44 results on '"Sumeet A. Khetarpal"'
Search Results
2. Polygenic determinants in extremes of high-density lipoprotein cholesterol
- Author
-
Jacqueline S. Dron, Jian Wang, Cécile Low-Kam, Sumeet A. Khetarpal, John F. Robinson, Adam D. McIntyre, Matthew R. Ban, Henian Cao, David Rhainds, Marie-Pierre Dubé, Daniel J. Rader, Guillaume Lettre, Jean-Claude Tardif, and Robert A. Hegele
- Subjects
genetics ,genomics ,dyslipidemias ,genes in lipid dysfunction ,complex trait ,rare variants ,Biochemistry ,QD415-436 - Abstract
HDL cholesterol (HDL-C) remains a superior biochemical predictor of CVD risk, but its genetic basis is incompletely defined. In patients with extreme HDL-C concentrations, we concurrently evaluated the contributions of multiple large- and small-effect genetic variants. In a discovery cohort of 255 unrelated lipid clinic patients with extreme HDL-C levels, we used a targeted next-generation sequencing panel to evaluate rare variants in known HDL metabolism genes, simultaneously with common variants bundled into a polygenic trait score. Two additional cohorts were used for validation and included 1,746 individuals from the Montréal Heart Institute Biobank and 1,048 individuals from the University of Pennsylvania. Findings were consistent between cohorts: we found rare heterozygous large-effect variants in 18.7% and 10.9% of low- and high-HDL-C patients, respectively. We also found common variant accumulation, indicated by extreme polygenic trait scores, in an additional 12.8% and 19.3% of overall cases of low- and high-HDL-C extremes, respectively. Thus, the genetic basis of extreme HDL-C concentrations encountered clinically is frequently polygenic, with contributions from both rare large-effect and common small-effect variants. Multiple types of genetic variants should be considered as contributing factors in patients with extreme dyslipidemia.
- Published
- 2017
- Full Text
- View/download PDF
3. ANGPTL3 inhibition, dyslipidemia, and cardiovascular diseases
- Author
-
Fei Luo, Avash Das, Sumeet A. Khetarpal, Zhenfei Fang, Thomas A Zelniker, Robert S. Rosenson, and Arman Qamar
- Subjects
Cardiology and Cardiovascular Medicine - Published
- 2023
4. Abstract 13879: Relationship of Serum Lipid Metabolites and Clonal Hematopoiesis of Indeterminate Potential Among 12,186 Participants of the UK Biobank
- Author
-
Sumeet A Khetarpal, Md Mesbah Uddin, Satoshi Koyama, Zhi Yu, Akhil Pampana, Abhishek Niroula, Christopher Gibson, Gabriel Griffin, Peter Libby, Benjamin Ebert, and Pradeep Natarajan
- Subjects
Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Background: Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of leukemogenic mutations in hematopoietic stem cells in asymptomatic individuals, is an emerging age-related risk factor for blood cancers and myriad cardio-metabolic diseases. The spectrum of metabolites that may protect from or predispose to development of CHIP remains unknown. Methods: We obtained CHIP genotypes and measured serum metabolites among UK Biobank, a population-based study of United Kingdom residents aged 40-70 years. CHIP was also categorized by driver genes DNMT3A and TET2 and presence of large CHIP clones (variant allele fraction or VAF > 10%). 152 lipid and lipoprotein metabolites were performed using NMR from blood samples. The relationship of CHIP to metabolites was assessed by multivariate linear regression adjusting for covariates of age, sex, smoking and principal components 1-10. Results: Among the 12,186 included UK Biobank participants with mean (SD) age 57.1 (8.0), we identified CHIP in 701 (5.75%). 313 participants with CHIP had large clones (VAF>10%), and of these, 169 had DNMT3A mutations and 75 had TET2 mutations. Presence of CHIP was nominally associated with multiple measures of HDL and apolipoprotein B-containing lipoprotein metabolites. Among HDL metabolites, CHIP was associated with reductions in the percentage of HDL total cholesterol (ß = -0.09, P = 0.01), free cholesterol (ß = -0.072, P = 0.01) and cholesteryl ester (ß = -0.087, P = 0.01) and increased HDL triglyceride percentage (ß = 0.09, P = 0.01). Similar findings were observed for small, medium and large HDL particles. CHIP was also associated with decreased percentage of small LDL free cholesterol (ß = -0.089, P = 0.016) and phospholipid (ß = -0.106, P = 0.0057) and increased cholesterol ester (ß = 0.105, P = 0.0061). For VLDL, CHIP was associated with increased VLDL particle number (ß = 0.077, P = 0.035) and VLDL phospholipid percentage (ß = 0.085, P = 0.025) in the largest VLDL particles. Similar findings among HDL and VLDL metabolites were seen in those with large CHIP clones due to TET2 mutations but not with large clones due to DNMT3A mutations. Conclusions: These results reveal novel relationships of CHIP with lipid and lipoprotein metabolites in a population-based cohort.
- Published
- 2021
5. Clonal Hematopoiesis of Indeterminate Potential Reshapes Age-Related CVD
- Author
-
Arman Qamar, Sekar Kathiresan, Siddhartha Jaiswal, Alexander G. Bick, Sumeet A. Khetarpal, Pradeep Natarajan, and José J. Fuster
- Subjects
medicine.medical_specialty ,business.industry ,Vascular disease ,Incidence (epidemiology) ,Hematopoietic stem cell ,030204 cardiovascular system & hematology ,Bioinformatics ,medicine.disease ,Human genetics ,Leukemogenic ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Diabetes mellitus ,Epidemiology ,medicine ,030212 general & internal medicine ,Risk factor ,Cardiology and Cardiovascular Medicine ,business - Abstract
The incidence of cardiovascular diseases increases with age and is also correlated with increased inflammatory burden. Recently, human genetics provided a new paradigm linking aging, inflammation, and atherosclerotic cardiovascular disease (ASCVD). Next-generation genetic sequencing of whole blood-derived DNA in humans showed that clonal expansion of hematopoietic cells with somatic mutations in leukemogenic genes was associated with age and correlated with increased mortality. This phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), was associated with hematologic malignancy as well as ASCVD independently of age and other traditional risk factors. Because the implication of CHIP with ASCVD, genetic loss-of-function studies of Tet2 and Dnmt3a in murine models have supported a mechanistic role for CHIP in promoting vascular disease. Despite the potential contribution of CHIP to myriad cardiovascular and aging-related diseases, the epidemiology and biology surrounding this phenomenon remains incompletely appreciated and understood, especially as applied to clinical practice and prognostication. Here, the authors review this emerging key risk factor, defining its discovery, relationship to cardiovascular diseases, preclinical evidence for causality, and implications for risk prediction and mitigation.
- Published
- 2019
6. Lipoprotein(a) and Coronary Artery Disease Risk Without a Family History of Heart Disease
- Author
-
Pradeep Natarajan, Phoebe Finneran, Mark Trinder, Aniruddh P. Patel, Gina M. Peloso, Kaavya Paruchuri, Akhil Pampana, Krishna G. Aragam, and Sumeet A. Khetarpal
- Subjects
Male ,medicine.medical_specialty ,Heart disease ,Heart Diseases ,primary prevention ,Coronary Artery Disease Risk ,Coronary Artery Disease ,Global Health ,Risk Factors ,cardiovascular disease ,Primary prevention ,Internal medicine ,Research Letter ,Medicine ,Humans ,Family history ,Medical History Taking ,biology ,business.industry ,Incidence ,lipoprotein ,risk assessment ,Lipoprotein(a) ,Middle Aged ,medicine.disease ,Survival Rate ,biology.protein ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Risk assessment ,Biomarkers ,Lipoprotein - Published
- 2021
7. ApoC-III helical structure determines its ability to bind plasma lipoproteins and inhibit Lipoprotein Lipase-mediated triglyceride lipolysis
- Author
-
Cecilia Vitali, Sumeet A. Khetarpal, Daniel J. Rader, John S. Millar, Sissel Lund-Katz, S. Walter Englander, Sylvia Stankov, Nicholas J. Hand, Michael C. Phillips, and Leland Mayne
- Subjects
chemistry.chemical_classification ,Very low-density lipoprotein ,Lipoprotein lipase ,Apolipoprotein B ,biology ,Triglyceride ,Chemistry ,Amino acid ,chemistry.chemical_compound ,Biochemistry ,Helix ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Alpha helix ,Lipoprotein - Abstract
In humans, apolipoprotein C-III (apoC-III) plasma levels have been associated with increased risk of cardiovascular disease. This association is in part explained by the effects of apoC-III on triglyceride (TG) metabolism; apoC-III raises plasma TG by increasing very low density lipoprotein (VLDL) secretion, inhibiting lipoprotein lipase (LPL)-mediated TG lipolysis, and impairing the removal of triglyceride-rich lipoprotein (TRL) remnants from the circulation. In this study, we explored the structure-function relationship the interaction of apoC-III with plasma lipoproteins and its ultimate impact on LPL activity. The structural and functional properties of wild-type (WT) apoC-III were compared with two missense variants previously associated with lower (A23T) and higher (Q38K) plasma TG. ApoC-III in the lipid-free state is unstructured but its helix content and stability increases when bound to lipid. Lipid-bound apoC-III contains two alpha helices spanning residues amino acids 11 - 38 (helix 1) and 44 – 64 (helix 2). Investigation of the structural and functional consequences of the A23T and Q38K variants showed that these amino acid substitutions within helix 1 do not significantly alter the stability of the helical structure but affect its hydrophilic-lipophilic properties. The A23T substitution impairs lipoprotein binding capacity, reduces LPL inhibition, and ultimately leads to lower plasma TG levels. Conversely, the Q to K substitution at position 38 enhances the lipid affinity of helix 1, increases TRL binding capacity and LPL inhibition, and is associated with hypertriglyceridemia. This study indicates that structural modifications that perturb the hydrophilic/lipophilic properties of the alpha helices can modulate the hypertriglyceridemic effects of apoC-III.
