azacitidine for MDS and showed transient improvement, but eventually died at age of 35 due to progression of MDS. Genetic screening revealed compound heterozygous variants in the BLM gene, with a recurrent variant previously reported in BS in one allele and a previously unreported variant in the other allele. Based on her characteristic clinical features and the presence of heterozygous variants in the BLM gene, she was diagnosed with BS harboring compound heterozygous BLM variants.

CRISPR-Cas9-guided amplification-free genomic diagnosis for familial hypercholesterolemia using nanopore sequencing.

Familial hypercholesterolemia is an inherited disorder that remains underdiagnosed. Conventional genetic testing methods such as next-generation sequencing (NGS) or target PCR are based on the amplification process. Due to the efficiency limits of polymerase and ligase enzymes, these methods usually target short regions and do not detect large mutations straightforwardly. This study combined the long-read nanopore sequencing and CRISPR-Cas9 system to sequence the target DNA molecules without amplification. We originally designed and optimized the CRISPR-RNA panel to target the low-density lipoprotein receptor gene (LDLR) and proprotein convertase subtilisin/kexin type 9 gene (PCSK9) from human genomic DNA followed by nanopore sequencing. The average coverages for LDLR and PCSK9 were 106× and 420×, versus 1.2× for the background genome. Among them, continuous reads were 52x and 307x, respectively, and spanned the entire length of LDLR and PCSK9. We identified pathogenic mutations in both coding and splicing donor regions in LDLR. We also detected an 11,029 bp large deletion in another case. Furthermore, using continuous long reads generated from the benchmark experiment, we demonstrated how a false-positive 670 bp deletion caused by PCR amplification errors was easily eliminated.

Cardiovascular Significance and Genetics of Epicardial and Pericardial Adiposity.

Importance: Epicardial and pericardial adipose tissue (EPAT) has been associated with cardiovascular diseases such as atrial fibrillation or flutter (AF) and coronary artery disease (CAD), but studies have been limited in sample size or drawn from selected populations. It has been suggested that the association between EPAT and cardiovascular disease could be mediated by local or paracrine effects. Objective: To evaluate the association of EPAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of EPAT in a large population cohort. Design, Setting, and Participants: A deep learning model was trained to quantify EPAT area from 4-chamber magnetic resonance images using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. Prospective associations were additionally controlled for abdominal visceral adipose tissue (VAT) volumes. A genome-wide association study was performed, and a polygenic score (PGS) for EPAT was examined in independent FinnGen cohort study participants. Data analyses were conducted from March 2022 to December 2023. Exposures: The primary exposures were magnetic resonance imaging-derived continuous measurements of epicardial and pericardial adipose tissue area and visceral adipose tissue volume. Main Outcomes and Measures: Prevalent and incident CAD, AF, heart failure (HF), stroke, and type 2 diabetes (T2D). Results: After exclusions, this study included 44 475 participants (mean [SD] age, 64.1 [7.7] years; 22 972 female [51.7%]) from the UK Biobank. Cross-sectional and prospective cardiovascular disease associations were evaluated for a mean (SD) of 3.2 (1.5) years of follow-up. Prospective associations were additionally controlled for abdominal VAT volumes for 38 527 participants. A PGS for EPAT was examined in 453 733 independent FinnGen cohort study participants. EPAT was positively associated with male sex (ß = +0.78 SD in EPAT; P < 3 × 10-324), age (Pearson r = 0.15; P = 9.3 × 10-229), body mass index (Pearson r = 0.47; P < 3 × 10-324), and VAT (Pearson r = 0.72; P < 3 × 10-324). EPAT was more elevated in prevalent HF (ß = +0.46 SD units) and T2D (ß = +0.56) than in CAD (ß = +0.23) or AF (ß = +0.18). EPAT was associated with incident HF (hazard ratio [HR], 1.29 per +1 SD in EPAT; 95% CI, 1.17-1.43), T2D (HR, 1.63; 95% CI, 1.51-1.76), and CAD (HR, 1.19; 95% CI, 1.11-1.28). However, the associations were no longer significant when controlling for VAT. Seven genetic loci were identified for EPAT, implicating transcriptional regulators of adipocyte morphology and brown adipogenesis (EBF1, EBF2, and CEBPA) and regulators of visceral adiposity (WARS2 and TRIB2). The EPAT PGS was associated with T2D (odds ratio [OR], 1.06; 95% CI, 1.05-1.07; P =3.6 × 10-44), HF (OR, 1.05; 95% CI, 1.04-1.06; P =4.8 × 10-15), CAD (OR, 1.04; 95% CI, 1.03-1.05; P =1.4 × 10-17), AF (OR, 1.04; 95% CI, 1.03-1.06; P =7.6 × 10-12), and stroke in FinnGen (OR, 1.02; 95% CI, 1.01-1.03; P =3.5 × 10-3) per 1 SD in PGS. Conclusions and Relevance: Results of this cohort study suggest that epicardial and pericardial adiposity was associated with incident cardiovascular diseases, but this may largely reflect a metabolically unhealthy adiposity phenotype similar to abdominal visceral adiposity.

Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health.

The human retina is a multilayered tissue that offers a unique window into systemic health. Optical coherence tomography (OCT) is widely used in eye care and allows the noninvasive, rapid capture of retinal anatomy in exquisite detail. We conducted genotypic and phenotypic analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed OCT layer cross-phenotype association analyses (OCT-XWAS), associating retinal thicknesses with 1866 incident conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association studies (GWASs), identifying inherited genetic markers that influence retinal layer thicknesses and replicated our associations among the LIFE-Adult Study (N = 6313). Last, we performed a comparative analysis of phenome- and genome-wide associations to identify putative causal links between retinal layer thicknesses and both ocular and systemic conditions. Independent associations with incident mortality were detected for thinner photoreceptor segments (PSs) and, separately, ganglion cell complex layers. Phenotypic associations were detected between thinner retinal layers and ocular, neuropsychiatric, cardiometabolic, and pulmonary conditions. A GWAS of retinal layer thicknesses yielded 259 unique loci. Consistency between epidemiologic and genetic associations suggested links between a thinner retinal nerve fiber layer with glaucoma, thinner PS with age-related macular degeneration, and poor cardiometabolic and pulmonary function with a thinner PS. In conclusion, we identified multiple inherited genetic loci and acquired systemic cardio-metabolic-pulmonary conditions associated with thinner retinal layers and identify retinal layers wherein thinning is predictive of future ocular and systemic conditions.

Cumulative Diastolic Blood Pressure Burden in Normal Systolic Blood Pressure and Cardiovascular Disease.

BACKGROUND: The clinical significance of isolated diastolic hypertension defined by the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guidelines remains inconsistent. We examined whether long-term diastolic burden predicts the first major adverse cardiovascular event in participants with sustained and untreated normal systolic BP. METHODS: The Mass General Brigham Biobank is a New England health care-based cohort recruited between 2010 and 2021. A total of 15 979 participants aged 18 to 64 years and without prior cardiovascular disease, antihypertensives, or high systolic BP were studied. The cumulative diastolic burden was determined as the area under the curve for diastolic BP (DBP) ≥80 mm Hg over 5 years before enrollment. Major adverse cardiovascular event was defined as a composite of first incident ischemic heart disease, stroke, heart failure, or all-cause death. RESULTS: Of the 15 979 participants, mean (SD) age at enrollment was 47.6 (14.3) years, 11 950 (74.8%) were women, and the mean (SD) systolic BP and DBP were 118.0 (12.9) and 72.2 (9.3) mm Hg, respectively. Over a median (interquartile range) follow-up of 3.5 (1.8-5.4) years, 2467 (15.4%) major adverse cardiovascular events occurred. Using Cox proportional hazards regression, each SD increase in cumulative DBP was independently associated with a hazard ratio (95% CI) of 1.06 (1.02-1.10) without effect modification by sex (P=0.65), age (P=0.46), or race/ethnicity (P=0.24). In addition to traditional risk factors, cumulative DBP modestly improved the discrimination C index (95% CI) from 0.74 (0.72-0.75) to 0.75 (0.74-0.76; likelihood ratio test, P=0.037). CONCLUSIONS: Among individuals with normal systolic BP, cumulative DBP may augment cardiovascular disease risk stratification beyond a single DBP measure and traditional risk factors.

Decoding Genetics, Ancestry, and Geospatial Context for Precision Health.

