Publications by authors named "Daniel J Rader"

666 Publications

Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins.

PLoS Genet 2021 Sep 20;17(9):e1009802. Epub 2021 Sep 20.

Departments of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized that endothelial lipase (EL), another extracellular lipase that primarily hydrolyzes lipoprotein phospholipids may also contribute to TRL metabolism. To explore this, we studied the impact of genetic EL loss-of-function on TRL metabolism in humans and mice. Humans carrying a loss-of-function missense variant in LIPG, p.Asn396Ser (rs77960347), demonstrated elevated plasma TGs and elevated phospholipids in TRLs, among other lipoprotein classes. Mice with germline EL deficiency challenged with excess dietary TG through refeeding or a high-fat diet exhibited elevated TGs, delayed dietary TRL clearance, and impaired TRL TG lipolysis in vivo that was rescued by EL reconstitution in the liver. Lipidomic analyses of postprandial plasma from high-fat fed Lipg-/- mice demonstrated accumulation of phospholipids and TGs harboring long-chain polyunsaturated fatty acids (PUFAs), known substrates for EL lipolysis. In vitro and in vivo, EL and LPL together promoted greater TG lipolysis than either extracellular lipase alone. Our data positions EL as a key collaborator of LPL to mediate efficient lipolysis of TRLs in humans and mice.
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http://dx.doi.org/10.1371/journal.pgen.1009802DOI Listing
September 2021

A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank.

Hum Mol Genet 2021 Sep 20. Epub 2021 Sep 20.

Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

'Genome-first' approaches to analyzing rare variants can reveal new insights into human biology and disease. Because pathogenic variants are often rare, new discovery requires aggregating rare coding variants into 'gene burdens' for sufficient power. However, a major challenge is deciding which variants to include in gene burden tests. Pathogenic variants in MYBPC3 and MYH7 are well-known causes of hypertrophic cardiomyopathy (HCM), and focusing on these 'positive control' genes in a genome-first approach could help inform variant selection methods and gene burdening strategies for other genes and diseases. Integrating exome sequences with electronic health records among 41 759 participants in the Penn Medicine BioBank, we evaluated the performance of aggregating predicted loss-of-function (pLOF) and/or predicted deleterious missense (pDM) variants in MYBPC3 and MYH7 for gene burden phenome-wide association studies (PheWAS). The approach to grouping rare variants for these two genes produced very different results: pLOFs but not pDM variants in MYBPC3 were strongly associated with HCM, whereas the opposite was true for MYH7. Detailed review of clinical charts revealed that only 38.5% of patients with HCM diagnoses carrying an HCM-associated variant in MYBPC3 or MYH7 had a clinical genetic test result. Additionally, 26.7% of MYBPC3 pLOF carriers without HCM diagnoses had clear evidence of left atrial enlargement and/or septal/LV hypertrophy on echocardiography. Our study shows the importance of evaluating both pLOF and pDM variants for gene burden testing in future studies to uncover novel gene-disease relationships and identify new pathogenic loss-of-function variants across the human genome through genome-first analyses of healthcare-based populations.
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http://dx.doi.org/10.1093/hmg/ddab249DOI Listing
September 2021

LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in obese adults with modest hypertriglyceridemia.

J Clin Endocrinol Metab 2021 Aug 25. Epub 2021 Aug 25.

Novartis Institutes for BioMedical Research, Cambridge, MA, USA and Basel, Switzerland.

Purpose: To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction.

Methods: A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every four weeks for three doses.

Results: Of 64 randomized study participants, 61 (mean±SD: age 45±11 years, 49% male, 80/15/5% Caucasian/African American/Other, BMI 36.1±3.8 kg/m 2) received LLF580 (n=30) or placebo (n=31) at 7 research sites in the USA. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, LDL-cholesterol 12%, and increased HDL-cholesterol 36% compared to placebo (all P<0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P<0.001) was also demonstrated, in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P<0.05). Insulin and C-peptide levels and insulin resistance by HOMA-IR were all lower, and adiponectin higher with LLF580 treatment compared to placebo, while fasting glucose and HbA1c were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects.