- Published
- 2020
8. Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function
- Author
-
Elena Gardella, Damir Musaev, Cecilia Vitali, Emanuele Agolini, Sumeet A. Khetarpal, Kimiyo Raymond, Daniel J. Rader, Camilla Gøbel Madsen, Valentina Stanley, Antonio Novelli, Andrew C. Edmondson, W. Timothy O'Brien, Heiko Reutter, John Hintze, Kristen Liedtke, Mahmoud Y. Issa, Lars Hansen, Christina Fenger, Kevin Rostasy, Rami Abou Jamra, Maha S. Zaki, Francesca Romana Lepri, Ulla E. Petäjä-Repo, Joseph G. Gleeson, Rikke S. Møller, Silvana Briuglia, Katrine T. Schjoldager, Lorenzo Sinibaldi, Viola Alesi, Guido Rubboli, Raffaella Cusmai, and Monica Zilmer
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Glycosylation ,Adolescent ,Congenital disorders of glycosylation, O-glycosylation, GALNT2, Apolipoprotein C-III glycosylation, HDL-cholesterol ,Developmental Disabilities ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Young Adult ,0302 clinical medicine ,Loss of Function Mutation ,Internal medicine ,medicine ,Animals ,Humans ,Congenital disorders of glycosylation ,Global developmental delay ,Child ,O-glycosylation ,Apolipoprotein C-III ,Original Articles ,medicine.disease ,HDL-cholesterol ,Pedigree ,Rats ,Developmental disorder ,030104 developmental biology ,Endocrinology ,chemistry ,GALNT2 ,Child, Preschool ,O-linked glycosylation ,Apolipoprotein C-III glycosylation ,N-Acetylgalactosaminyltransferases ,Apolipoprotein C3 ,lipids (amino acids, peptides, and proteins) ,Female ,Neurology (clinical) ,Congenital disorder of glycosylation ,Lipid glycosylation ,030217 neurology & neurosurgery ,Congenital disorder - Abstract
Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.
- Published
- 2020
9. The effects of apolipoprotein F deficiency on high density lipoprotein cholesterol metabolism in mice.
- Author
-
William R Lagor, David W Fields, Sumeet A Khetarpal, Arthi Kumaravel, Wen Lin, Nathaniel Weintraub, Kaijin Wu, Sarah F Hamm-Alvarez, Denise Drazul-Schrader, Margarita de la Llera-Moya, George H Rothblat, and Daniel J Rader
- Subjects
Medicine ,Science - Abstract
Apolipoprotein F (apoF) is 29 kilodalton secreted sialoglycoprotein that resides on the HDL and LDL fractions of human plasma. Human ApoF is also known as Lipid Transfer Inhibitor protein (LTIP) based on its ability to inhibit cholesteryl ester transfer protein (CETP)-mediated transfer events between lipoproteins. In contrast to other apolipoproteins, ApoF is predicted to lack strong amphipathic alpha helices and its true physiological function remains unknown. We previously showed that overexpression of Apolipoprotein F in mice reduced HDL cholesterol levels by 20-25% by accelerating clearance from the circulation. In order to investigate the effect of physiological levels of ApoF expression on HDL cholesterol metabolism, we generated ApoF deficient mice. Unexpectedly, deletion of ApoF had no substantial impact on plasma lipid concentrations, HDL size, lipid or protein composition. Sex-specific differences were observed in hepatic cholesterol content as well as serum cholesterol efflux capacity. Female ApoF KO mice had increased liver cholesteryl ester content relative to wild type controls on a chow diet (KO: 3.4+/-0.9 mg/dl vs. WT: 1.2+/-0.3 mg/dl, p
- Published
- 2012
- Full Text
- View/download PDF
10. Volanesorsen, Familial Chylomicronemia Syndrome, and Thrombocytopenia. Reply
- Author
-
Sumeet A. Khetarpal, Amit Khera, and Minxian Wang
- Subjects
Apolipoprotein C-III ,business.industry ,MEDLINE ,Oligonucleotides ,General Medicine ,Familial Chylomicronemia ,Bioinformatics ,Thrombocytopenia ,Article ,HYPERLIPOPROTEINEMIA TYPE I ,Medicine ,Humans ,Hyperlipoproteinemia Type I ,business ,Triglycerides - Published
- 2019
11. Natural human genetic variation determines basal and inducible expression of PM20D1, an obesity-associated gene
- Author
-
Lin Wang, Satoshi Yoshino, Kiara K. Benson, Eric Chen, Benjamin F. Voight, Sumeet A. Khetarpal, Alexis H. Bennett, Angela H. Weller, William P. Bone, Raymond E. Soccio, Wenxiang Hu, and Joshua D. Rabinowitz
- Subjects
Male ,Response element ,Peroxisome proliferator-activated receptor ,Gene Expression ,Biology ,Amidohydrolases ,chemistry.chemical_compound ,Mice ,Adipocyte ,Gene duplication ,Adipocytes ,Animals ,Humans ,Obesity ,Gene ,Regulation of gene expression ,chemistry.chemical_classification ,Multidisciplinary ,Genetic Variation ,Biological Sciences ,Cell biology ,PPAR gamma ,Phenotype ,chemistry ,Nuclear receptor ,Adipose Tissue ,Gene Expression Regulation ,DNA methylation ,Thiazolidinediones - Abstract
PM20D1 is a candidate thermogenic enzyme in mouse fat, with its expression cold-induced and enriched in brown versus white adipocytes. Thiazolidinedione (TZD) antidiabetic drugs, which activate the peroxisome proliferator-activated receptor-γ (PPARγ) nuclear receptor, are potent stimuli for adipocyte browning yet fail to induce Pm20d1 expression in mouse adipocytes. In contrast, PM20D1 is one of the most strongly TZD-induced transcripts in human adipocytes, although not in cells from all individuals. Two putative PPARγ binding sites exist near the gene’s transcription start site (TSS) in human but not mouse adipocytes. The −4 kb upstream site falls in a segmental duplication of a nearly identical intronic region +2.5 kb downstream of the TSS, and this duplication occurred in the primate lineage and not in other mammals, like mice. PPARγ binding and gene activation occur via this upstream duplicated site, thus explaining the species difference. Furthermore, this functional upstream PPARγ site exhibits genetic variation among people, with 1 SNP allele disrupting a PPAR response element and giving less activation by PPARγ and TZDs. In addition to this upstream variant that determines PPARγ regulation of PM20D1 in adipocytes, distinct variants downstream of the TSS have strong effects on PM20D1 expression in human fat as well as other tissues. A haplotype of 7 tightly linked downstream SNP alleles is associated with very low PMD201 expression and correspondingly high DNA methylation at the TSS. These PM20D1 low-expression variants may account for human genetic associations in this region with obesity as well as neurodegenerative diseases.
- Published
- 2019
12. Implications of Premature Coronary Artery Calcification in Primary and Secondary Prevention of Atherosclerotic Cardiovascular Disease
- Author
-
Pradeep Natarajan, Michael C. Honigberg, and Sumeet A. Khetarpal
- Subjects
Male ,Secondary prevention ,medicine.medical_specialty ,business.industry ,Atherosclerotic cardiovascular disease ,Coronary arteriosclerosis ,Middle Aged ,Atherosclerosis ,Coronary Vessels ,Article ,Primary Prevention ,Coronary artery calcium ,Cardiovascular Diseases ,Internal medicine ,Coronary artery calcification ,Secondary Prevention ,Cardiology ,Humans ,Medicine ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Tomography, X-Ray Computed ,Vascular Calcification ,Cardiology and Cardiovascular Medicine ,business - Published
- 2021
13. Mining the LIPG allelic spectrum reveals the contribution of rare and common regulatory variants to HDL cholesterol.
- Author
-
Sumeet A Khetarpal, Andrew C Edmondson, Avanthi Raghavan, Hemanth Neeli, Weijun Jin, Karen O Badellino, Serkalem Demissie, Alisa K Manning, Stephanie L DerOhannessian, Megan L Wolfe, L Adrienne Cupples, Mingyao Li, Sekar Kathiresan, and Daniel J Rader
- Subjects
Genetics ,QH426-470 - Abstract
Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5' UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5' UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci.
