Genetic Architecture of Plasma Alpha-Aminoadipic Acid Reveals a Relationship With High-Density Lipoprotein Cholesterol

Publication Description
Background Elevated plasma levels of alpha-aminoadipic acid (2-AAA) have been associated with the development of type 2 diabetes and atherosclerosis. However, the nature of the association remains unknown. Methods and Results We identified genetic determinants of plasma 2-AAA through meta-analysis of genome-wide association study data in 5456 individuals of European, African, and Asian ancestry from the Framingham Heart Study, Diabetes Prevention Program, Jackson Heart Study, and Shanghai Women's and Men's Health Studies. No single nucleotide polymorphisms reached genome-wide significance across all samples. However, the top associations from the meta-analysis included single-nucleotide polymorphisms in the known 2-AAA pathway gene DHTKD1, and single-nucleotide polymorphisms in genes involved in mitochondrial respiration (NDUFS4) and macrophage function (MSR1). We used a Mendelian randomization instrumental variable approach to evaluate relationships between 2-AAA and cardiometabolic phenotypes in large disease genome-wide association studies. Mendelian randomization identified a suggestive inverse association between increased 2-AAA and lower high-density lipoprotein cholesterol (P=0.005). We further characterized the genetically predicted relationship through measurement of plasma 2-AAA and high-density lipoprotein cholesterol in 2 separate samples of individuals with and without cardiometabolic disease (N=98), and confirmed a significant negative correlation between 2-AAA and high-density lipoprotein (r(s)=-0.53, P

Primary Author
Shi,M.
Wang,C.
Mei,H.
Temprosa,M.
Florez,J. C.
Tripputi,M.
Merino,J.
Lipworth,L.
Shu,X. O.
Gerszten,R. E.
Wang,T. J.
Beckman,J. A.
Gamboa,J. L.
Mosley,J. D.
Ferguson,J. F.
Diabetes Prevention Program Research Group

Author Address
Department of Biomedical Informatics Vanderbilt University Medical Center Nashville TN.; Division of Cardiovascular Medicine Department of Medicine Vanderbilt University Medical Center Nashville TN.; Department of Data Science School of Population Health University of Mississippi Medical Center Jackson MS.; Department of Biostatistics and Bioinformatics Milken Institute School of Public HealthGeorge Washington University Rockville MD.; Center for Genomic Medicine and Diabetes Unit Massachusetts General Hospital Boston MA.; Programs in Metabolism and Medical & Population Genetics Broad Institute Cambridge MA.; Department of Medicine Harvard Medical School Boston MA.; Department of Biostatistics and Bioinformatics Milken Institute School of Public HealthGeorge Washington University Rockville MD.; Center for Genomic Medicine and Diabetes Unit Massachusetts General Hospital Boston MA.; Programs in Metabolism and Medical & Population Genetics Broad Institute Cambridge MA.; Department of Medicine Harvard Medical School Boston MA.; Division of Epidemiology Department of Medicine Vanderbilt University Medical Center Nashville TN.; Division of Epidemiology Department of Medicine Vanderbilt University Medical Center Nashville TN.; Division of Cardiovascular Medicine Beth Israel Deaconess Medical Center Boston MA.; Broad Institute of Harvard and MIT Cambridge MA.; Department of Medicine UT Southwestern Medical Center Dallas TX.; Division of Cardiovascular Medicine Department of Medicine Vanderbilt University Medical Center Nashville TN.; Division of Clinical Pharmacology Department of Medicine Vanderbilt University Medical Center Nashville TN.; Department of Biomedical Informatics Vanderbilt University Medical Center Nashville TN.; Division of Clinical Pharmacology Department of Medicine Vanderbilt University Medical Center Nashville TN.; Division of Cardiovascular Medicine Department of Medicine Vanderbilt University Medical Center Nashville TN.

Other Pages
e024388

Author Address
Department of Biomedical Informatics Vanderbilt University Medical Center Nashville TN.; Division of Cardiovascular Medicine Department of Medicine Vanderbilt University Medical Center Nashville TN.; Department of Data Science School of Population Health University of Mississippi Medical Center Jackson MS.; Department of Biostatistics and Bioinformatics Milken Institute School of Public HealthGeorge Washington University Rockville MD.; Center for Genomic Medicine and Diabetes Unit Massachusetts General Hospital Boston MA.; Programs in Metabolism and Medical & Population Genetics Broad Institute Cambridge MA.; Department of Medicine Harvard Medical School Boston MA.; Department of Biostatistics and Bioinformatics Milken Institute School of Public HealthGeorge Washington University Rockville MD.; Center for Genomic Medicine and Diabetes Unit Massachusetts General Hospital Boston MA.; Programs in Metabolism and Medical & Population Genetics Broad Institute Cambridge MA.; Department of Medicine Harvard Medical School Boston MA.; Division of Epidemiology Department of Medicine Vanderbilt University Medical Center Nashville TN.; Division of Epidemiology Department of Medicine Vanderbilt University Medical Center Nashville TN.; Division of Cardiovascular Medicine Beth Israel Deaconess Medical Center Boston MA.; Broad Institute of Harvard and MIT Cambridge MA.; Department of Medicine UT Southwestern Medical Center Dallas TX.; Division of Cardiovascular Medicine Department of Medicine Vanderbilt University Medical Center Nashville TN.; Division of Clinical Pharmacology Department of Medicine Vanderbilt University Medical Center Nashville TN.; Department of Biomedical Informatics Vanderbilt University Medical Center Nashville TN.; Division of Clinical Pharmacology Department of Medicine Vanderbilt University Medical Center Nashville TN.; Division of Cardiovascular Medicine Department of Medicine Vanderbilt University Medical Center Nashville TN.

PMID
35621206



Reference Type
Journal Article

Periodical Full
Journal of the American Heart Association

Publication Year
2022

Publication Date
27-May

Place of Publication
England

ISSN/ISBN
2047-9980

Document Object Index
10.1161/JAHA.121.024388 [doi]

Accession Number
PMID: 35621206