Conclusions: In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and non-alcoholic fatty liver disease. Assessments of longer-term safety and efficacy are warranted.
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http://dx.doi.org/10.1210/clinem/dgab624DOI Listing
August 2021

Associations of endogenous hormones with HDL novel metrics across the menopause transition: The SWAN HDL Study.

J Clin Endocrinol Metab 2021 Aug 14. Epub 2021 Aug 14.

Department of Epidemiology, University of Pittsburgh, Graduate School of Public Health Pittsburgh PA.

Context: Novel metrics of HDL (subclasses, lipid content and function) may better characterize the anti-atherogenic features of HDL. In midlife women, changes in these metrics vary by time relative to the final menstrual period (FMP), supporting a contribution of menopause hormones estradiol (E2) and follicle-stimulating hormone (FSH).

Objective: To test associations of endogenous E2 and FSH with novel HDL metrics and to assess whether these associations vary by time relative to FMP.

Design: Longitudinal analysis from the Study of Women's Health Across the Nation (SWAN) HDL study.

Setting: Community-based cohort.

Participants: 463 women, baseline mean age 50.2 (2.7) years.

Exposures: E2 and FSH.

Main Outcome Measures: HDL cholesterol efflux capacity (HDL-CEC), HDL phospholipids (HDL-PL), HDL triglycerides (HDL-Tg), HDL-particles (HDL-P), HDL size, HDL-cholesterol (HDL-C).

Results: In multivariable analyses, E2 was positively associated with HDL size, large HDL-P, HDL-CEC and HDL-Tg, but negatively with medium HDL-P, p-values<0.05. The positive association between E2 and HDL-Tg was stronger 2 years post FMP than before, interaction p-value=0.031. FSH was positively related to total and medium HDL-P, but negatively to HDL size, large HDL-P, and HDL-CEC per particle, p-values<0.05. Associations of higher FSH with greater total HDL-P and smaller HDL size were only evident at/after menopause, interaction p-values<0.05.

Conclusions: Some of the associations linking E2 and FSH with novel HDL metrics were vulnerable to time relative to menopause onset. Whether a late initiation of hormone therapy relative to menopause could have a detrimental effect on lipid content of HDL particles should be tested in the future.
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http://dx.doi.org/10.1210/clinem/dgab595DOI Listing
August 2021

Associations of HDL metrics with coronary artery calcium score and density among women traversing menopause.

J Lipid Res 2021 Jul 22;62:100098. Epub 2021 Jul 22.

Departments of Medicine and Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

The cardioprotective association of high-density lipoprotein cholesterol (HDL-C) may vary by menopause stage or estradiol level. We tested whether associations of comprehensive HDL metrics (HDL subclasses, phospholipid and triglyceride content, and HDL cholesterol efflux capacity [HDL-CEC]) with coronary artery calcium (CAC) score and density vary by menopause stage or estradiol level in women transitioning through menopause. Participants (N = 294; mean age [SD]: 51.3 [2.9]) had data on HDL metrics and CAC measures at one or two time points during the menopause transition. Generalized estimating equations were used for analyses. Effect modifications by menopause stage or estradiol level were tested in multivariable models. In adjusted models, menopause stage modified the associations of specific HDL metrics with CAC measures. Higher small HDL particles (HDL-P) concentrations (p-interaction = 0.008) and smaller HDL size (p-interaction = 0.02) were associated with greater odds of CAC presence in late perimenopause than in pre/early perimenopause stage. Women in the highest estradiol tertile, but not the lower tertiles, showed a protective association of small HDL-P with CAC presence (p-interaction = 0.007). Lower large HDL-P concentrations (p-interaction = 0.03) and smaller HDL size (p-interaction = 0.03) were associated with lower CAC density in late perimenopause than in postmenopause stage. Associations of HDL phospholipid and triglyceride content and HDL-CEC with CAC measures did not vary by menopause stage or estradiol level. We concluded that HDL subclasses may impact the likelihood of CAC presence and the stability of coronary plaque differently over the menopause transition. Endogenous estradiol levels may contribute to this observation.
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http://dx.doi.org/10.1016/j.jlr.2021.100098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385165PMC
July 2021

Genetic regulation of nonsense-mediated decay underlies association with risk of severe COVID-19.

medRxiv 2021 Jul 13. Epub 2021 Jul 13.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of . We suggest that genetically-regulated loss of expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the risk haplotypes.
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http://dx.doi.org/10.1101/2021.07.09.21260221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288155PMC
July 2021

A Genome-First Approach to Rare Variants in Dominant Postlingual Hearing Loss Genes in a Large Adult Population.