- Published
- 2011
- Full Text
- View/download PDF
14. Polygenic determinants in extremes of high-density lipoprotein cholesterol
- Author
-
Cécile Low-Kam, Marie-Pierre Dubé, Sumeet A. Khetarpal, Jacqueline S. Dron, Henian Cao, Adam D. McIntyre, Daniel J. Rader, Robert A. Hegele, Guillaume Lettre, Matthew R. Ban, Jean-Claude Tardif, Jian Wang, David Rhainds, and John F. Robinson
- Subjects
Adult ,Male ,0301 basic medicine ,Genotype ,Genomics ,QD415-436 ,030204 cardiovascular system & hematology ,Biology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,High-density lipoprotein ,common variants ,Genetic variation ,genomics ,medicine ,Humans ,genetics ,dyslipidemias ,Gene ,Aged ,genes in lipid dysfunction ,Genetics ,Cholesterol ,Cholesterol, HDL ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,rare variants ,Cell Biology ,Middle Aged ,medicine.disease ,3. Good health ,030104 developmental biology ,complex trait ,chemistry ,polygenic risk score ,Cohort ,Female ,next-generation sequencing ,lipids (amino acids, peptides, and proteins) ,Patient-Oriented and Epidemiological Research ,Dyslipidemia - Abstract
HDL cholesterol (HDL-C) remains a superior biochemical predictor of CVD risk, but its genetic basis is incompletely defined. In patients with extreme HDL-C concentrations, we concurrently evaluated the contributions of multiple large- and small-effect genetic variants. In a discovery cohort of 255 unrelated lipid clinic patients with extreme HDL-C levels, we used a targeted next-generation sequencing panel to evaluate rare variants in known HDL metabolism genes, simultaneously with common variants bundled into a polygenic trait score. Two additional cohorts were used for validation and included 1,746 individuals from the Montréal Heart Institute Biobank and 1,048 individuals from the University of Pennsylvania. Findings were consistent between cohorts: we found rare heterozygous large-effect variants in 18.7% and 10.9% of low- and high-HDL-C patients, respectively. We also found common variant accumulation, indicated by extreme polygenic trait scores, in an additional 12.8% and 19.3% of overall cases of low- and high-HDL-C extremes, respectively. Thus, the genetic basis of extreme HDL-C concentrations encountered clinically is frequently polygenic, with contributions from both rare large-effect and common small-effect variants. Multiple types of genetic variants should be considered as contributing factors in patients with extreme dyslipidemia.
- Published
- 2017
15. Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins
- Author
-
Michael G. Levin, Jeffrey T. Billheimer, John S. Millar, Sumeet A. Khetarpal, Joseph Park, Takashi Kuwano, Daniel J. Rader, Pradeep Natarajan, Derek Klarin, Cecilia Vitali, Papasani V. Subbaiah, Dhavamani Sugasini, and Akhil Pampana
- Subjects
Endothelial lipase ,Cancer Research ,Hydrolases ,QH426-470 ,Biochemistry ,Fats ,Mice ,chemistry.chemical_compound ,Medicine and Health Sciences ,Lipases ,Phospholipids ,Genetics (clinical) ,chemistry.chemical_classification ,Lipoprotein lipase ,biology ,Hydrolysis ,Chemical Reactions ,Postprandial Period ,Lipids ,Enzymes ,Chemistry ,Physical Sciences ,lipids (amino acids, peptides, and proteins) ,Energy source ,Research Article ,Polyunsaturated fatty acid ,medicine.medical_specialty ,Lipolysis ,Lipoproteins ,Mutation, Missense ,Diet, High-Fat ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Lipase ,Molecular Biology ,Triglycerides ,Ecology, Evolution, Behavior and Systematics ,Nutrition ,Triglyceride ,Biology and Life Sciences ,Proteins ,Human Genetics ,Diet ,Endocrinology ,chemistry ,Liposomes ,Enzymology ,biology.protein ,Lipoprotein - Abstract
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., Author summary Endothelial lipase (EL) plays a pivotal role in the breakdown of high-density lipoproteins (HDLs) by hydrolyzing phospholipids on HDL surfaces. Here we show through studies of humans and mice with genetic loss-of-function of EL activity that EL is also crucial in catabolizing triglyceride (TG)-rich lipoproteins, particularly in states of nutrient excess such as after refeeding or after feeding a high-fat diet. We demonstrate that EL collaborates with lipoprotein lipase (LPL), the predominant enzyme hydrolysing triglycerides, to promote the breakdown of triglycerides on lipoproteins. The mechanism for this may be due to an underappreciated ability of EL to hydrolyze TGs and cooperate with LPL to efficiently break down and clear these particles. Our data adds important insights into the mechanisms of circulating TG metabolism in mice and humans as informed by large-scale human genetics.
- Published
- 2021
16. Deep Apolipoprotein Proteomics to Uncover Mechanisms of Coronary Disease Risk ∗
- Author
-
Daniel J. Rader, Sumeet A. Khetarpal, and Archna Bajaj
- Subjects
0301 basic medicine ,Apolipoprotein E ,Very low-density lipoprotein ,medicine.medical_specialty ,Apolipoprotein B ,biology ,business.industry ,Apolipoprotein C-II ,Apolipoprotein C-III ,030204 cardiovascular system & hematology ,Coronary disease ,Proteomics ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,biology.protein ,Apolipoprotein C2 ,Cardiology and Cardiovascular Medicine ,business - Published
- 2017
17. Deciphering Cardiovascular Genomics and How They Apply to Cardiovascular Disease Prevention
- Author
-
Sumeet A. Khetarpal and Kiran Musunuru
- Published
- 2018
18. LIPOPROTEIN(A) CONFERS INCIDENT CORONARY ARTERY DISEASE RISK AMONG 243,474 INDIVIDUALS WITHOUT A FAMILY HISTORY OF HEART DISEASE
- Author
-
Phoebe Finneran, Akhil Pampana, Krishna G. Aragam, Pradeep Natarajan, and Sumeet A. Khetarpal
- Subjects
medicine.medical_specialty ,biology ,Heart disease ,business.industry ,Lipoprotein(a) ,medicine.disease ,Biobank ,Coronary artery disease ,Internal medicine ,biology.protein ,Cardiology ,Medicine ,Family history ,Risk factor ,Cardiology and Cardiovascular Medicine ,business ,Prospective cohort study ,Lipoprotein - Abstract
Lipoprotein(a) [Lp(a)] is an independent, highly heritable risk factor for coronary artery disease (CAD) risk. However, the incident CAD risk of elevated Lp(a) in those without a family history of heart disease is poorly understood. We studied participants of the prospective cohort, the UK Biobank
- Published
- 2020
19. Multiplexed Targeted Resequencing Identifies Coding and Regulatory Variation Underlying Phenotypic Extremes of High-Density Lipoprotein Cholesterol in Humans
- Author
-
Christopher D. Brown, Daniel J. Rader, William F. Hancock-Cerutti, Benjamin F. Voight, Wei Zhao, Paul L. Babb, and Sumeet A. Khetarpal
- Subjects
0301 basic medicine ,Genetics ,Cholesterol ,Genome-wide association study ,General Medicine ,Biology ,Phenotype ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,High-density lipoprotein ,Variation (linguistics) ,chemistry ,Genetic variation ,lipids (amino acids, peptides, and proteins) ,030217 neurology & neurosurgery ,Lipoprotein cholesterol ,Genetic association - Abstract
Background: Genome-wide association studies have uncovered common variants at many loci influencing human complex traits, such as high-density lipoprotein cholesterol (HDL-C). However, the contribu...
- Published
- 2018
20. Multiplexed targeted resequencing identifies coding and regulatory variation underlying phenotypic extremes of HDL-cholesterol in humans
- Author
-
Christopher D. Brown, Wei Zhao, Daniel J. Rader, Benjamin F. Voight, William F. Hancock-Cerutti, Paul L. Babb, and Sumeet A. Khetarpal
- Subjects
Genetics ,Adult ,Male ,Multifactorial Inheritance ,Concordance ,Cholesterol, HDL ,Genomics ,Genome-wide association study ,Biology ,Regulatory Sequences, Nucleic Acid ,Phenotype ,Polymorphism, Single Nucleotide ,SCARB1 ,Article ,Open Reading Frames ,Humans ,Female ,lipids (amino acids, peptides, and proteins) ,Genotyping ,Gene ,Genetic association ,Genome-Wide Association Study - Abstract
Genome-wide association studies have uncovered common variants at many loci influencing human complex traits and diseases, such as high-density lipoprotein cholesterol (HDL-C). However, the contribution of the identified genes is difficult to ascertain from current efforts interrogating common variants with small effects. Thus, there is a pressing need for scalable, cost-effective strategies for uncovering causal variants, many of which may be rare and noncoding. Here, we used a multiplexed inversion probe (MIP) target capture approach to resequence both coding and regulatory regions at seven HDL-C associated loci in 797 individuals with extremely high HDL-C vs. 735 low-to-normal HDL-C controls. Our targets included protein-coding regions of GALNT2, APOA5, APOC3, SCARB1, CCDC92, ZNF664, CETP, and LIPG (>9 kb), and proximate noncoding regulatory features (>42 kb). Exome-wide genotyping in 1,114 of the 1,532 participants yielded a >90% genotyping concordance rate with MIP-identified variants in ~90% of participants. This approach rediscovered nearly all established GWAS associations in GALNT2, CETP, and LIPG loci with significant and concordant associations with HDL-C from our phenotypic-extremes design at 0.1% of the sample size of lipid GWAS studies. In addition, we identified a novel, rare, CETP noncoding variant enriched in the extreme high HDL-C group (P
- Published
- 2017
- Full Text
- View/download PDF
21. HDL Cholesterol Metabolism and the Risk of CHD: New Insights from Human Genetics
- Author
-
Cecilia Vitali, Daniel J. Rader, and Sumeet A. Khetarpal
- Subjects
0301 basic medicine ,Candidate gene ,Genomics ,Genome-wide association study ,Context (language use) ,Coronary Disease ,Computational biology ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Mendelian randomization ,Exome Sequencing ,Medicine ,Humans ,Genetic Predisposition to Disease ,Molecular Targeted Therapy ,Exome ,Exome sequencing ,business.industry ,Cholesterol, HDL ,Mendelian Randomization Analysis ,Lipid Metabolism ,Human genetics ,030104 developmental biology ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Genome-Wide Association Study - Abstract
Elevated high-density lipoprotein cholesterol levels in the blood (HDL-C) represent one of the strongest epidemiological surrogates for protection against coronary heart disease (CHD), but recent human genetic and pharmacological intervention studies have raised controversy about the causality of this relationship. Here, we review recent discoveries from human genome studies using new analytic tools as well as relevant animal studies that have both addressed, and in some cases, fueled this controversy. Methodologic developments in genotyping and sequencing, such as genome-wide association studies (GWAS), exome sequencing, and exome array genotyping, have been applied to the study of HDL-C and risk of CHD in large, multi-ethnic populations. Some of these efforts focused on population-wide variation in common variants have uncovered new polymorphisms at novel loci associated with HDL-C and, in some cases, CHD risk. Other efforts have discovered loss-of-function variants for the first time in genes previously implicated in HDL metabolism through common variant studies or animal models. These studies have allowed the genetic relationship between these pathways, HDL-C and CHD to be explored in humans for the first time through analysis tools such as Mendelian randomization. We explore these discoveries for selected key HDL-C genes CETP, LCAT, LIPG, SCARB1, and novel loci implicated from GWAS including GALNT2, KLF14, and TTC39B. Recent human genetics findings have identified new nodes regulating HDL metabolism while reshaping our current understanding of known candidate genes to HDL and CHD risk through the study of critical variants across model systems. Despite their effect on HDL-C, variants in many of the reviewed genes were found to lack any association with CHD. These data collectively indicate that HDL-C concentration, which represents a static picture of a very dynamic and heterogeneous metabolic milieu, is unlikely to be itself causally protective against CHD. In this context, human genetics represent an extremely valuable tool to further explore the biological mechanisms regulating HDL metabolism and investigate what role, if any, HDL plays in the pathogenesis of CHD.
