Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease
Objective: Identify and characterize circulating metabolite profiles associated with adiposity to inform precision medicine. Methods: Untargeted plasma metabolomic profiles in the Insulin Resistance Atherosclerosis Family Study (IRASFS) Mexican American cohort (n = 1108) were analyzed for associatio...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-12-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877821001897 |
| _version_ | 1828138775506583552 |
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| author | Swapan K. Das Hannah C. Ainsworth Latchezar Dimitrov Hayrettin Okut Mary E. Comeau Neeraj Sharma Maggie C.Y. Ng Jill M. Norris Yii-der I. Chen Lynne E. Wagenknecht Donald W. Bowden Fang-Chi Hsu Kent D. Taylor Carl D. Langefeld Nicholette D. Palmer |
| author_facet | Swapan K. Das Hannah C. Ainsworth Latchezar Dimitrov Hayrettin Okut Mary E. Comeau Neeraj Sharma Maggie C.Y. Ng Jill M. Norris Yii-der I. Chen Lynne E. Wagenknecht Donald W. Bowden Fang-Chi Hsu Kent D. Taylor Carl D. Langefeld Nicholette D. Palmer |
| author_sort | Swapan K. Das |
| collection | DOAJ |
| description | Objective: Identify and characterize circulating metabolite profiles associated with adiposity to inform precision medicine. Methods: Untargeted plasma metabolomic profiles in the Insulin Resistance Atherosclerosis Family Study (IRASFS) Mexican American cohort (n = 1108) were analyzed for association with anthropometric (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, WHR) and computed tomography measures (visceral adipose tissue, VAT; subcutaneous adipose tissue, SAT; visceral-to-subcutaneous ratio, VSR) of adiposity. Genetic data, inclusive of genome-wide array-based genotyping, whole exome sequencing (WES) and whole genome sequencing (WGS), were evaluated to identify the genetic contributors. Phenotypic and genetic association signals were replicated across ancestries. Transcriptomic data were analyzed to explore the relationship between genetic and metabolomic data. Results: A partially characterized metabolite, tentatively named metabolonic lactone sulfate (X-12063), was consistently associated with BMI, WC, WHR, VAT, and SAT in IRASFS Mexican Americans (PMA <2.02 × 10−27). Trait associations were replicated in IRASFS African Americans (PAA < 1.12 × 10−07). Expanded analyses revealed associations with multiple phenotypic measures of cardiometabolic health, e.g. insulin sensitivity (SI), triglycerides (TG), diastolic blood pressure (DBP) and plasminogen activator inhibitor-1 (PAI-1) in both ancestries. Metabolonic lactone sulfate levels were heritable (h2 > 0.47), and a significant genetic signal at the ZSCAN25/CYP3A5 locus (PMA = 9.00 × 10−41, PAA = 2.31 × 10−10) was observed, highlighting a putative functional variant (rs776746, CYP3A5∗3). Transcriptomic analysis in the African American Genetics of Metabolism and Expression (AAGMEx) cohort supported the association of CYP3A5 with metabolonic lactone sulfate levels (PFDR = 6.64 × 10−07). Conclusions: Variant rs776746 is associated with a decrease in the transcript levels of CYP3A5, which in turn is associated with increased metabolonic lactone sulfate levels and poor cardiometabolic health. |
| first_indexed | 2024-04-11T18:41:36Z |
| format | Article |
| id | doaj.art-1b6c0a5707c340ee89b7191753cae8d7 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-11T18:41:36Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-1b6c0a5707c340ee89b7191753cae8d72022-12-22T04:08:58ZengElsevierMolecular Metabolism2212-87782021-12-0154101342Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic diseaseSwapan K. Das0Hannah C. Ainsworth1Latchezar Dimitrov2Hayrettin Okut3Mary E. Comeau4Neeraj Sharma5Maggie C.Y. Ng6Jill M. Norris7Yii-der I. Chen8Lynne E. Wagenknecht9Donald W. Bowden10Fang-Chi Hsu11Kent D. Taylor12Carl D. Langefeld13Nicholette D. Palmer14Department of Internal Medicine, Wake Forest School of Medicine, Winston–Salem, North Carolina, USADepartment of Biostatistics and Data Science, Wake Forest School of Medicine, Winston–Salem, North Carolina, USADepartment of Epidemiology and Prevention, Wake Forest School of Medicine, Winston–Salem, North Carolina, USAOffice of Research, University of Kansas Medical Center, Wichita, Kansas, USADepartment of Biostatistics and Data