Abstract
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 poly-morphisms 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 randomi-zation 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 (rs =−0.53, P<0.0001). CONCLUSIONS: 2-AAA levels in plasma may be regulated, in part, by common variants in genes involved in mitochondrial and macrophage function. Elevated plasma 2-AAA associates with reduced levels of high-density lipoprotein cholesterol. Further mechanistic studies are required to probe this as a possible mechanism linking 2-AAA to future cardiometabolic risk.
| Original language | English (US) |
|---|---|
| Article number | e024388 |
| Journal | Journal of the American Heart Association |
| Volume | 11 |
| Issue number | 11 |
| DOIs | |
| State | Published - Jun 7 2022 |
| Externally published | Yes |
Keywords
- 2-aminoadipic acid
- HDL cholesterol
- Mendelian randomization analysis
- genome-wide association study
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
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In: Journal of the American Heart Association, Vol. 11, No. 11, e024388, 07.06.2022.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Genetic Architecture of Plasma Alpha-Aminoadipic Acid Reveals a Relationship With High-Density Lipoprotein Cholesterol
AU - Shi, Mingjian
AU - Wang, Chuan
AU - Mei, Hao
AU - Temprosa, Marinella
AU - Florez, Jose C.
AU - Tripputi, Mark
AU - Merino, Jordi
AU - Lipworth, Loren
AU - Shu, Xiao Ou
AU - Gerszten, Robert E.
AU - Wang, Thomas J.
AU - Beckman, Joshua A.
AU - Gamboa, Jorge L.
AU - Mosley, Jonathan D.
AU - Ferguson, Jane F.
N1 - Funding Information: This work was funded by the National Institutes of Health (NIH) (R01 DK117144 and R01 HL142856 to Ferguson). Gamboa was supported by NIH (K23 DK100533). Data sets used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH funded Shared Instrumentation Grant S10OD017985 and S10RR025141; and Clinical and Translational Science Awards grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include NIH (U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711); and additional funding sources listed at https://victr.vumc.org/biovu-funding/. The Shanghai Women’s Health Study (UM1 CA182910) and Shanghai Men’s Health Study (UM1 CA173640) are supported by the National Institutes of Health. The Jackson Heart Study is supported by and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I), and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities (NIMHD). The views expressed in this article are those of the authors and do not necessarily represent the views of the NHLBI; the NIH; or the US Department of Health and Human Services. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH under award numbers U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, and U01 DK048400; by providing funding during DPP (Diabetes Prevention Program) and DPPOS (Diabetes Prevention Program Outcomes Study) to the clinical centers and the Coordinating Center for the design and conduct of the study; and collection, management, analysis, and interpretation of the data. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the NHLBI, the National Cancer Institute, the Office of Research on Women’s Health, the NIMHD, the Centers for Disease Control and Prevention, and the American Diabetes Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Merck KGaA provided medication for DPPOS. DPP/ DPPOS have also received donated materials, equipment, or medicines for concomitant conditions from Bristol-Myers Squibb, Parke-Davis, and LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co., McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the DPP Coordinating Center. The sponsor of this study was represented on the steering committee and played a part in study design, how the study was done, and publication. All authors in the writing group had access to all data. The opinions expressed are those of the study group and do not necessarily reflect the views of the funding agencies. A complete list of centers, investigators, and staff can be found in the Appendix. Funding Information: The DPP Research Group gratefully acknowledges the commitment and dedication of the participants of the DPP and DPPOS. The authors also thank the staffs and participants of the JHS. Sources of Funding This work was funded by the National Institutes of Health (NIH) (R01 DK117144 and R01 HL142856 to Ferguson). Gamboa was supported by NIH (K23 DK100533). Data sets used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by nu-merous sources: institutional funding, private agencies, and federal grants. These include the NIH funded Shared Instrumentation Grant S10OD017985 and S10RR025141; and Clinical and Translational Science Awards grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include NIH (U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711); and additional funding sources listed at https://victr.vumc.org/biovu-funding/. The Shanghai Women’s Health Study (UM1 CA182910) and Shanghai Men’s Health Study (UM1 CA173640) are supported by the National Institutes of Health. The Jackson Heart Study is supported by and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I), and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities (NIMHD). The views expressed in this article are those of the authors and do not necessarily represent the views of the NHLBI; the NIH; or the US Department of Health and Human Services. Research re-ported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH under award numbers U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, and U01 DK048400; by providing funding during DPP (Diabetes Prevention Program) and DPPOS (Diabetes Prevention Program Outcomes Study) to the clinical centers and the Coordinating Center for the design and conduct of the study; and collection, management, analysis, and interpretation of the data. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the NHLBI, the National Cancer Institute, the Office of Research on Women’s Health, the NIMHD, the Centers for Disease Control and Prevention, and the American Diabetes Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Merck KGaA provided medication for DPPOS. DPP/ DPPOS have also received donated materials, equipment, or medicines for concomitant conditions from Bristol-Myers Squibb, Parke-Davis, and LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co., McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under sub-contract with the DPP Coordinating Center. The sponsor of this study was rep-resented on the steering committee and played a part in study design, how the study was done, and publication. All authors in the writing group had access to all data. The opinions expressed are those of the study group and do not necessarily reflect the views of the funding agencies. A complete list of centers, investigators, and staff can be found in the Appendix. Publisher Copyright: © 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2022/6/7
Y1 - 2022/6/7
N2 - 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 poly-morphisms 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 randomi-zation 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 (rs =−0.53, P<0.0001). CONCLUSIONS: 2-AAA levels in plasma may be regulated, in part, by common variants in genes involved in mitochondrial and macrophage function. Elevated plasma 2-AAA associates with reduced levels of high-density lipoprotein cholesterol. Further mechanistic studies are required to probe this as a possible mechanism linking 2-AAA to future cardiometabolic risk.
AB - 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 poly-morphisms 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 randomi-zation 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 (rs =−0.53, P<0.0001). CONCLUSIONS: 2-AAA levels in plasma may be regulated, in part, by common variants in genes involved in mitochondrial and macrophage function. Elevated plasma 2-AAA associates with reduced levels of high-density lipoprotein cholesterol. Further mechanistic studies are required to probe this as a possible mechanism linking 2-AAA to future cardiometabolic risk.
KW - 2-aminoadipic acid
KW - HDL cholesterol
KW - Mendelian randomization analysis
KW - genome-wide association study
UR - http://www.scopus.com/inward/record.url?scp=85132454202&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85132454202&partnerID=8YFLogxK
U2 - 10.1161/JAHA.121.024388
DO - 10.1161/JAHA.121.024388
M3 - Article
C2 - 35621206
AN - SCOPUS:85132454202
SN - 2047-9980
VL - 11
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 11
M1 - e024388
ER -