- Published
- 2017
22. Plasma Apolipoprotein C-III Levels, Triglycerides, and Coronary Artery Calcification in Type 2 Diabetics
- Author
-
Daniel J. Rader, Arman Qamar, Sumeet A. Khetarpal, Muredach P. Reilly, Atif Qasim, and Amit Khera
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Apolipoprotein B ,Cross-sectional study ,Coronary Artery Disease ,Diabetic angiopathy ,Article ,Coronary artery disease ,Risk Factors ,Internal medicine ,medicine ,Humans ,Vascular Calcification ,Triglycerides ,Aged ,Dyslipidemias ,Philadelphia ,Apolipoprotein C-III ,Lipoprotein lipase ,biology ,business.industry ,Type 2 Diabetes Mellitus ,Middle Aged ,medicine.disease ,Up-Regulation ,Cross-Sectional Studies ,Phenotype ,Endocrinology ,Diabetes Mellitus, Type 2 ,Coronary artery calcification ,biology.protein ,Cardiology ,Female ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Diabetic Angiopathies - Abstract
Objective— Triglyceride-rich lipoproteins have emerged as causal risk factors for developing coronary heart disease independent of low-density lipoprotein cholesterol levels. Apolipoprotein C-III (ApoC-III) modulates triglyceride-rich lipoprotein metabolism through inhibition of lipoprotein lipase and hepatic uptake of triglyceride-rich lipoproteins. Mutations causing loss-of-function of ApoC-III lower triglycerides and reduce coronary heart disease risk, suggestive of a causal role for ApoC-III. Little data exist about the relationship of ApoC-III, triglycerides, and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Here, we examined the relationships between plasma ApoC-III, triglycerides, and coronary artery calcification in patients with T2DM. Approach and Results— Plasma ApoC-III levels were measured in a cross-sectional study of 1422 subjects with T2DM but without clinically manifest coronary heart disease. ApoC-III levels were positively associated with total cholesterol (Spearman r =0.36), triglycerides ( r =0.59), low-density lipoprotein cholesterol ( r =0.16), fasting glucose ( r =0.16), and glycosylated hemoglobin ( r =0.12; P P P =0.086) and separately for very low–density lipoprotein cholesterol (Tobit regression ratio, 1.14; 95% confidence interval, 0.75–1.71; P =0.53). Conclusions— In persons with T2DM, increased plasma ApoC-III is associated with higher triglycerides, less favorable cardiometabolic phenotypes, and higher coronary artery calcification, a measure of subclinical atherosclerosis. Therapeutic inhibition of ApoC-III may thus be a novel strategy for reducing plasma triglyceride-rich lipoproteins and cardiovascular risk in T2DM.
- Published
- 2015
23. Genetics of lipid traits: Genome-wide approaches yield new biology and clues to causality in coronary artery disease
- Author
-
Daniel J. Rader and Sumeet A. Khetarpal
- Subjects
Genetics ,0303 health sciences ,Candidate gene ,Genome-wide association ,Lipoproteins ,Genome-wide association study ,Single-nucleotide polymorphism ,Biology ,Complex traits ,Causality ,Genome ,03 medical and health sciences ,0302 clinical medicine ,Molecular Medicine ,Identification (biology) ,Gene ,Molecular Biology ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
A wealth of novel lipid loci have been identified through a variety of approaches focused on common and low-frequency variation and collaborative metaanalyses in multiethnic populations. Despite progress in identification of loci, the task of determining causal variants remains challenging. This work will undoubtedly be enhanced by improved understanding of regulatory DNA at a genomewide level as well as new methodologies for interrogating the relationships between noncoding SNPs and regulatory regions. Equally challenging is the identification of causal genes at novel loci. Some progress has been made for a handful of genes and comprehensive testing of candidate genes using multiple model systems is underway. Additional insights will be gleaned from focusing on low frequency and rare coding variation at candidate loci in large populations. This article is part of a Special Issue entitled: From Genome to Function.
- Published
- 2014
- Full Text
- View/download PDF
24. Abstract 367: Extreme High-Density Lipoprotein Cholesterol Genetics: An Assortment of Large and Small Polygenic Effects
- Author
-
Jacqueline S Dron, Jian Wang, Cécile Low-Kam, Sumeet A Khetarpal, John F Robinson, Adam D McIntyre, Matthew R Ban, Henian Cao, David Rhainds, Marie-Pierre Dubé, Daniel J Rader, Guillaume Lettre, Jean-Claude Tardif, and Robert A Hegele
- Subjects
Cardiology and Cardiovascular Medicine - Abstract
Rationale: Although HDL-C levels are known to have a complex genetic basis, most studies have focused solely on identifying rare variants with large phenotypic effects to explain extreme HDL-C phenotypes. Objective: Here we concurrently evaluate the contribution of both rare and common genetic variants, as well as large-scale copy number variations (CNVs), towards extreme HDL-C concentrations. Methods: In clinically ascertained patients with low ( N =136) and high ( N =119) HDL-C profiles, we applied our targeted next-generation sequencing panel (LipidSeq TM ) to sequence genes involved in HDL metabolism, which were subsequently screened for rare variants and CNVs. We also developed a novel polygenic trait score (PTS) to assess patients’ genetic accumulations of common variants that have been shown by genome-wide association studies to associate primarily with HDL-C levels. Two additional cohorts of patients with extremely low and high HDL-C (total N =1,746 and N =1,139, respectively) were used for PTS validation. Results: In the discovery cohort, 32.4% of low HDL-C patients carried rare variants or CNVs in primary ( ABCA1 , APOA1 , LCAT ) and secondary ( LPL , LMF1 , GPD1 , APOE ) HDL-C–altering genes. Additionally, 13.4% of high HDL-C patients carried rare variants or CNVs in primary ( SCARB1 , CETP , LIPC , LIPG ) and secondary ( APOC3 , ANGPTL4 ) HDL-C–altering genes. For polygenic effects, patients with abnormal HDL-C profiles but without rare variants or CNVs were ~2-fold more likely to have an extreme PTS compared to normolipidemic individuals, indicating an increased frequency of common HDL-C–associated variants in these patients. Similar results in the two validation cohorts demonstrate that this novel PTS successfully quantifies common variant accumulation, further characterizing the polygenic basis for extreme HDL-C phenotypes. Conclusions: Patients with extreme HDL-C levels have various combinations of rare variants, common variants, or CNVs driving their phenotypes. Fully characterizing the genetic basis of HDL-C levels must extend to encompass multiple types of genetic determinants—not just rare variants—to further our understanding of this complex, controversial quantitative trait.