Otolaryngol Head Neck Surg 2021 Jul 20:1945998211029544. Epub 2021 Jul 20.

Department of Otorhinolaryngology Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objective: To investigate the importance of rare variants in adult-onset hearing loss.

Study Design: Genomic association study.

Setting: Large biobank from tertiary care center.

Methods: We investigated rare variants (minor allele frequency <5%) in 42 autosomal dominant (DFNA) postlingual hearing loss (HL) genes in 16,657 unselected individuals in the Penn Medicine Biobank. We determined the prevalence of known pathogenic and predicted deleterious variants in subjects with audiometric-proven sensorineural hearing loss. We scanned across known postlingual DFNA HL genes to determine those most significantly contributing to the phenotype. We replicated findings in an independent cohort (UK Biobank).

Results: While rare individually, when considering the accumulation of variants in all postlingual DFNA genes, more than 90% of participants carried at least 1 rare variant. Rare variants predicted to be deleterious were enriched in adults with audiometric-proven hearing loss (pure-tone average >25 dB; = .015). Patients with a rare predicted deleterious variant had an odds ratio of 1.27 for HL compared with genotypic controls ( = .029). Gene burden in , and were independently associated with sensorineural hearing loss.

Conclusion: Although prior reports have focused on common variants, we find that rare predicted deleterious variants in DFNA postlingual HL genes are enriched in patients with adult-onset HL in a large health care system population. We show the value of investigating rare variants to uncover hearing loss phenotypes related to implicated genes.
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http://dx.doi.org/10.1177/01945998211029544DOI Listing
July 2021

A genome-first approach to mortality and metabolic phenotypes in p.Ala165Thr (rs2642438) heterozygotes and homozygotes.

Med (N Y) 2021 Jul;2(7):851-863.e3

Division of Translational Medicine and Human Genetics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Background: A coding variant in (rs2642438; p.Ala165Thr) was recently associated with protection from cirrhosis in European individuals. However, its impact on overall and cause-specific mortality remained elusive.

Methods: Using a genome-first approach, we explored a range of metabolic phenotypes and outcomes associated with p.Ala165Thr in the UKBiobank and the Penn-Medicine BioBank.

Findings: p.Ala165Thr was significantly associated with higher triglycerides, lower total cholesterol, lower LDL-C, lower ApoB, lower HDL-C, lower ApoA-I and higher IGF-1. Per each minor allele, the risk of NAFLD was reduced by ~15%. The ALT-lowering and NAFLD-protective effect of p.Ala165Thr was amplified by obesity, diabetes mellitus and presence of rs738409:G. In African-American and Black-British individuals, the allele frequency of p.Ala165Thr was lower, but carriers showed the same distinctive lipid phenotype. Importantly, p.Ala165Thr carriers did not show higher cardiovascular disease burden as evidenced by cardiac MRI and carotid ultrasound. In prospective analyses, the homozygous minor allele was associated with up to 39% lower rates of liver-related mortality, while no risk of increased overall or cardiovascular death could be observed. Strikingly, liver-related mortality was more than 50% reduced in diabetic participants or carriers of rs738409:G.

Conclusions: Together these data highlight as an important liver disease modifier that influences plasma lipids in an allele-dose-dependent manner without increasing cardiovascular outcomes. Our results point toward potential mechanisms and reveal a remarkable association with liver-related mortality calling for future studies exploring its therapeutic potential.

Funding: This study was funded by the German Research Foundation (DFG).
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http://dx.doi.org/10.1016/j.medj.2021.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274545PMC
July 2021

Heritability of quantitative autism spectrum traits in adults: A family-based study.

Autism Res 2021 08 10;14(8):1543-1553. Epub 2021 Jul 10.

Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Translational Research Laboratory, Philadelphia, Pennsylvania, USA.

