Genome-wide analysis of blood lipid metabolites in over 5000 South Asians reveals biological insights at cardiometabolic disease loci.

Asian People / genetics Genetic Predisposition to Disease Genome-Wide Association Study Humans Lipids Myocardial Infarction Polymorphism, Single Nucleotide White People
Gaussian Graphical Modelling Genetics Lipidomics Network analysis South Asian

Journal

BMC medicine
ISSN: 1741-7015
Titre abrégé: BMC Med
Pays: England
ID NLM: 101190723

Informations de publication

Date de publication:
10 09 2021
Historique:
received: 25 09 2020
accepted: 04 08 2021
entrez: 10 9 2021
pubmed: 11 9 2021
medline: 16 10 2021
Statut: epublish

Résumé

Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies. We characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci. We identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci. Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.

Sections du résumé

BACKGROUND
Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies.
METHODS
We characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci.
RESULTS
We identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci.
CONCLUSIONS
Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.

Identifiants

DOI: 10.1186/s12916-021-02087-1 PMID: 34503513 PMC: PMC8431908
pubmed: 34503513
doi: 10.1186/s12916-021-02087-1
pii: 10.1186/s12916-021-02087-1
pmc: PMC8431908
doi:

Substances chimiques

Lipids 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

232

Subventions

Organisme : Medical Research Council
ID : MC_PC_13030
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L003120/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/13/13/30194
Pays : United Kingdom
Organisme : British Heart Foundation (GB)
ID : SP/09/002
Organisme : Medical Research Council
ID : G0800783
Pays : United Kingdom
Organisme : British Heart Foundation
ID : SP/09/002
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_A090_1006
Pays : United Kingdom
Organisme : Medical Research Council (GB)
ID : MR/L003120/1
Organisme : British Heart Foundation (GB)
ID : RG/13/13/30194
Organisme : Wellcome Trust
ID : 105602/Z/14/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800270
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/18/13/33946
Pays : United Kingdom

Informations de copyright

© 2021. The Author(s).

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Auteurs

Eric L Harshfield (EL)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. eh457@medschl.cam.ac.uk.
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK. eh457@medschl.cam.ac.uk.

Eric B Fauman (EB)

Internal Medicine Research Unit, Pfizer Worldwide Research, Development and Medical, Cambridge, Massachusetts, 02139, USA.

David Stacey (D)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.

Dirk S Paul (DS)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, CB2 0QQ, UK.
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK.
National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, CB2 0QQ, UK.
Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, CB10 1SA, UK.
Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.

Daniel Ziemek (D)

Inflammation and Immunology, Pfizer Worldwide Research, Development and Medical, 10785, Berlin, Germany.

Rachel M Y Ong (RMY)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.

John Danesh (J)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, CB2 0QQ, UK.
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK.
National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, CB2 0QQ, UK.
Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, CB10 1SA, UK.
Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.

Adam S Butterworth (AS)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, CB2 0QQ, UK.
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK.
National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, CB2 0QQ, UK.
Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, CB10 1SA, UK.
Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.

Asif Rasheed (A)

Center for Non-Communicable Diseases, Karachi, 75300, Pakistan.

Taniya Sattar (T)

Center for Non-Communicable Diseases, Karachi, 75300, Pakistan.
Center for Non-Communicable Diseases, Karachi, 75300, Pakistan.

Imran Saleem (I)

Center for Non-Communicable Diseases, Karachi, 75300, Pakistan.

Zoubia Hina (Z)

Center for Non-Communicable Diseases, Karachi, 75300, Pakistan.

Unzila Ishtiaq (U)

Center for Non-Communicable Diseases, Karachi, 75300, Pakistan.

Nadeem Qamar (N)

National Institute of Cardiovascular Diseases, Karachi, 75510, Pakistan.

Nadeem Hayat Mallick (NH)

Punjab Institute of Cardiology, Lahore, 42000, Pakistan.

Zia Yaqub (Z)

National Institute of Cardiovascular Diseases, Karachi, 75510, Pakistan.

Tahir Saghir (T)

National Institute of Cardiovascular Diseases, Karachi, 75510, Pakistan.

Syed Nadeem Hasan Rizvi (SNH)

National Institute of Cardiovascular Diseases, Karachi, 75510, Pakistan.

Anis Memon (A)

National Institute of Cardiovascular Diseases, Karachi, 75510, Pakistan.

Mohammad Ishaq (M)

Karachi Institute of Heart Diseases, Karachi, 75950, Pakistan.

Syed Zahed Rasheed (SZ)

Karachi Institute of Heart Diseases, Karachi, 75950, Pakistan.

Fazal-Ur-Rehman Memon (FU)

Red Crescent Institute of Cardiology, Hyderabad, 71500, Pakistan.

Anjum Jalal (A)

Faisalabad Institute of Cardiology, Faisalabad, 38000, Pakistan.

Shahid Abbas (S)

Faisalabad Institute of Cardiology, Faisalabad, 38000, Pakistan.

Philippe Frossard (P)

Center for Non-Communicable Diseases, Karachi, 75300, Pakistan.

Danish Saleheen (D)

Center for Non-Communicable Diseases, Karachi, 75300, Pakistan.
Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA.

Angela M Wood (AM)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, CB2 0QQ, UK.
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK.
National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, CB2 0QQ, UK.
Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, CB10 1SA, UK.
Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.

Julian L Griffin (JL)

Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, CB2 1GA, UK. julian.griffin@imperial.ac.uk.
Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, SW7 2AZ, UK. julian.griffin@imperial.ac.uk.

Albert Koulman (A)

Core Metabolomics and Lipidomics Laboratory, National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, UK. ak675@medschl.cam.ac.uk.

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