Mass General Brigham, an integrated healthcare system based in the Greater Boston area of Massachusetts, annually serves 1.5 million patients. We established the Mass General Brigham Biobank (MGBB), encompassing 142,238 participants, to unravel the intricate relationships among genomic profiles, environmental context, and disease manifestations within clinical practice. In this study, we highlight the impact of ancestral diversity in the MGBB by employing population genetics, geospatial assessment, and association analyses of rare and common genetic variants. The population structures captured by the genetics mirror the sequential immigration to the Greater Boston area throughout American history, highlighting communities tied to shared genetic and environmental factors. Our investigation underscores the potency of unbiased, large-scale analyses in a healthcare-affiliated biobank, elucidating the dynamic interplay across genetics, immigration, structural geospatial factors, and health outcomes in one of the earliest American sites of European colonization.

Clinical Findings, Response to Steroid Treatment, and Recurrence Rate in Alopecia Areata Patients with or without a Nonsynonymous Variant of Coiled-Coil Alpha-Helical Rod Protein 1.

BACKGROUND: Alopecia areata (AA) is considered complex genetic and tissue-specific autoimmune disease. We recently discovered a nonsynonymous variant in the coiled-coil alpha-helical rod protein 1 (CCHCR1) gene within the AA risk haplotype. And a water avoidance stress test on CCHCR1 knockout mice induced AA-like lesions. OBJECTIVE: To investigate the difference clinical findings of AA in patients with the CCHCR1 variant and without. METHODS: We conducted a retrospective analysis of the data from 142 AA patients. Among these patients, 20 (14.1%) had a variant of CCHCR1. We evaluated the sex distribution of the patients, age at onset, distribution of the clinical types, prevalence of a positive family history of AA, prevalence of association of AA with atopic dermatitis, response to steroid therapy, and recurrence rate. We used multivariate logistic regression analysis and Fisher's exact test for statistical analysis. We also investigate electron microscopic observations of hair samples with the CCHCR1 variant and without. RESULTS: The results showed a significant correlation between the CCHCR1 variant and the recurrence rate compared with the variant-negative group (p=0.0072). Electron microscopy revealed abnormalities in the hair shaft structure and hair cuticle in patients with the CCHCR1 variant (p=0.00174). CONCLUSION: Our results suggest that AA with CCHCR1 variant is clinically characterized by a high recurrence rate and hair morphological abnormality.

AORTA Gene: Polygenic prediction improves detection of thoracic aortic aneurysm.

Background: Thoracic aortic disease is an important cause of morbidity and mortality in the US, and aortic diameter is a heritable contributor to risk. Could a polygenic prediction of ascending aortic diameter improve detection of aortic aneurysm? Methods: Deep learning was used to measure ascending thoracic aortic diameter in 49,939 UK Biobank participants. A genome-wide association study (GWAS) was conducted in 39,524 participants and leveraged to build a 1.1 million-variant polygenic score with PRScs-auto. Aortic diameter prediction models were built with the polygenic score ("AORTA Gene") and without it. The models were tested in a held-out set of 4,962 UK Biobank participants and externally validated in 5,469 participants from Mass General Brigham Biobank (MGB), 1,298 from the Framingham Heart Study (FHS), and 610 participants from All of Us. Results: In each test set, the AORTA Gene model explained more of the variance in thoracic aortic diameter compared to clinical factors alone: 39.9% (95% CI 37.8-42.0%) vs 29.2% (95% CI 27.1-31.4%) in UK Biobank, 36.5% (95% CI 34.4-38.5%) vs 32.5% (95% CI 30.4-34.5%) in MGB, 41.8% (95% CI 37.7-45.9%) vs 33.0% (95% CI 28.9-37.2%) in FHS, and 34.9% (95% CI 28.8-41.0%) vs 28.9% (95% CI 22.9-35.0%) in All of Us. AORTA Gene had a greater AUROC for identifying diameter ≥4cm in each test set: 0.834 vs 0.765 (P=7.3E-10) in UK Biobank, 0.808 vs 0.767 in MGB (P=4.5E-12), 0.856 vs 0.818 in FHS (P=8.5E-05), and 0.827 vs 0.791 (P=7.8E-03) in All of Us. Conclusions: Genetic information improved estimation of thoracic aortic diameter when added to clinical risk factors. Larger and more diverse cohorts will be needed to develop more powerful and equitable scores.

Bayesian multivariate genetic analysis improves translational insights.