Autism spectrum disorder (ASD) comprises a multi-dimensional set of quantitative behavioral traits expressed along a continuum in autistic and neurotypical individuals. ASD diagnosis-a dichotomous trait-is known to be highly heritable and has been used as the phenotype for most ASD genetic studies. But less is known about the heritability of autism spectrum quantitative traits, especially in adults, an important prerequisite for gene discovery. We sought to measure the heritability of many autism-relevant quantitative traits in adults high in autism spectrum traits and their extended family members. Among adults high in autism spectrum traits (n = 158) and their extended family members (n = 245), we calculated univariate and bivariate heritability estimates for 19 autism spectrum traits across several behavioral domains. We found nearly all tested autism spectrum quantitative traits to be significantly heritable (h  = 0.24-0.79), including overall ASD traits, restricted repetitive behaviors, broader autism phenotype traits, social anxiety, and executive functioning. The degree of shared heritability varied based on method and specificity of the assessment measure. We found high shared heritability for the self-report measures and for most of the informant-report measures, with little shared heritability among performance-based cognition tasks. These findings suggest that many autism spectrum quantitative traits would be good, feasible candidates for future genetics studies, allowing for an increase in the power of autism gene discovery. Our findings suggest that the degree of shared heritability between traits depends on the assessment method (self-report vs. informant-report vs. performance-based tasks), as well as trait-specificity. LAY SUMMARY: We found that the scores from questionnaires and tasks measuring different types of behaviors and abilities related to autism spectrum disorder (ASD) were heritable (strongly influenced by gene variants passed down through a family) among autistic adults and their family members. These findings mean that these scores can be used in future studies interested in identifying specific genes and gene variants that are associated with different behaviors and abilities related with ASD.
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http://dx.doi.org/10.1002/aur.2571DOI Listing
August 2021

Health care worker seromonitoring reveals complex relationships between common coronavirus antibodies and COVID-19 symptom duration.

JCI Insight 2021 08 23;6(16). Epub 2021 Aug 23.

Department of Microbiology.

Some studies suggest that recent common coronavirus (CCV) infections are associated with reduced COVID-19 severity upon SARS-CoV-2 infection. We completed serological assays using samples collected from health care workers to identify antibody types associated with SARS-CoV-2 protection and COVID-19 symptom duration. Rare SARS-CoV-2 cross-reactive antibodies elicited by past CCV infections were not associated with protection; however, the duration of symptoms following SARS-CoV-2 infections was significantly reduced in individuals with higher common betacoronavirus (βCoV) antibody titers. Since antibody titers decline over time after CCV infections, individuals in our cohort with higher βCoV antibody titers were more likely recently infected with common βCoVs compared with individuals with lower antibody titers. Therefore, our data suggest that recent βCoV infections potentially limit the duration of symptoms following SARS-CoV-2 infections through mechanisms that do not involve cross-reactive antibodies. Our data are consistent with the emerging hypothesis that cellular immune responses elicited by recent common βCoV infections transiently reduce symptom duration following SARS-CoV-2 infections.
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http://dx.doi.org/10.1172/jci.insight.150449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410018PMC
August 2021

Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids.

Cell Metab 2021 Aug 6;33(8):1592-1609.e7. Epub 2021 Jul 6.

Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address:

Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-term use has severe metabolic side effects. Here, by treating multiple individual adipose stem cell-derived adipocytes and induced pluripotent stem cell-derived hepatocytes with the potent GC dexamethasone (Dex), we uncovered cell-type-specific and individual-specific GC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Individual-specific GR binding could be traced to single-nucleotide polymorphisms (SNPs) that altered the binding motifs of GR or its cooperating factors. We also discovered another set of genetic variants that modulated Dex response through affecting chromatin accessibility or chromatin architecture. Several SNPs that altered Dex-regulated GR binding and gene expression controlled Dex-driven metabolic perturbations. Remarkably, these genetic variations were highly associated with increases in serum glucose, lipids, and body mass in subjects on GC therapy. Knowledge of the genetic variants that predispose individuals to metabolic side effects allows for a precision medicine approach to the use of clinically relevant GCs.
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http://dx.doi.org/10.1016/j.cmet.2021.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340270PMC
August 2021

Sequencing of 640,000 exomes identifies variants associated with protection from obesity.