Science, Wake Forest School of Medicine, Winston–Salem, North Carolina, USADepartment of Internal Medicine, Wake Forest School of Medicine, Winston–Salem, North Carolina, USADivision of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USADepartment of Epidemiology, Colorado School of Public Health, Aurora, CO, USAThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USADepartment of Epidemiology and Prevention, Wake Forest School of Medicine, Winston–Salem, North Carolina, USADepartment of Biochemistry, Wake Forest School of Medicine, Winston–Salem, North Carolina, USADepartment of Biostatistics and Data Science, Wake Forest School of Medicine, Winston–Salem, North Carolina, USAThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USADepartment of Biostatistics and Data Science, Wake Forest School of Medicine, Winston–Salem, North Carolina, USADepartment of Biochemistry, Wake Forest School of Medicine, Winston–Salem, North Carolina, USA; Corresponding author. Department of Biochemistry, 1 Medical Center Blvd, Winston–Salem, NC, 27040, USA.Objective: Identify and characterize circulating metabolite profiles associated with adiposity to inform precision medicine. Methods: Untargeted plasma metabolomic profiles in the Insulin Resistance Atherosclerosis Family Study (IRASFS) Mexican American cohort (n = 1108) were analyzed for association with anthropometric (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, WHR) and computed tomography measures (visceral adipose tissue, VAT; subcutaneous adipose tissue, SAT; visceral-to-subcutaneous ratio, VSR) of adiposity. Genetic data, inclusive of genome-wide array-based genotyping, whole exome sequencing (WES) and whole genome sequencing (WGS), were evaluated to identify the genetic contributors. Phenotypic and genetic association signals were replicated across ancestries. Transcriptomic data were analyzed to explore the relationship between genetic and metabolomic data. Results: A partially characterized metabolite, tentatively named metabolonic lactone sulfate (X-12063), was consistently associated with BMI, WC, WHR, VAT, and SAT in IRASFS Mexican Americans (PMA <2.02 × 10−27). Trait associations were replicated in IRASFS African Americans (PAA < 1.12 × 10−07). Expanded analyses revealed associations with multiple phenotypic measures of cardiometabolic health, e.g. insulin sensitivity (SI), triglycerides (TG), diastolic blood pressure (DBP) and plasminogen activator inhibitor-1 (PAI-1) in both ancestries. Metabolonic lactone sulfate levels were heritable (h2 > 0.47), and a significant genetic signal at the ZSCAN25/CYP3A5 locus (PMA = 9.00 × 10−41, PAA = 2.31 × 10−10) was observed, highlighting a putative functional variant (rs776746, CYP3A5∗3). Transcriptomic analysis in the African American Genetics of Metabolism and Expression (AAGMEx) cohort supported the association of CYP3A5 with metabolonic lactone sulfate levels (PFDR = 6.64 × 10−07). Conclusions: Variant rs776746 is associated with a decrease in the transcript levels of CYP3A5, which in turn is associated with increased metabolonic lactone sulfate levels and poor cardiometabolic health.http://www.sciencedirect.com/science/article/pii/S2212877821001897ObesityMetabolomicsCardiometabolic diseaseMinority populations |
| spellingShingle | Swapan K. Das Hannah C. Ainsworth Latchezar Dimitrov Hayrettin Okut Mary E. Comeau Neeraj Sharma Maggie C.Y. Ng Jill M. Norris Yii-der I. Chen Lynne E. Wagenknecht Donald W. Bowden Fang-Chi Hsu Kent D. Taylor Carl D. Langefeld Nicholette D. Palmer Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease Molecular Metabolism Obesity Metabolomics Cardiometabolic disease Minority populations |
| title | Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease |
| title_full | Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease |
| title_fullStr | Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease |
| title_full_unstemmed | Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease |
| title_short | Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease |
| title_sort | metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease |
| topic | Obesity Metabolomics Cardiometabolic disease Minority populations |
| url | http://www.sciencedirect.com/science/article/pii/S2212877821001897 |
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