- Published
- 2017
25. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity
- Author
-
Sumeet A. Khetarpal, Maria Samuel, Khan Shah Zaman, Khalid Mahmood, Saba Akhtar, Daniel J. Rader, Kevin Trindade, Shahid Abbas, Syed Nadeem Hasan Rizvi, Zia Yaqoob, Pradeep Natarajan, Faisal Majeed, Syed Zahed Rasheed, Asif Rasheed, Benjamin Weisburd, Atif Imran, Nadeem Hayat Mallick, Namrata Gupta, Daniel G. MacArthur, John Danesh, Kaitlin E. Samocha, Hong-Hee Won, Madiha Ishaq, Wei Zhao, Mozzam Zaidi, Mohammad Ishaq, Anis Memon, Anne H. O’Donnell-Luria, Nadeem Qamar, Eric S. Lander, Fazal-ur-Rehman Memon, Irina M. Armean, Konrad J. Karczewski, Tahir Saghir, Ronald M. Krauss, Megan L. Mucksavage, Philippe M. Frossard, Naveeduddin Ahmed, Stacey Gabriel, Danish Saleheen, Sekar Kathiresan, Ron Do, Mark J. Daly, Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Male ,DNA Mutational Analysis ,Myocardial Infarction ,Coronary Disease ,medicine.disease_cause ,Cohort Studies ,Consanguinity ,Gene Frequency ,Pakistan ,Exome ,Neuregulins ,Genetics ,Mutation ,Multidisciplinary ,Homozygote ,Fasting ,Middle Aged ,Postprandial Period ,Circadian Rhythm ,3. Good health ,Pedigree ,Phenotype ,Female ,Sodium-Hydrogen Exchangers ,Offspring ,General Science & Technology ,Sodium-Hydrogen Antiporter ,Biology ,Article ,03 medical and health sciences ,medicine ,Humans ,Cytochrome P450 Family 2 ,Gene ,Allele frequency ,Gene knockout ,Triglycerides ,Genetic Association Studies ,Apolipoprotein C-III ,Interleukin-8 ,Phosphoproteins ,Dietary Fats ,Reverse Genetics ,Minor allele frequency ,030104 developmental biology ,Genes ,1-Alkyl-2-acetylglycerophosphocholine Esterase ,RNA Splice Sites ,Gene Deletion - Abstract
A major goal of biomedicine is to understand the function of every gene in the human genome.1 Loss-of-function (LoF) mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such ‘human knockouts’ can provide insight into gene function. Consanguineous unions are more likely to result in offspring who carry LoF mutations in a homozygous state. In Pakistan, consanguinity rates are notably high.2 Here, we sequenced the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS) designed to understand the determinants of cardiometabolic diseases in South Asians.3 We identified individuals carrying predicted LoF (pLoF) mutations in the homozygous state, and performed phenotypic analysis involving >200 biochemical and disease traits. We enumerated 49,138 rare (
- Published
- 2017
26. Loss of function of GALNT2 lowers high density lipoproteins in humans, nonhuman primates, and rodents
- Author
-
Hans H. Wandall, Reda Ouazzani, Rami Abou Jamra, Wei Zhao, Gayani Fernando, Henrik Clausen, Sekar Kathiresan, Eric Noé, John S. Millar, Lars Hansen, YoSon Park, Valentin Livanov, Seungbum Choi, Eric P. Bennett, Heiko Reutter, Danish Saleheen, Todd G. Kirchgessner, Cecilia Vitali, Bouhouche Ahmed, Katrine T. Schjoldager, Avanthi Raghavan, Sergey Y. Vakhrushev, Sumeet A. Khetarpal, Amritha Varshini Hanasoge Somasundara, Pritesh Patel, Gina M. Peloso, Christina Christoffersen, Christopher D. Brown, Daniel J. Rader, Andrew C. Edmondson, Eric LeGuern, and Siew Peng Ho
- Subjects
0301 basic medicine ,Proteomics ,Physiology ,Genome-wide association study ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,ANGPTL3 ,Phospholipid transfer protein ,Phospholipid Transfer Proteins ,Genetics ,Mice, Knockout ,Homozygote ,Phenotype ,Glycoproteomics ,Liver ,Gene Knockdown Techniques ,Models, Animal ,N-Acetylgalactosaminyltransferases ,lipids (amino acids, peptides, and proteins) ,Lipoproteins, HDL ,Primates ,medicine.medical_specialty ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Molecular Biology ,Loss function ,Triglycerides ,Angiopoietin-Like Protein 3 ,Glycoproteins ,Base Sequence ,Cholesterol ,Cholesterol, HDL ,nutritional and metabolic diseases ,Cell Biology ,Human genetics ,Rats ,030104 developmental biology ,Endocrinology ,Angiopoietin-like Proteins ,chemistry ,Mutation ,Angiopoietins ,030217 neurology & neurosurgery - Abstract
Human genetics studies have implicated GALNT2, encoding GalNAc-T2, as a novel regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, but the mechanisms relating GALNT2 to HDL-C remain unclear. We investigated the impact of homozygous GALNT2 deficiency on HDL-C in humans and mammalian models. We identified two humans homozygous for loss-of-function mutations in GALNT2 who demonstrated low HDL-C. We also found that GALNT2 loss-of-function in mice, rats, and nonhuman primates decreased HDL-C. O-glycoproteomics studies of a human GALNT2 deficient subject validated ANGPTL3 and ApoC-III as GalNAc-T2 targets. Additional glycoproteomics in rodents identified targets influencing HDL-C, including phospholipid transfer protein (PLTP). GALNT2 deficiency reduced plasma PLTP activity in humans and rodents, and in mice this was rescued by reconstitution of hepatic Galnt2. We also found that GALNT2 GWAS SNPs associated with reduced HDL-C also correlate with lower hepatic GALNT2 expression. These results posit GALNT2 as a direct modulator of HDL metabolism across mammals.
- Published
- 2016
27. Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks
- Author
-
Albert Hofman, Megan L. Grove, Jennifer A. Brody, Adolfo Correa, Kim Lawson, Jose M. Ordovas, Yingchang Lu, André G. Uitterlinden, Riccardo E. Marioni, Nathan O. Stitziel, Oscar H. Franco, Yongmei Liu, Ingrid B. Borecki, Aron Y. Joon, Lindsay M. Reynolds, Ozren Polasek, Kelli K. Ryckman, Muredach P. Reilly, Johanna Jakobsdottir, Abbas Dehghan, L. Adrienne Cupples, Tamara B. Harris, Michael Griswold, Judy Wang, Christopher S. Carlson, Caroline Hayward, Leslie A. Lange, Stephen S. Rich, Kenneth Rice, Jacy R Crosby, Diego Ardissino, Charles Kooperberg, Gudny Eiriksdottir, Rachel H. Mackey, Ani Manichaikul, Martin Farrall, Jennifer E. Huffman, Albert V. Smith, Vilmundur Gudnason, Aniruddh P. Patel, Ruth J. F. Loos, Sumeet A. Khetarpal, Daniel J. Rader, Domenico Girelli, Eric Boerwinkle, Qunyuan Zhang, Valeska Redon, Anuj Goel, Cornelia M. van Duijn, Bruce M. Psaty, Ruth McPherson, Piera Angelica Merlini, Daniel Levy, Ian J. Deary, Christopher J. O'Donnell, Kurt Lohman, Josyf C. Mychaleckyj, Brian W. Davis, Mary F. Feitosa, Kent D. Taylor, James S. Pankow, Marju Orho-Melander, Alanna C. Morrison, Igor Rudan, Alexander P. Reiner, William E. Kraus, Ulrike Peters, Paul L. Auer, Paolo Zanoni, Svati H. Shah, Olle Melander, Jennifer G. Robinson, Joshua C. Bis, Erwin P. Bottinger, Mingyao Li, George Hindy, Omri Gottesman, Stefano Duga, Herman A. Taylor, Y.-D. Ida Chen, David S. Siscovick, Aaron Isaacs, Michael Y. Tsai, Sekar Kathiresan, James G. Wilson, Pamela J. Schreiner, Nicola Martinelli, Myriam Fornage, Serkalem Demissie, Lenore J. Launer, Hugh Watkins, Arend Voorman, Jerome I. Rotter, Jeanette M. Stafford, John M. Starr, Gina M. Peloso, Rosanna Asselta, Gail Davies, Rebecca D. Jackson, Epidemiology, and Internal Medicine
- Subjects
Male ,Blood lipids ,Coronary Disease ,030204 cardiovascular system & hematology ,Inbred C57BL ,Cohort Studies ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Gene Frequency ,Genotype ,Genetics(clinical) ,Subtilisins ,European Continental Ancestry Group/genetics ,Exome ,Genetics (clinical) ,Genetics ,0303 health sciences ,Cholesterol, HDL/blood ,1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics ,Middle Aged ,3. Good health ,LDL/blood ,Triglycerides/blood ,Cholesterol ,Phenotype ,Cholesterol, LDL/blood ,Genetic Code ,HDL/blood ,lipids (amino acids, peptides, and proteins) ,Female ,Sequence Analysis ,Microtubule-Associated Proteins ,Adult ,Sequence analysis ,Black People ,Biology ,White People ,Article ,03 medical and health sciences ,Coronary Disease/blood ,Animals ,Humans ,Allele frequency ,Gene ,Alleles ,Genetic Association Studies ,Triglycerides ,030304 developmental biology ,Aged ,PCSK9 ,Cholesterol, HDL ,African Continental Ancestry Group/genetics ,Genetic Variation ,DNA ,Cholesterol, LDL ,Sequence Analysis, DNA ,Microtubule-Associated Proteins/genetics ,Subtilisins/genetics ,Mice, Inbred C57BL ,chemistry ,1-Alkyl-2-acetylglycerophosphocholine Esterase ,Linear Models - Abstract
Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
- Published
- 2016
28. Targeting ApoC-III to Reduce Coronary Disease Risk
- Author
-
Arman Qamar, Daniel J. Rader, Sumeet A. Khetarpal, and John S. Millar
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Statin ,Apoc iii ,Apolipoprotein B ,medicine.drug_class ,Lipoproteins ,Peroxisome proliferator-activated receptor ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Bioinformatics ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Lipolysis ,Triglycerides ,chemistry.chemical_classification ,Apolipoprotein C-III ,biology ,business.industry ,nutritional and metabolic diseases ,Oligonucleotides, Antisense ,medicine.disease ,Human genetics ,030104 developmental biology ,Endocrinology ,chemistry ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,business ,Niacin - Abstract
Triglyceride-rich lipoproteins (TRLs) are causal contributors to the risk of developing coronary artery disease (CAD). Apolipoprotein C-III (apoC-III) is a component of TRLs that elevates plasma triglycerides (TGs) through delaying the lipolysis of TGs and the catabolism of TRL remnants. Recent human genetics approaches have shown that heterozygous loss-of-function mutations in APOC3, the gene encoding apoC-III, lower plasma TGs and protect from CAD. This observation has spawned new interest in therapeutic efforts to target apoC-III. Here, we briefly review both currently available as well as developing therapies for reducing apoC-III levels and function to lower TGs and cardiovascular risk. These therapies include existing options including statins, fibrates, thiazolidinediones, omega-3-fatty acids, and niacin, as well as an antisense oligonucleotide targeting APOC3 currently in clinical development. We review the mechanisms of action by which these drugs reduce apoC-III and the current understanding of how reduction in apoC-III may impact CAD risk.