While lipid traits are known essential mediators of cardiovascular disease, few approaches have taken advantage of their shared genetic effects. We apply a Bayesian multivariate size estimator, mash, to GWAS of four lipid traits in the Million Veterans Program (MVP) and provide posterior mean and local false sign rates for all effects. These estimates borrow information across traits to improve effect size accuracy. We show that controlling local false sign rates accurately and powerfully identifies replicable genetic associations and that multivariate control furthers the ability to explain complex diseases. Our application yields high concordance between independent datasets, more accurately prioritizes causal genes, and significantly improves polygenic prediction beyond state-of-the-art methods by up to 59% for lipid traits. The use of Bayesian multivariate genetic shrinkage has yet to be applied to human quantitative trait GWAS results, and we present a staged approach to prediction on a polygenic scale.

Fibrinogen Aα-chain amyloidosis outbreaks in Japanese squirrels (Sciurus lis): a potential disease model.

Fibrinogen Aα-chain amyloidosis is a hereditary systemic amyloidosis characterized by glomerular amyloid depositions, which are derived from the fibrinogen Aα-chain variant in humans. Despite its unique pathology, the pathogenic mechanisms of this disease are only partially understood. This is in part because comparative pathological studies on fibrinogen Aα-chain amyloidosis are currently unavailable as there is a lack of reported cases in animals other than humans. In this study, mass spectrometry-based proteomic analyses of Japanese squirrels (Sciurus lis) that died in five Japanese zoos showed that they developed glomerular-associated fibrinogen Aα-chain amyloidosis with an extremely high incidence rate (29/38 cases, 76.3%). The condition was found to be age-dependent in the Japanese squirrels, with 89% of individuals over 4 years of age affected. Mass spectrometry revealed that the C-terminal region of the fibrinogen Aα-chain was involved in amyloidogenesis in Japanese squirrels as well as humans. No gene variations were identified between amyloid-positive and amyloid-negative squirrels, which contrasted with the available data for humans. The results indicate that fibrinogen Aα-chain amyloidosis is a senile amyloidosis in Japanese squirrels. The results have also provided comparative pathological support that the amyloidogenic C-terminal region of the fibrinogen Aα-chain is involved in the characteristic glomerular pathology, regardless of the animal species. This study elucidates the potential causes of death in Japanese squirrels and will contribute to future comparative pathological studies of fibrinogen Aα-chain amyloidosis. © 2023 The Pathological Society of Great Britain and Ireland.

A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease.

Identification of individuals at highest risk of coronary artery disease (CAD)-ideally before onset-remains an important public health need. Prior studies have developed genome-wide polygenic scores to enable risk stratification, reflecting the substantial inherited component to CAD risk. Here we develop a new and significantly improved polygenic score for CAD, termed GPSMult, that incorporates genome-wide association data across five ancestries for CAD (>269,000 cases and >1,178,000 controls) and ten CAD risk factors. GPSMult strongly associated with prevalent CAD (odds ratio per standard deviation 2.14, 95% confidence interval 2.10-2.19, P < 0.001) in UK Biobank participants of European ancestry, identifying 20.0% of the population with 3-fold increased risk and conversely 13.9% with 3-fold decreased risk as compared with those in the middle quintile. GPSMult was also associated with incident CAD events (hazard ratio per standard deviation 1.73, 95% confidence interval 1.70-1.76, P < 0.001), identifying 3% of healthy individuals with risk of future CAD events equivalent to those with existing disease and significantly improving risk discrimination and reclassification. Across multiethnic, external validation datasets inclusive of 33,096, 124,467, 16,433 and 16,874 participants of African, European, Hispanic and South Asian ancestry, respectively, GPSMult demonstrated increased strength of associations across all ancestries and outperformed all available previously published CAD polygenic scores. These data contribute a new GPSMult for CAD to the field and provide a generalizable framework for how large-scale integration of genetic association data for CAD and related traits from diverse populations can meaningfully improve polygenic risk prediction.

The Cardiovascular Impact and Genetics of Pericardial Adiposity.