Science 2021 07;373(6550)

Geisinger Obesity Institute, Geisinger Health System, Danville, PA 17882, USA.

Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors (, , , , and ). Protein-truncating variants in were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.
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http://dx.doi.org/10.1126/science.abf8683DOI Listing
July 2021

Potential role of hepatic lipase in the accretion of docosahexaenoic acid (DHA) by the brain.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Oct 29;1866(10):159002. Epub 2021 Jun 29.

Department of Medicine, University of Illinois, Chicago, IL 60612, USA; Jesse Brown VA Medical Center, Chicago, IL 60612, USA. Electronic address:

DHA (docosahexaenoic acid) is an essential fatty acid that is required for the normal development and function of the brain. Because of its inability to synthesize adequate amounts of DHA from the precursors, the brain has to acquire DHA from plasma through the blood brain barrier (BBB). Recent studies demonstrated the presence of a transporter at the BBB that specifically transports DHA into the brain in the form of lysophosphatidylcholine (LPC-DHA). However, the mechanism by which LPC-DHA is generated in the plasma is not known. Our previous studies showed that there are at least three different enzymes - lecithin cholesterol acyltransferase (LCAT), endothelial lipase (EL), and hepatic lipase (HL), which can generate LPC-DHA from sn-2 DHA phosphatidylcholine. Here we determined the relative contributions of these enzymes in the delivery of DHA to the brain by measuring the brain DHA levels in the mice deficient in each of these enzymes. The results show that the brain DHA levels of LCAT-deficient mice or EL-deficient mice were not significantly lower than those of their littermates. However, brain DHA was significantly decreased in HL deficient mice (13.5% of total fatty acids) compared to their littermates (17.1%) (p < 0.002), and further decreased to 8.3% of total fatty acids in mice deficient in both HL and EL. These results suggest that HL activity may be the major source for the generation of LPC-DHA in the plasma necessary for transport into the brain, and EL might contribute to this process in the absence of HL.
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http://dx.doi.org/10.1016/j.bbalip.2021.159002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325639PMC
October 2021

Lipid droplet screen in human hepatocytes identifies TRRAP as a regulator of cellular triglyceride metabolism.

Clin Transl Sci 2021 Jul 22;14(4):1369-1379. Epub 2021 Jun 22.

Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Hepatocytes store triglycerides (TGs) in the form of lipid droplets (LDs), which are increased in hepatosteatosis. The regulation of hepatic LDs is poorly understood and new therapies to reduce hepatosteatosis are needed. We performed a siRNA kinase and phosphatase screen in HuH-7 cells using high-content automated imaging of LDs. Changes in accumulated lipids were quantified with developed pipeline that measures intensity, area, and number of LDs. Selected "hits," which reduced lipid accumulation, were further validated with other lipid and expression assays. Among several siRNAs that resulted in significantly reduced LDs, one was targeted to the nuclear adapter protein, transformation/transcription domain-associated protein (TRRAP). Knockdown of TRRAP reduced triglyceride accumulation in HuH-7 hepatocytes, in part by reducing C/EBPα-mediated de novo synthesis of TGs. These findings implicate TRRAP as a novel regulator of hepatic TG metabolism and nominate it as a potential drug target for hepatosteatosis.
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http://dx.doi.org/10.1111/cts.12988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301584PMC
July 2021

Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation.

Am J Hum Genet 2021 07 17;108(7):1342-1349. Epub 2021 Jun 17.

Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address:

EDEM3 encodes a protein that converts ManGlcNAc isomer B to ManGlcNAc. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of ManGlcNAc isomer B to ManGlcNAc, consistent with loss of EDEM3 enzymatic activity. In human cells, ManGlcNAc to ManGlcNAc conversion is also diminished with an increase of GlcManGlcNAc. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG.
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http://dx.doi.org/10.1016/j.ajhg.2021.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322938PMC
July 2021

A unified framework identifies new links between plasma lipids and diseases from electronic medical records across large-scale cohorts.

Nat Genet 2021 07 17;53(7):972-981. Epub 2021 Jun 17.

