Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis
Year: 2023
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. RESULTS: Using a Bonferroni-corrected significance threshold of P <1.6×10 −4 , we identified 3 genes ( ATP1B1 , ARVCF , and LIPG ) associated with CAC and 2 genes ( ABCG8 and EIF2B2 ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both ATP1B1 and ARVCF also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis. CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.
Authors: Natalie R. Hasbani, Kenneth E. Westerman, Soo Heon Kwak, Han Chen, Xihao Li, Daniel Di Corpo, Jennifer Wessel, Joshua C. Bis, Chloè Sarnowski, Peitao Wu, Lawrence F. Bielak, Xiuqing Guo, Nancy Heard-Costa, Gregory L. Kinney, Michael C. Mahaney, May E. Montasser, Nicholette D. Palmer, Laura M. Raffield, James G. Terry, Lisa R. Yanek, Jessica Bon, Donald W. Bowden, Jennifer A. Brody, Ravindranath Duggirala, David R. Jacobs, Rita R. Kalyani, Leslie A. Lange, Braxton D. Mitchell, Jennifer A. Smith, Kent D. Taylor, April P. Carson, Joanne E. Curran, Myriam Fornage, Barry I. Freedman, Stacey Gabriel, Richard A. Gibbs, Namrata Gupta, Sharon L.R. Kardia, Brian G. Kral, Zeineen Momin, Anne B. Newman, Wendy S. Post, Karine A. Viaud-Martinez, Kendra A. Young, Lewis C. Becker, Alain G. Bertoni, John Blangero, John J. Carr, Katherine Pratte, Bruce M. Psaty, Stephen S. Rich, Joseph C. Wu, Rajeev Malhotra, Patricia A. Peyser, Alanna C. Morrison, Ramachandran S. Vasan, Xihong Lin, Jerome I. Rotter, James B. Meigs, Alisa K. Manning, Paul S. de Vries
Institutions: The University of Texas Health Science Center at Houston, Broad Institute, Harvard University, Massachusetts General Hospital, Seoul National University, Seoul National University Hospital, Boston University, University of Washington, University of California, Los Angeles, The Lundquist Institute, Los Angeles Medical Center, Harbor–UCLA Medical Center, Framingham Heart Study, Colorado School of Public Health, The University of Texas Rio Grande Valley, University of Maryland, Baltimore, Wake Forest University Health Sciences, Wake Forest University, University of North Carolina at Chapel Hill, Vanderbilt University, Vanderbilt University Medical Center, Johns Hopkins University, Johns Hopkins Medicine, University of Pittsburgh, University of Pittsburgh Medical Center, University of Colorado Anschutz, University of Colorado Denver, Baltimore VA Medical Center, University of Michigan, Institute for Social Research, University of Mississippi Medical Center, Baylor College of Medicine, Johns Hopkins Hospital, Illumina (United States), National Jewish Health, ORCID, Stanford Cardiovascular Institute, University of Virginia, Stanford University, Stanford Medicine, The University of Texas at San Antonio Health Science Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: American Heart Association, Massachusetts General Hospital, Vanderbilt University, Wake Forest University, University of Washington, Johns Hopkins University, University of Pittsburgh, Harvard T.H. Chan School of Public Health, School of Public Health, University of Michigan, National Jewish Health, University of Texas Health Science Center at Houston, Vanderbilt University Medical Center, Broad Institute, University of Texas Rio Grande Valley, Seoul National University, Seoul National University Hospital, National Institutes of Health, School of Medicine, Stanford University, University of California, Los Angeles, Medical Center, University of Pittsburgh, University of North Carolina at Chapel Hill, Wake Forest School of Medicine, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, NIH Clinical Center, Stanford Cardiovascular Institute, School of Medicine, Stanford University
Awards: G1161164076, The Role of Histone Deacetylase 9 in Vascular Calcification, Rare variants and NHLBI traits in deeply phenotyped cohorts, G220423607, G232264632, G2961175032, Characterization of Functional Iron Deficiency and Repletion in Heart Failure with Preserved Ejection Fraction, G3256118428, G3257426095, G4050667541, Rare variants and NHLBI traits in deeply phenotyped cohorts, G4301368905, G4429312988, G4847032609, Methods and Software for Large-Scale Gene-Environment Interaction Studies, G50080621, G6086533272, G6612147123, G7136812375, G805890577, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, Whole Genome Sequencing to Identify Causal Genetic Variants Influencing CVD Risk
OpenAlex ID: W4389089990