Background: While previous studies have reported associations of pericardial adipose tissue (PAT) with cardiovascular diseases such as atrial fibrillation and coronary artery disease, they have been limited in sample size or drawn from selected populations. Additionally, the genetic determinants of PAT remain largely unknown. We aimed to evaluate the association of PAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of PAT in a large population cohort. Methods: A deep learning model was trained to quantify PAT area from four-chamber magnetic resonance images in the UK Biobank using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. A genome-wide association study was performed, and a polygenic score (PGS) for PAT was examined in 453,733 independent FinnGen study participants. Results: A total of 44,725 UK Biobank participants (51.7% female, mean [SD] age 64.1 [7.7] years) were included. PAT was positively associated with male sex (ß = +0.76 SD in PAT), age (r = 0.15), body mass index (BMI; r = 0.47) and waist-to-hip ratio (r = 0.55) (P < 1×10-230). PAT was more elevated in prevalent heart failure (ß = +0.46 SD units) and type 2 diabetes (ß = +0.56) than in coronary artery disease (ß = +0.22) or AF (ß = +0.18). PAT was associated with incident heart failure (HR = 1.29 per +1 SD in PAT [95% CI 1.17-1.43]) and type 2 diabetes (HR = 1.63 [1.51-1.76]) during a mean 3.2 (±1.5) years of follow-up; the associations remained significant when controlling for BMI. We identified 5 novel genetic loci for PAT and implicated transcriptional regulators of adipocyte morphology and brown adipogenesis (EBF1, EBF2 and CEBPA) and regulators of visceral adiposity (WARS2 and TRIB2). The PAT PGS was associated with T2D, heart failure, coronary artery disease and atrial fibrillation in FinnGen (ORs 1.03-1.06 per +1 SD in PGS, P < 2×10-10). Conclusions: PAT shares genetic determinants with abdominal adiposity and is an independent predictor of incident type 2 diabetes and heart failure.

Integrative metabolomics differentiate coronary artery disease, peripheral artery disease, and venous thromboembolism risks.

Rationale: Arterial and venous cardiovascular conditions, such as coronary artery disease (CAD), peripheral artery disease (PAD), and venous thromboembolism (VTE), are genetically correlated. Interrogating distinct and overlapping mechanisms may shed new light on disease mechanisms. Objective: In this study, we aimed to: identify and compare (1) epidemiologic and (2) causal, genetic relationships between metabolites and CAD, PAD, and VTE. Methods: We used metabolomic data from 95,402 individuals in the UK Biobank, excluding individuals with prevalent cardiovascular disease. Logistic regression models adjusted for age, sex, genotyping array, first five principal components of ancestry, and statin use estimated the epidemiologic associations of 249 metabolites with incident CAD, PAD, or VTE. Bidirectional two-sample Mendelian randomization (MR) estimated the causal effects between metabolites and cardiovascular phenotypes using genome-wide association summary statistics for metabolites (N = 118,466 from UK Biobank), CAD (N = 184,305 from CARDIoGRAMplusC4D 2015), PAD (N = 243,060 from Million Veterans Project) and VTE (N = 650,119 from Million Veterans Project). Multivariable MR (MVMR) was performed in subsequent analyses. Results: We found that 194, 111, and 69 metabolites were epidemiologically associated (P < 0.001) with CAD, PAD, and VTE, respectively. Metabolomic profiles exhibited variable similarity between disease pairs: CAD and PAD (N = 100 shared associations, R2 = 0.499), CAD and VTE (N = 68, R2 = 0.455), and PAD and VTE (N = 54, R2 = 0.752). MR revealed 28 metabolites that increased risk for both CAD and PAD and 2 metabolites that increased risk for CAD but decreased risk for VTE. Despite strong epidemiologic overlap, no metabolites had a shared genetic relationship between PAD and VTE. MVMR revealed several metabolites with shared causal effects on CAD and PAD related to cholesterol content within very-low-density lipoprotein particles. Conclusions: While common arterial and venous conditions are associated with overlapping metabolomic profiles, MR prioritized the role of remnant cholesterol in arterial diseases but not venous thrombosis.