Department of Genetics and Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify new lipid-associated genes and study the relationships among lipids, genotypes, gene expression and hundreds of complex human diseases from the Electronic Medical Records and Genomics (347 traits) and the UK Biobank (549 traits). Aside from 67 new lipid-associated genes with strong replication, we found evidence for pleiotropic SNPs/genes between lipids and diseases across the phenome. These include discordant pleiotropy in the HLA region between lipids and multiple sclerosis and putative causal paths between triglycerides and gout, among several others. Our findings give insights into the genetic basis of the relationship between plasma lipids and diseases on a phenome-wide scale and can provide context for future prevention and treatment strategies.
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http://dx.doi.org/10.1038/s41588-021-00879-yDOI Listing
July 2021

Prioritizing the Role of Major Lipoproteins and Subfractions as Risk Factors for Peripheral Artery Disease.

Circulation 2021 Aug 18;144(5):353-364. Epub 2021 Jun 18.

Department of Surgery (V.M.W., S.M.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia.

Background: Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk.

Methods: Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies.

Results: ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86; =0.003) and CAD (marginal inclusion probability, 0.92; =0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB [95% CI, 0.84-0.91]; =9×10) and CAD (odds ratio,0.66 [95% CI, 0.63-0.69]; =4×10), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 [95% CI, 2.29-4.60]; <1×10). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91; =2.3×10), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95; =0.011). Genes associated with extra-small very-low-density lipoprotein particle and large low-density lipoprotein particle concentration included canonical ApoB pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD independently of ApoB (odds ratio, 1.04 [95% CI, 1.03-1.04]; =1.0×10).

Conclusions: ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323712PMC
August 2021

SARS-CoV-2 Seropositivity and Seroconversion in Patients Undergoing Active Cancer-Directed Therapy.

JCO Oncol Pract 2021 Jun 16:OP2100113. Epub 2021 Jun 16.

Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Purpose: Multiple studies have demonstrated the negative impact of cancer care delays during the COVID-19 pandemic, and transmission mitigation techniques are imperative for continued cancer care delivery. We aimed to gauge the effectiveness of these measures at the University of Pennsylvania.

Methods: We conducted a longitudinal study of SARS-CoV-2 antibody seropositivity and seroconversion in patients presenting to infusion centers for cancer-directed therapy between May 21, 2020, and October 8, 2020. Participants completed questionnaires and had up to five serial blood collections.

Results: Of 124 enrolled patients, only two (1.6%) had detectable SARS-CoV-2 antibodies on initial blood draw, and no initially seronegative patients developed newly detectable antibodies on subsequent blood draw(s), corresponding to a seroconversion rate of 0% (95% CI, 0.0 TO 4.1%) over 14.8 person-years of follow up, with a median of 13 health care visits per patient.

Conclusion: These results suggest that patients with cancer receiving in-person care at a facility with aggressive mitigation efforts have an extremely low likelihood of COVID-19 infection.
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http://dx.doi.org/10.1200/OP.21.00113DOI Listing
June 2021

Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals.

Am J Hum Genet 2021 07 3;108(7):1350-1355. Epub 2021 Jun 3.

Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 0AA, UK.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.
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http://dx.doi.org/10.1016/j.ajhg.2021.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173480PMC
July 2021

Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry.

Sci Rep 2021 Jun 2;11(1):11645. Epub 2021 Jun 2.

Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA.

Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3-4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n = 6062). Significant associations were tested for replication in the Penn Medicine Biobank (n = 5737) and the Million Veteran Program (n = 82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR] = 6.4, 95% confidence interval [CI] 2.6-15.6, p = 4.2 × 10), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2-2.4, p = 6.0 × 10) and Million Veteran Program (OR = 1.5, 95% CI 1.2-1.8, p = 1.8 × 10). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, 95% CI 1.7-4.5, p = 2.6 × 10) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment.
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http://dx.doi.org/10.1038/s41598-021-91113-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172853PMC
June 2021

A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia.

Genet Med 2021 May 26. Epub 2021 May 26.

Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Purpose: Family-based cascade screening from index probands is considered an effective way of identifying undiagnosed individuals with familial hypercholesterolemia (FH). The role of genetic testing of the proband in the success of cascade screening for FH is unknown.

