Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.

TitleType 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.
Publication TypeJournal Article
Year of Publication2023
AuthorsHasbani, NR, Westerman, KE, Kwak, SHeon, Chen, H, Li, X, Di Corpo, D, Wessel, J, Bis, JC, Sarnowski, C, Wu, P, Bielak, LF, Guo, X, Heard-Costa, N, Kinney, GL, Mahaney, MC, Montasser, ME, Palmer, ND, Raffield, LM, Terry, JG, Yanek, LR, Bon, J, Bowden, DW, Brody, JA, Duggirala, R, Jacobs, DR, Kalyani, RR, Lange, LA, Mitchell, BD, Smith, JA, Taylor, KD, Carson, AP, Curran, JE, Fornage, M, Freedman, BI, Gabriel, S, Gibbs, RA, Gupta, N, Kardia, SLR, Kral, BG, Momin, Z, Newman, AB, Post, WS, Viaud-Martinez, KA, Young, KA, Becker, LC, Bertoni, AG, Blangero, J, Carr, JJ, Pratte, K, Psaty, BM, Rich, SS, Wu, JC, Malhotra, R, Peyser, PA, Morrison, AC, Vasan, RS, Lin, X, Rotter, JI, Meigs, JB, Manning, AK, de Vries, PS
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Atherosclerosis Working Group; TOPMed Diabetes Working Group
JournalCirc Genom Precis Med
Volume16
Issue6
Paginatione004176
Date Published2023 Dec
ISSN2574-8300
KeywordsAtherosclerosis, Carotid Intima-Media Thickness, Coronary Artery Disease, Diabetes Mellitus, Type 2, Genomics, Humans, Plaque, Atherosclerotic, Risk Factors
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

CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

DOI10.1161/CIRCGEN.123.004176
Alternate JournalCirc Genom Precis Med
PubMed ID38014529
PubMed Central IDPMC10843644
Grant ListR00 AG066849 / AG / NIA NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
K01 DK133637 / DK / NIDDK NIH HHS / United States
R01 HL139553 / HL / NHLBI NIH HHS / United States
K99 AG066849 / AG / NIA NIH HHS / United States
U01 HL120393 / HL / NHLBI NIH HHS / United States
R01 HL159514 / HL / NHLBI NIH HHS / United States
R01 HL146860 / HL / NHLBI NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
R01 HL145025 / HL / NHLBI NIH HHS / United States
R01 HL117626 / HL / NHLBI NIH HHS / United States
R01 HL142809 / HL / NHLBI NIH HHS / United States
R01 HL151855 / HL / NHLBI NIH HHS / United States
UM1 DK078616 / DK / NIDDK NIH HHS / United States

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