- Published
- 2016
29. Lnc-ing Common Polymorphisms to Statin Responsiveness at the MYLIP Locus
- Author
-
John S. Millar and Sumeet A. Khetarpal
- Subjects
0301 basic medicine ,Statin ,medicine.drug_class ,Single-nucleotide polymorphism ,MYLIP ,030204 cardiovascular system & hematology ,Pharmacology ,Bioinformatics ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genetics ,medicine ,Adverse effect ,Allele frequency ,Genetics (clinical) ,Cholesterol ,business.industry ,Cholesterol, LDL ,030104 developmental biology ,Tolerability ,chemistry ,Receptors, LDL ,Pharmacogenomics ,lipids (amino acids, peptides, and proteins) ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,business - Abstract
3-Hydroxymethylglutaryl coenzyme A reductase inhibitors, commonly known as statins, are among the most widely prescribed drugs in the world. Indeed, In the United States at least one quarter of adults over the age of 40 years is prescribed a statin.1 Recent evidence suggests that wider prescription of statins to those with even moderate risk of cardiovascular disease may be greatly beneficial in primary risk prevention.2 Statins are highly efficacious in lowering low-density lipoprotein cholesterol (LDL-C) levels by inhibiting 3-hydroxymethylglutaryl coenzyme A reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, resulting in increased transcription of hepatic LDL receptor levels.1 Yet despite their immense success, statin use is still limited, in part, by variable responsiveness with regard to LDL-C lowering and side effects, which include risk of developing insulin resistance, myopathy, cognitive impairment, and other morbidities.1 These concerns have prompted extensive studies focused on identifying the precise patients likely to benefit most from statins as well as those most at risk of developing adverse effects. Article, see p 223 Pharmacogenomics studies have been used to identify patients who would benefit the most from statins or are at risk of side effects. These studies relate natural genetic variants and associated genes and pathways to efficacy and tolerability of drugs at the individual level. At a basic level, these studies compare genotype frequencies for polymorphisms at individual genes or across multiple genomic loci among individuals with differing responsiveness for a given drug and identify those single-nucleotide polymorphisms (SNPs) whose allele frequencies differ across the drug-responsiveness groups. Pharmacogenomics approaches have been applied widely to identify genes that influence the LDL-C–lowering efficacy of many statins as well as their variable adverse effect profiles.3 Such efforts have been performed at times to compare the SNP–drug interactions across different statins and in …
- Published
- 2016
30. Abstract 400: Determining the Contribution of Endothelial Lipase-mediated Lipolysis to Brain Phospholipid Metabolism
- Author
-
Papasani V. Subbaiah, Daniel J. Rader, Cecilia Vitali, Jeffrey T. Billheimer, and Sumeet A. Khetarpal
- Subjects
Endothelial lipase ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Phospholipid ,Lipolysis ,lipids (amino acids, peptides, and proteins) ,Metabolism ,Cardiology and Cardiovascular Medicine - Abstract
Polyunsaturated fatty acids (PUFA) are essential constituents of the cell membrane. Brain PUFA content is critical for synaptic function and neuroinflammation and PUFA deficiency may underlie several neurological disorders. Prior work in murine models has showed that the predominant source of central nervous system (CNS) PUFAs is 2-acyl-lysophophatidylcholine (2-lysoPC), a class of phospholipids (PLs) circulating on blood lipoproteins that is formed from the enzymatic activity of phospholipases. Endothelial lipase (EL) is a phospholipase that is a critical determinant of HDL metabolism in humans and the predominant generator of 2-lysoPC on HDL particles. While the contribution of EL to circulating HDL metabolism is well-established, its contribution to CNS fatty acid availability and brain function has not been explored. In order to investigate the physiological contribution of EL to brain FA availability in vivo, we studied PL-derived PUFA uptake in mice with EL deficiency. We adopted a method for measuring EL activity using a fluorescent synthetic HDL particle containing sn2-TopFluor-PC, a fluorescent precursor of 2-lysoPC and demonstrated its utility in vitro. Next, we tested the clearance of this synthetic HDL-derived 2-lysoPC in C57BL/6 (WT) vs EL KO mice (n=12/group). Circulating plasma 2-lysoPC clearance was significantly impaired in in EL KO mice (-32%, p=0.024) and was accompanied by a slower remodeling of the HDL particles. Measurement of labeled PL content in tissues showed a significant reduction in hepatic uptake in KO mice (22% decrease, p=0.002). No significant differences were observed in total brain PL uptake, but the distribution of PL uptake differed between WT and KOs. Ongoing studies are evaluating the physiological consequences of reduced circulating 2-lysoPC clearance, reduced hepatic uptake, and altered distribution of brain PL uptake in EL KO mice. Collectively, our data demonstrate that EL is a key physiological regulator of systemic PL catabolism.
- Published
- 2016
31. Abstract 17: APOC3 A43T Variant Promotes ApoC-III Catabolism and Accelerates TG-rich Lipoprotein Clearance in Mice and Humans
- Author
-
Leland Mayne, Xuemei Zeng, Pradeep Natarajan, Marina Cuchel, Nathan A. Yates, S.W. Englander, James T McParland, Cecilia Vitali, Paolo Zanoni, John S. Millar, Amritha Varshini, Daniel J. Rader, Michael C. Phillips, Mary G. McCoy, David Nguyen, Zhiyuan Sun, Sumeet A. Khetarpal, Sissel Lund-Katz, and Sekar Kathiresan
- Subjects
medicine.medical_specialty ,Endocrinology ,Apoc iii ,Catabolism ,Chemistry ,Internal medicine ,medicine ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,Lipoprotein - Abstract
Humans with loss-of-function (LoF) variants in APOC3 , the gene encoding apolipoprotein C-III (apoC-III), have significantly reduced plasma triglycerides (TG) and protection from coronary disease. These findings suggest that apoC-III may be a viable therapeutic target for decreasing vascular risk through TG reduction, and that elucidation of the protective mechanism of APOC3 LoF variants would inform such strategies. We report here the protective mechanism of the APOC3 A43T missense variant, one of four recently identified CAD-protective variants. By genotyping >8,000 human participants with low TG, we identified 17 APOC3 A43T carriers and phenotyped 6 carriers and 54 matched controls. A43T heterozygotes demonstrate a significant reduction in apoC-III levels relative to non-carriers (50% reduction, P3-fold higher apoC-III clearance rate in vivo (Pin vivo . We are currently performing analogous studies of WT vs. A43T apoC-III turnover and VLDL clearance in human APOC3 A43T carriers. Collectively, our results support the rationale for therapeutic efforts to target circulating apoC-III through disruption of its binding to lipoproteins, mirroring the genetics-driven approaches for targeting PCSK9 that have recently yielded novel therapies.
- Published
- 2016
32. Therapeutic Targets of Triglyceride Metabolism as Informed by Human Genetics
- Author
-
Nicholas J. Hand, Sumeet A. Khetarpal, Robert C. Bauer, and Daniel J. Rader
- Subjects
0301 basic medicine ,Lipoproteins ,Genome-wide association study ,Coronary Artery Disease ,Bioinformatics ,03 medical and health sciences ,Risk Factors ,Hyperlipidemia ,medicine ,Humans ,Molecular Targeted Therapy ,Molecular Biology ,Exome sequencing ,Triglycerides ,Genetic association ,Lipoprotein lipase ,business.industry ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,PCSK9 ,Hydrolysis ,Lipogenesis ,Toll-Like Receptors ,medicine.disease ,Lipid Metabolism ,Human genetics ,030104 developmental biology ,Gene Expression Regulation ,Liver ,Molecular Medicine ,business ,Genome-Wide Association Study ,Signal Transduction - Abstract
Human genetics has contributed to the development of multiple drugs to treat hyperlipidemia and coronary artery disease (CAD), most recently including antibodies targeting PCSK9 to reduce LDL cholesterol. Despite these successes, a large burden of CAD remains. Genetic and epidemiological studies have suggested that circulating triglyceride (TG)-rich lipoproteins (TRLs) are a causal risk factor for CAD, presenting an opportunity for novel therapeutic strategies. We discuss recent unbiased human genetics testing, including genome-wide association studies (GWAS) and whole-genome or -exome sequencing, that have identified the lipoprotein lipase (LPL) and hepatic lipogenesis pathways as important mechanisms in the regulation of circulating TRLs. Further strengthening the causal relationship between TRLs and CAD, findings such as these may provide novel targets for much-needed potential therapeutic interventions.