Methods: We randomized 240 individuals with a clinical diagnosis of FH to genetic testing for FH (n = 160) or usual care with lipid testing alone (n = 80). The primary study endpoint was the proportion of probands with at least one relative enrolled in the study within one year after the notification of results.

Results: Proband median age was 59 (47-67) and 71% were female. Only 28 (12%) probands succeeded in enrolling a relative. While the genetic testing group had a higher proportion of probands with relatives enrolled (13.1%) compared with the usual care group (8.8%), this difference was not significant (p = 0.40). In subgroup analyses, enrollment of a relative was higher in the pathogenic variant group (22.7%) compared to the no pathogenic variant (9.5%) and usual care groups (8.8%) (p = 0.04).

Conclusion: We observed a low rate of family participation in cascade screening despite repeated recommendations to probands. Compared to usual care, genetic testing did not improve family participation in cascade screening for FH.

Clinical Trial Number: NCT04526457.
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http://dx.doi.org/10.1038/s41436-021-01192-zDOI Listing
May 2021

Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.

JAMA Cardiol 2021 Aug;6(8):902-909

Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Importance: Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants.

Objective: To identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)-based comprehensive testing.

Design, Setting, And Participants: This cross-sectional study compared comprehensive genetic test results for clinically significant variants associated with FH with results for a subset of 24 variants screened by a limited-variant array. Data were deidentified next-generation sequencing results from indication-based or proactive gene panels. Individuals receiving next-generation sequencing-based genetic testing, either for an FH indication between November 2015 and June 2020 or as proactive health screening between February 2016 and June 2020 were included. Ancestry was reported by clinicians who could select from preset options or enter free text on the test requisition form.

Main Outcomes And Measures: Number of pathogenic or likely pathogenic (P/LP) variants identified.

Results: This study included 4563 individuals who were referred for FH diagnostic testing and 6482 individuals who received next-generation sequencing of FH-associated genes as part of a proactive genetic test. Among individuals in the indication cohort, the median (interquartile range) age at testing was 49 (32-61) years, 55.4% (2528 of 4563) were female, and 63.6% (2902 of 4563) were self-reported White/Caucasian. In the indication cohort, the positive detection rate would have been 8.4% (382 of 4563) for a limited-variant screen compared with the 27.0% (1230 of 4563) observed with the next-generation sequencing-based comprehensive test. As a result, 68.9% (848 of 1230) of individuals with a P/LP finding in an FH-associated gene would have been missed by the limited screen. The potential for missed findings in the indication cohort varied by ancestry; among individuals with a P/LP finding, 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed by the limited-variant screen, compared with 33.3% (4 of 12) of Ashkenazi Jewish individuals. In the proactive cohort, the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test, and 61.8% (21 of 34) of individuals with an FH-associated P/LP finding would have been missed by a limited-variant screen.

Conclusions And Relevance: Limited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry.
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http://dx.doi.org/10.1001/jamacardio.2021.1301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156154PMC
August 2021

Sero-monitoring of health care workers reveals complex relationships between common coronavirus antibodies and SARS-CoV-2 severity.

medRxiv 2021 Apr 19. Epub 2021 Apr 19.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Recent common coronavirus (CCV) infections are associated with reduced COVID-19 severity upon SARS-CoV-2 infection, however the immunological mechanisms involved are unknown. We completed serological assays using samples collected from health care workers to identify antibody types associated with SARS-CoV-2 protection and COVID-19 severity. Rare SARS-CoV-2 cross-reactive antibodies elicited by past CCV infections were not associated with protection; however, the duration of symptoms following SARS-CoV-2 infections was significantly reduced in individuals with higher common betacoronavirus (βCoV) antibody titers. Since antibody titers decline over time after CCV infections, individuals in our cohort with higher βCoV antibody titers were more likely recently infected with common βCoVs compared to individuals with lower antibody titers. Therefore, our data suggest that recent βCoV infections potentially limit the severity of SARS-CoV-2 infections through mechanisms that do not involve cross-reactive antibodies. Our data are consistent with the emerging hypothesis that cellular immune responses elicited by recent common βCoV infections transiently reduce disease severity following SARS-CoV-2 infections.
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http://dx.doi.org/10.1101/2021.04.12.21255324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077588PMC
April 2021

Functional Characterization of Organoids Derived From Irreversibly Damaged Liver of Patients With NASH.

