Genetic Architecture of Plasma Alpha‐Aminoadipic Acid Reveals a Relationship With High‐Density Lipoprotein Cholesterol
Year: 2022
Type: article
Study design: Observational Study
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 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 <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.
Institutions: Vanderbilt University Medical Center, Vanderbilt University, University of Mississippi Medical Center, George Washington University, Broad Institute, Harvard University, Massachusetts General Hospital, Beth Israel Deaconess Medical Center, Massachusetts Institute of Technology, The University of Texas Southwestern Medical Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,700
Funders: University of Southern California, Vanderbilt University, Jackson State University, George Washington University, Johns Hopkins University, University of Pittsburgh, Vanderbilt University Medical Center, Mississippi State Department of Health, National Institutes of Health, Centers for Disease Control and Prevention, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1093951984, G1295889178, G1485640885, G153916420, G1540916838, GENERAL CLINICAL RESEARCH CENTER, G1711244518, G1730507467, G1766209448, G1776253575, G1967470738, G1986296333, G2000805413, G2006034517, G2141991604, Understanding the genetic risk underlying racial disparities in uterine fibroids, G2221742881, G2247587933, G2310098089, G2316258288, G2328519459, G2415573643, G2439437419, 8/22 Limited Competition for the Continuation of the Diabetes Prevention Program Outcomes Study (DPPOS) - Clinical Center, G2491623767, G25420283, G265762973, G2683268942, G2702067867, G2809357584, G3057025668, G3289176252, G3395468139, G3398210748, G3407579893, G3420921512, G347469348, G350245564, G3619590958, G3714318003, G4175770015, Determinants of alpha-aminoadipic acid (2-AAA) and relationship to diabetes, Automated Storage and Retrieval of Biological Systems, G433373727, G4410787187, G4711807797, G47192932, G4897018079, G4997665424, BioVU Plasma Storage Equipment, G5361611515, G5390604924, 9/22 Limited Competition for Continuation of the Diabetes Prevention Program Outcomes Study (DPPOS) - Clinical Center, G5478822001, G560889077, G5679716143, G5717004637, G579045871, G5842795995, G5947254055, Genetic Epidemiology of Multiple Sclerosis, G609523450, G6106528919, G6156766399, 7/22 Limited Competition for the Continuation of the Diabetes Prevention Program Outcomes Study (DPPOS) - Clinical Center, G6571475356, G6766166885, G7091571603, G7163342664, G7526106616, The Vanderbilt Institute for Clinical and Translational Research (VICTR), Epidemiologic Architecture for Genes Linked to Environment (EAGLE), G8332127685, 16/22 Limited Competition for the Continuation of the Diabetes Prevention Program Outcomes Study (DPPOS) – Clinical Center, G87163782, G89699440, G9000000197, G9000008449, G9000022789, G9000043901, G9000054231, G9000090229, G9000119601, G9000139424, G9000167145, G9000173344, G9000229765, G9000328931, G949362299, G95160140
OpenAlex ID: W4281752074