- Published
- 2016
33. A systematic study of modulation of ADAM-mediated ectodomain shedding by site-specific O-glycosylation
- Author
-
Adnan Halim, Daniel J. Rader, Henrik Clausen, Katrine T. Schjoldager, Sumeet A. Khetarpal, and Christoffer K. Goth
- Subjects
Lipopolysaccharides ,Proteases ,Cell signaling ,Glycosylation ,ADAM10 ,Blotting, Western ,Molecular Sequence Data ,Biology ,Substrate Specificity ,Genes, Reporter ,Disintegrin ,Animals ,Humans ,Amino Acid Sequence ,Mice, Knockout ,Multidisciplinary ,Tumor Necrosis Factor-alpha ,Glycopeptides ,Hep G2 Cells ,Biological Sciences ,ADAM Proteins ,Molecular biology ,Protein Structure, Tertiary ,carbohydrates (lipids) ,Crosstalk (biology) ,HEK293 Cells ,Membrane protein ,Ectodomain ,Mutation ,biology.protein ,N-Acetylgalactosaminyltransferases ,lipids (amino acids, peptides, and proteins) - Abstract
Regulated shedding of the ectodomain of cell membrane proteins by proteases is a common process that releases the extracellular domain from the cell and activates cell signaling. Ectodomain shedding occurs in the immediate extracellular juxtamembrane region, which is also where O-glycosylation is often found and examples of crosstalk between shedding and O-glycosylation have been reported. Here, we systematically investigated the potential of site-specific O-glycosylation mediated by distinct polypeptide GalNAc-transferase (GalNAc-T) isoforms to coregulate ectodomain shedding mediated by the A Disintegrin And Metalloproteinase (ADAM) subfamily of proteases and in particular ADAM17. We analyzed 25 membrane proteins that are known to undergo ADAM17 shedding and where the processing sites included Ser/Thr residues within ± 4 residues that could represent O-glycosites. We used in vitro GalNAc-T enzyme and ADAM cleavage assays to demonstrate that shedding of at least 12 of these proteins are potentially coregulated by O-glycosylation. Using TNF-α as an example, we confirmed that shedding mediated by ADAM17 is coregulated by O-glycosylation controlled by the GalNAc-T2 isoform both ex vivo in isogenic cell models and in vivo in mouse Galnt2 knockouts. The study provides compelling evidence for a wider role of site-specific O-glycosylation in ectodomain shedding.
- Published
- 2015
34. Triglyceride-rich lipoproteins and coronary artery disease risk: new insights from human genetics
- Author
-
Sumeet A. Khetarpal and Daniel J. Rader
- Subjects
medicine.medical_specialty ,Lipoproteins ,Single-nucleotide polymorphism ,Disease ,Coronary Artery Disease ,Apolipoproteins A ,Biology ,Coronary artery disease ,Risk Factors ,Internal medicine ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Myocardial infarction ,Molecular Targeted Therapy ,Triglycerides ,Hypolipidemic Agents ,Genetics ,Lipoprotein lipase ,Apolipoprotein C-III ,medicine.diagnostic_test ,medicine.disease ,Human genetics ,Up-Regulation ,Lipoprotein Lipase ,Endocrinology ,Phenotype ,Apolipoprotein A-V ,Drug Design ,Mutation ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,Lipid profile ,Biomarkers - Abstract
Despite ample success in reducing coronary artery disease (CAD) risk through reduction of low-density lipoprotein cholesterol (LDL-C), there remains substantial residual risk.1–4 Recent prospective studies have demonstrated that elevated triglycerides (TGs) are independent predictors of CAD risk.5–9 Furthermore, TGs are strongly associated with incident CAD events in patients with low LDL-C levels treated with statin.10 Thus, triglyceride-rich lipoproteins (TRLs) offer a potentially orthogonal risk factor to LDL-C for lowering CAD risk, but only if TRLs are causally associated with atherosclerotic disease.11 Human genetics has the potential to reveal the causal relationships of biomarkers found to be associated with disease outcomes.12–15 For example, genetic variants associated with plasma LDL-C levels are consistently associated with CAD risk in the right direction,15–18 consistent with a causal relationship. Importantly, similar studies have causally implicated the key TG-regulating enzyme lipoprotein lipase (LPL) in CAD risk. A common gain-of-function LPL variant, S447X, confers an antiatherogenic lipid profile characterized by low levels of TGs, and in several studies, it has been associated with lower incidence of vascular disease or myocardial infarction (MI).19–25 Conversely, several loss-of-function (LOF) LPL variants associated with elevated TG levels have been reported to be associated with increased CAD risk.21,26 Furthermore, multiple genome-wide association studies in the last 5 years have identified common noncoding variants at the LPL gene locus associated with both TG and CAD risk in the same direction.27–29 Beyond LPL itself, common variants that influence TG levels are significantly associated with CAD risk even after adjusting for their effects on other lipid traits.30 Do et al30 surveyed 185 single-nucleotide polymorphisms (SNPs) that were genome-wide significantly associated with ≥1 plasma lipid trait and identified a subset of …
- Published
- 2015
35. Lipoprotein Physiology
- Author
-
Daniel J. Rader and Sumeet A. Khetarpal
- Published
- 2015
36. Genetics of lipid traits: Genome-wide approaches yield new biology and clues to causality in coronary artery disease
- Author
-
Sumeet A, Khetarpal and Daniel J, Rader
- Abstract
A wealth of novel lipid loci have been identified through a variety of approaches focused on common and low-frequency variation and collaborative metaanalyses in multiethnic populations. Despite progress in identification of loci, the task of determining causal variants remains challenging. This work will undoubtedly be enhanced by improved understanding of regulatory DNA at a genomewide level as well as new methodologies for interrogating the relationships between noncoding SNPs and regulatory regions. Equally challenging is the identification of causal genes at novel loci. Some progress has been made for a handful of genes and comprehensive testing of candidate genes using multiple model systems is underway. Additional insights will be gleaned from focusing on low frequency and rare coding variation at candidate loci in large populations. This article is part of a Special Issue entitled: From Genome to Function.
- Published
- 2014
37. The effects of apolipoprotein F deficiency on high density lipoprotein cholesterol metabolism in mice
- Author
-
Daniel J. Rader, Kaijin Wu, William R. Lagor, Wen Lin, George H. Rothblat, Arthi Kumaravel, Nathaniel Weintraub, Margarita de la Llera-Moya, Sarah F. Hamm-Alvarez, David W Fields, Sumeet A. Khetarpal, and Denise Drazul-Schrader
- Subjects
Male ,Glycosylation ,Apolipoprotein B ,lcsh:Medicine ,030204 cardiovascular system & hematology ,Cardiovascular ,Biochemistry ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,High-density lipoprotein ,Genes, Reporter ,Blood plasma ,lcsh:Science ,2. Zero hunger ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,biology ,Animal Models ,Lipids ,Cholesteryl ester ,Medicine ,Female ,lipids (amino acids, peptides, and proteins) ,Research Article ,medicine.medical_specialty ,Lipoproteins ,APOF ,Diet, High-Fat ,03 medical and health sciences ,Model Organisms ,Sialoglycoprotein ,Internal medicine ,Cholesterylester transfer protein ,medicine ,Animals ,Humans ,Biology ,030304 developmental biology ,Staining and Labeling ,Cholesterol ,Cholesterol, HDL ,lcsh:R ,Proteins ,Biological Transport ,Feeding Behavior ,beta-Galactosidase ,Molecular Weight ,Endocrinology ,Apolipoproteins ,HEK293 Cells ,chemistry ,biology.protein ,lcsh:Q ,Protein Processing, Post-Translational - Abstract
Apolipoprotein F (apoF) is 29 kilodalton secreted sialoglycoprotein that resides on the HDL and LDL fractions of human plasma. Human ApoF is also known as Lipid Transfer Inhibitor protein (LTIP) based on its ability to inhibit cholesteryl ester transfer protein (CETP)-mediated transfer events between lipoproteins. In contrast to other apolipoproteins, ApoF is predicted to lack strong amphipathic alpha helices and its true physiological function remains unknown. We previously showed that overexpression of Apolipoprotein F in mice reduced HDL cholesterol levels by 20–25% by accelerating clearance from the circulation. In order to investigate the effect of physiological levels of ApoF expression on HDL cholesterol metabolism, we generated ApoF deficient mice. Unexpectedly, deletion of ApoF had no substantial impact on plasma lipid concentrations, HDL size, lipid or protein composition. Sex-specific differences were observed in hepatic cholesterol content as well as serum cholesterol efflux capacity. Female ApoF KO mice had increased liver cholesteryl ester content relative to wild type controls on a chow diet (KO: 3.4+/−0.9 mg/dl vs. WT: 1.2+/−0.3 mg/dl, p
- Published
- 2012
38. Mining the LIPG allelic spectrum reveals the contribution of rare and common regulatory variants to HDL cholesterol
- Author
-
Hemanth Neeli, Megan L. Wolfe, Avanthi Raghavan, Weijun Jin, Daniel J. Rader, Serkalem Demissie, Karen O. Badellino, Sumeet A. Khetarpal, Mingyao Li, L. Adrienne Cupples, Alisa K. Manning, Stephanie DerOhannessian, Andrew C. Edmondson, and Sekar Kathiresan
- Subjects
Nonsynonymous substitution ,Adult ,Male ,Cancer Research ,Linkage disequilibrium ,lcsh:QH426-470 ,Genotype ,Gene Expression ,Genome-wide association study ,030204 cardiovascular system & hematology ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,Missing heritability problem ,Genes, Regulator ,Genetics ,Human Umbilical Vein Endothelial Cells ,Humans ,Promoter Regions, Genetic ,Molecular Biology ,Gene ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,Alleles ,030304 developmental biology ,Genetic association ,Aged ,0303 health sciences ,Haplotype ,Cholesterol, HDL ,High-Throughput Nucleotide Sequencing ,Lipase ,Middle Aged ,Lipid Metabolism ,lcsh:Genetics ,Phenotype ,Haplotypes ,Mutagenesis, Site-Directed ,Medicine ,Female ,5' Untranslated Regions ,Common disease-common variant ,Genome-Wide Association Study ,Research Article - Abstract
Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5′ UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5′ UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci., Author Summary Genetic association studies have identified genomic regions that affect quantifiable traits such as lipid levels. When a gene and a trait are found to be associated with one another, the gene is often further studied to determine its role in affecting the trait. One approach is to sequence the gene in individuals at the extremes of the trait's distribution with the hope of finding rare mutations that directly contribute to the trait. Until now studies using this approach have focused on genetic variation in the protein coding sequence of these genes and have been largely successful in identifying functionally important mutations. However, other studies have found an abundance of noncoding variation in the genome that may also contribute to the heritability of these traits. Here we seek to determine the contribution of such noncoding mutations to high density lipoprotein cholesterol (HDL-C) levels in humans using the HDL-C candidate gene LIPG as an example. Through a sequencing study in individuals with high and low HDL-C levels, we demonstrate that both rare and common noncoding mutations are influential contributors to the allelic spectrum of such traits and should be further characterized after initial association with the trait.