Hepatology 2021 Apr 26. Epub 2021 Apr 26.

Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Background And Aims: NASH will soon become the leading cause of liver transplantation in the United States and is also associated with increased COVID-19 mortality. Currently, there are no Food and Drug Administration-approved drugs available that slow NASH progression or address NASH liver involvement in COVID-19. Because animal models cannot fully recapitulate human NASH, we hypothesized that stem cells isolated directly from end-stage liver from patients with NASH may address current knowledge gaps in human NASH pathology.

Approach And Results: We devised methods that allow the derivation, proliferation, hepatic differentiation, and extensive characterization of bipotent ductal organoids from irreversibly damaged liver from patients with NASH. The transcriptomes of organoids derived from NASH liver, but not healthy liver, show significant up-regulation of proinflammatory and cytochrome p450-related pathways, as well as of known liver fibrosis and tumor markers, with the degree of up-regulation being patient-specific. Functionally, NASH liver organoids exhibit reduced passaging/growth capacity and hallmarks of NASH liver, including decreased albumin production, increased free fatty acid-induced lipid accumulation, increased sensitivity to apoptotic stimuli, and increased cytochrome P450 metabolism. After hepatic differentiation, NASH liver organoids exhibit reduced ability to dedifferentiate back to the biliary state, consistent with the known reduced regenerative ability of NASH livers. Intriguingly, NASH liver organoids also show strongly increased permissiveness to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vesicular stomatitis pseudovirus as well as up-regulation of ubiquitin D, a known inhibitor of the antiviral interferon host response.

Conclusion: Expansion of primary liver stem cells/organoids derived directly from irreversibly damaged liver from patients with NASH opens up experimental avenues for personalized disease modeling and drug development that has the potential to slow human NASH progression and to counteract NASH-related SARS-CoV-2 effects.
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http://dx.doi.org/10.1002/hep.31857DOI Listing
April 2021

A Mendelian randomization study of the role of lipoprotein subfractions in coronary artery disease.

Elife 2021 Apr 26;10. Epub 2021 Apr 26.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.

Recent genetic data can offer important insights into the roles of lipoprotein subfractions and particle sizes in preventing coronary artery disease (CAD), as previous observational studies have often reported conflicting results. We used the LD score regression to estimate the genetic correlation of 77 subfraction traits with traditional lipid profile and identified 27 traits that may represent distinct genetic mechanisms. We then used Mendelian randomization (MR) to estimate the causal effect of these traits on the risk of CAD. In univariable MR, the concentration and content of medium high-density lipoprotein (HDL) particles showed a protective effect against CAD. The effect was not attenuated in multivariable analyses. Multivariable MR analyses also found that small HDL particles and smaller mean HDL particle diameter may have a protective effect. We identified four genetic markers for HDL particle size and CAD. Further investigations are needed to fully understand the role of HDL particle size.
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http://dx.doi.org/10.7554/eLife.58361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163505PMC
April 2021

Nuclear receptors FXR and SHP regulate protein N-glycan modifications in the liver.

Sci Adv 2021 Apr 21;7(17). Epub 2021 Apr 21.

Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are key regulators of metabolism. Here, we report a previously unknown function for the hepatic FXR-SHP axis in controlling protein N-linked glycosylation. Transcriptome analysis in liver-specific Fxr-Shp double knockout (LDKO) livers revealed induction of genes encoding enzymes in the N-glycosylation pathway, including , , , and FXR activation suppressed , while Shp deletion induced and Increased percentages of core-fucosylated and triantennary glycan moieties were seen in LDKO livers, and proteins with the "hyperglycoforms" preferentially localized to exosomes and lysosomes. This up-regulation of N-glycosylation machinery was specific to the Golgi apparatus and not the endoplasmic reticulum. The increased glycan complexity in the LDKO correlated well with dilated unstacked Golgi ribbons and alterations in the secretion of albumin, cholesterol, and triglycerides. Our findings demonstrate a role for the FXR-SHP axis in maintaining glycoprotein diversity in the liver.
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http://dx.doi.org/10.1126/sciadv.abf4865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059921PMC
April 2021
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