Inhibition of microRNA-33b in humanized mice ameliorates nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma in their advanced stages; however, there are currently no approved therapies. Here, we show that microRNA (miR)-33b in hepatocytes is critical for the development of NASH. miR-33b is located in the intron of sterol regulatory element-binding transcription factor 1 and is abundantly expressed in humans, but absent in rodents. miR-33b knock-in (KI) mice, which have a miR-33b sequence in the same intron of sterol regulatory element-binding transcription factor 1 as humans and express miR-33b similar to humans, exhibit NASH under high-fat diet feeding. This condition is ameliorated by hepatocyte-specific miR-33b deficiency but unaffected by macrophage-specific miR-33b deficiency. Anti-miR-33b oligonucleotide improves the phenotype of NASH in miR-33b KI mice fed a Gubra Amylin NASH diet, which induces miR-33b and worsens NASH more than a high-fat diet. Anti-miR-33b treatment reduces hepatic free cholesterol and triglyceride accumulation through up-regulation of the lipid metabolism-related target genes. Furthermore, it decreases the expression of fibrosis marker genes in cultured hepatic stellate cells. Thus, inhibition of miR-33b using nucleic acid medicine is a promising treatment for NASH.

Genetic, sociodemographic, lifestyle, and clinical risk factors of recurrent coronary artery disease events: a population-based cohort study.

AIMS: Complications of coronary artery disease (CAD) represent the leading cause of death among adults globally. This study examined the associations and clinical utilities of genetic, sociodemographic, lifestyle, and clinical risk factors on CAD recurrence. METHODS AND RESULTS: Data were from 7024 UK Biobank middle-aged adults with established CAD at enrolment. Cox proportional hazards regressions modelled associations of age at enrolment, age at first CAD diagnosis, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, blood pressure, blood lipids, glucose, lipoprotein(a), C reactive protein, estimated glomerular filtration rate (eGFR), statin prescription, and CAD polygenic risk score (PRS) with first post-enrolment CAD recurrence. Over a median [interquartile range] follow-up of 11.6 [7.2-12.7] years, 2003 (28.5%) recurrent CAD events occurred. The hazard ratio (95% confidence interval [CI]) for CAD recurrence was the most pronounced with current smoking (1.35, 1.13-1.61) and per standard deviation increase in age at first CAD (0.74, 0.67-0.82). Additionally, age at enrolment, CAD PRS, C-reactive protein, lipoprotein(a), glucose, low-density lipoprotein cholesterol, deprivation, sleep quality, eGFR, and high-density lipoprotein (HDL) cholesterol also significantly associated with recurrence risk. Based on C indices (95% CI), the strongest predictors were CAD PRS (0.58, 0.57-0.59), HDL cholesterol (0.57, 0.57-0.58), and age at initial CAD event (0.57, 0.56-0.57). In addition to traditional risk factors, a comprehensive model improved the C index from 0.644 (0.632-0.654) to 0.676 (0.667-0.686). CONCLUSION: Sociodemographic, clinical, and laboratory factors are each associated with CAD recurrence with genetic risk, age at first CAD event, and HDL cholesterol concentration explaining the most.

Birth Weight Is Associated With Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Outcomes in Adulthood.

Background High and low birth weight are independently associated with increased cardiovascular disease risk in adulthood. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic cells with preleukemic somatic mutations, predicts incident cardiovascular disease independent of traditional cardiovascular risk factors. Whether birth weight predicts development of CHIP later in life is unknown. Methods and Results A total of 221 047 adults enrolled in the UK Biobank with whole exome sequences and self-reported birth weight were analyzed. Of those, 22 030 (11.5%) had low (<2.5 kg) and 29 292 (14.7%) high birth weight (>4.0 kg). CHIP prevalence was higher among participants with low (6.0%, P=0.049) and high (6.3%, P<0.001) versus normal birth weight (5.7%, ref.). Multivariable-adjusted logistic regression analyses demonstrated that each 1-kg increase in birth weight was associated with a 3% increased risk of CHIP (odds ratio, 1.03 [95% CI, 1.00-1.06]; P=0.04), driven by a stronger association observed between birth weight and DNMT3A CHIP (odds ratio, 1.04 per 1-kg increase [95% CI, 1.01-1.08]; P=0.02). Mendelian randomization analyses supported a causal relationship of longer gestational age at delivery with DNMT3A CHIP. Multivariable Cox regression demonstrated that CHIP was independently and additively associated with incident cardiovascular disease or death across birth weight groups, with highest absolute risks in those with CHIP plus high or low birth weight. Conclusions Higher birth weight is associated with increased risk of developing CHIP in midlife, especially DNMT3A CHIP. These findings identify a novel risk factor for CHIP and provide insights into the relationships among early-life environment, CHIP, cancer, and cardiovascular disease.