Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis
Authors: Hasbani Natalie R. , Westerman Kenneth E. , Kwak Soo Heon , Chen Han , Li Xihao , Di Corpo Daniel , Wessel Jennifer , Bis Joshua C. , Sarnowski Chloè , Wu Peitao , Bielak Lawrence F. , Guo Xiuqing , Heard-Costa Nancy , Kinney Gregory L. , Mahaney Michael C. , Montasser May E. , Palmer Nicholette D. , Raffield Laura M. , Terry James G. , Yanek Lisa R. , Bon Jessica , Bowden Donald W. , Brody Jennifer A. , Duggirala Ravindranath , Jacobs David R. , Kalyani Rita R. , Lange Leslie A. , Mitchell Braxton D. , Smith Jennifer A. , Taylor Kent D. , Carson April P. , Curran Joanne E. , Fornage Myriam , Freedman Barry I. , Gabriel Stacey , Gibbs Richard A. , Gupta Namrata , Kardia Sharon L.R. , Kral Brian G. , Momin Zeineen , Newman Anne B. , Post Wendy S. , Viaud-Martinez Karine A. , Young Kendra A. , Becker Lewis C. , Bertoni Alain G. , Blangero John , Carr John J. , Pratte Katherine , Psaty Bruce M. , Rich Stephen S. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Atherosclerosis Working Group; TOPMed Diabetes Working Group, Wu Joseph C. , Malhotra Rajeev , Peyser Patricia A. , Morrison Alanna C. , Vasan Ramachandran S. , Lin Xihong , Rotter Jerome I. , Meigs James B. , Manning Alisa K. , de Vries Paul S. 
Published: November 2023

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.