- Published
- 2011
39. Bilateral Earlobe Creases and Coronary Artery Disease
- Author
-
Arman Qamar, Sumeet A. Khetarpal, Kimon L.H. Ioannides, and Daniel Kiss
- Subjects
Male ,medicine.medical_specialty ,Ischemia ,Physical examination ,Coronary Angiography ,Coronary artery disease ,Physiology (medical) ,Earlobe creases ,medicine ,Humans ,Outpatient clinic ,cardiovascular diseases ,Coronary Artery Bypass ,Ear, External ,Family history ,Earlobe ,Aged ,medicine.diagnostic_test ,business.industry ,Coronary Stenosis ,medicine.disease ,Surgery ,Early Diagnosis ,medicine.anatomical_structure ,Disease Susceptibility ,Cardiology and Cardiovascular Medicine ,business ,Perfusion - Abstract
A 73-year–old man with a history of hypertension and a family history of coronary artery disease (CAD) was seen in an outpatient clinic for stable angina. Physical examination showed bilateral earlobe creases, known as Frank’s sign (Figure 1), and no other relevant cardiac findings. Figure 1. Bilateral earlobe crease (Frank’s sign). ECG showed normal sinus rhythm with no signs of ischemia. He was evaluated with a nuclear stress test, which revealed moderate reversible perfusion defects localized to the …
- Published
- 2014
40. Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans
- Author
-
Majken K. Jensen, Stephanie DerOhannessian, Alisa K. Manning, Muredach P. Reilly, David M. Evans, Amrith Rodrigues, Daniel J. Rader, Robert A. Hegele, Megan L. Wolfe, Vaneeta Bamba, L. Adrienne Cupples, Sumeet A. Khetarpal, Jens Aberle, Sekar Kathiresan, Robert J. Brown, Serkalem Demissie, Mingyao Li, Eric B. Rimm, Jian Wang, and Andrew C. Edmondson
- Subjects
Male ,Endothelial lipase ,Inbred C57BL ,medicine.disease_cause ,Cohort Studies ,Mice ,Exon ,chemistry.chemical_compound ,Polymorphism (computer science) ,Sequence Deletion ,Mice, Knockout ,Mutation ,biology ,Exons ,Single Nucleotide ,General Medicine ,Middle Aged ,Cholesterol ,Biochemistry ,Female ,lipids (amino acids, peptides, and proteins) ,Research Article ,Adult ,medicine.medical_specialty ,HDL ,Endocrinology, Diabetes, and Metabolism ,Knockout ,Polymorphism, Single Nucleotide ,In vivo ,Internal medicine ,medicine ,Animals ,Humans ,Polymorphism ,Lipase ,Aged ,Cholesterol, HDL ,Genetic Variation ,nutritional and metabolic diseases ,Atherosclerosis ,In vitro ,Mice, Inbred C57BL ,Cross-Sectional Studies ,Endocrinology ,Amino Acid Substitution ,chemistry ,biology.protein - Abstract
Elevated plasma concentrations of HDL cholesterol (HDL-C) are associated with protection from atherosclerotic cardiovascular disease. Animal models indicate that decreased expression of endothelial lipase (LIPG) is inversely associated with HDL-C levels, and genome-wide association studies have identified LIPG variants as being associated with HDL-C levels in humans. We hypothesized that loss-of-function mutations in LIPG may result in elevated HDL-C and therefore performed deep resequencing of LIPG exons in cases with elevated HDL-C levels and controls with decreased HDL-C levels. We identified a significant excess of nonsynonymous LIPG variants unique to cases with elevated HDL-C. In vitro lipase activity assays demonstrated that these variants significantly decreased endothelial lipase activity. In addition, a meta-analysis across 5 cohorts demonstrated that the low-frequency Asn396Ser variant is significantly associated with increased HDL-C, while the common Thr111Ile variant is not. Functional analysis confirmed that the Asn396Ser variant has significantly decreased lipase activity both in vitro and in vivo, while the Thr111Ile variant has normal lipase activity. Our results establish that loss-of-function mutations in LIPG lead to increased HDL-C levels and support the idea that inhibition of endothelial lipase may be an effective mechanism to raise HDL-C.
- Published
- 2009
41. Coronary artery disease-protective A43T variant in APOC3 alters circulating ApoC-III levels in vivo
- Author
-
Daniel Kiss, Sumeet A. Khetarpal, Sissel Lund-Katz, Sekar Kathiresan, Marina Cuchel, Amrith Rodrigues, Megan L. Mucksavage, Paolo Zanoni, Mary G. McCoy, John S. Millar, James T McParland, Daniel J. Rader, Daniel B. Larach, Amritha Varshini, Michael C. Phillips, and Jennifer Tabita-Martinez
- Subjects
Coronary artery disease ,medicine.medical_specialty ,Apoc iii ,Endocrinology ,business.industry ,In vivo ,Internal medicine ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,medicine.disease - Published
- 2015
42. A loss-of-function mutation in scarb1 severely impairs sr-bi processing and activity in humans
- Author
-
Daniel B. Larach, Gina M. Peloso, Marina Cuchel, S. Kathiresan, Junichiro Tohyama, Daniel J. Rader, William F. Hancock-Cerutti, Jeffrey T. Billheimer, Sumeet A. Khetarpal, Paolo Zanoni, and Amrith Rodrigues
- Subjects
Loss of function mutation ,Chemistry ,Cardiology and Cardiovascular Medicine ,SCARB1 ,Cell biology - Published
- 2014
43. PLASMA APOC-III LEVELS, TRIGLYCERIDES, AND CORONARY ARTERY CALCIFICATION IN TYPE 2 DIABETICS
- Author
-
Amit Khera, Daniel J. Rader, Arman Qamar, Sumeet A. Khetarpal, Atif Qasim, and Muredach P. Reilly
- Subjects
medicine.medical_specialty ,Lipoprotein lipase ,Apoc iii ,Triglyceride ,Apolipoprotein B ,biology ,business.industry ,Metabolism ,Coronary heart disease ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Levels triglycerides ,Coronary artery calcification ,Internal medicine ,medicine ,biology.protein ,lipids (amino acids, peptides, and proteins) ,business ,Cardiology and Cardiovascular Medicine - Abstract
Triglyceride (TG) rich lipoproteins have emerged as causal risk factors for the development of coronary heart disease (CHD) independent of circulating low-density lipoprotein cholesterol levels. Apolipoprotein C-III (ApoC-III) is a modulator of TG metabolism through inhibition of lipoprotein lipase
- Full Text
- View/download PDF
44. Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins.
- Author
-
Sumeet A Khetarpal, Cecilia Vitali, Michael G Levin, Derek Klarin, Joseph Park, Akhil Pampana, John S Millar, Takashi Kuwano, Dhavamani Sugasini, Papasani V Subbaiah, Jeffrey T Billheimer, Pradeep Natarajan, and Daniel J Rader
- Subjects
Genetics ,QH426-470 - Abstract
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.
- Published
- 2021
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.