Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification

Kavousi, Maryam; Bos, Maxime M.; Barnes, Hanna J.; Lino Cardenas, Christian L.; Wong, Doris; Lu, Haojie; Hodonsky, Chani J.; Landsmeer, Lennart P. L.; Turner, Adam W.; Kho, Minjung; Hasbani, Natalie R.; de Vries, Paul S.; Bowden, Donald W.; Chopade, Sandesh; Deelen, Joris; Benavente, Ernest Diez; Guo, Xiuqing; Hofer, Edith; Hwang, Shih-Jen; Lutz, Sharon M.; Lyytikäinen, Leo-Pekka; Slenders, Lotte; Smith, Albert V.; Stanislawski, Maggie A.; van Setten, Jessica; Wong, Quenna; Yanek, Lisa R.; Becker, Diane M.; Beekman, Marian; Budoff, Matthew J.; Feitosa, Mary F.; Finan, Chris; Hilliard, Austin T.; Kardia, Sharon L. R.; Kovacic, Jason C.; Kral, Brian G.; Langefeld, Carl D.; Launer, Lenore J.; Malik, Shaista; Hoesein, Firdaus A. A. Mohamed; Mokry, Michal; Schmidt, Reinhold; Smith, Jennifer A.; Taylor, Kent D.; Terry, James G.; van der Grond, Jeroen; van Meurs, Joyce; Vliegenthart, Rozemarijn; Xu, Jianzhao; Young, Kendra A.; Zilhão, Nuno R.; Zweiker, Robert; Assimes, Themistocles L.; Becker, Lewis C.; Bos, Daniel; Carr, J. Jeffrey; Cupples, L. Adrienne; de Kleijn, Dominique P. v.; de Winther, Menno; den Ruijter, Hester M.; Fornage, Myriam; Freedman, Barry I.; Gudnason, Vilmundur; Hingorani, Aroon D.; Hokanson, John E.; Ikram, M. Arfan; Išgum, Ivana; Jacobs, David R.; Kähönen, Mika; Lange, Leslie A.; Lehtimäki, Terho; Pasterkamp, Gerard; Raitakari, Olli T.; Schmidt, Helena; Slagboom, P. Eline; Uitterlinden, André G.; Vernooij, Meike W.; Bis, Joshua C.; Franceschini, Nora; Psaty, Bruce M.; Post, Wendy S.; Rotter, Jerome I.; Björkegren, Johan L. M.; O’Donnell, Christopher J.; Bielak, Lawrence F.; Peyser, Patricia A.; Malhotra, Rajeev; van der Laan, Sander W.; Miller, Clint L.

doi:10.1038/s41588-023-01518-4

Cited by 23 publications

(25 citation statements)

References 108 publications

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“…Neither gene had previously been reported associated with CAC. 22,25,31 Furthermore, despite common variant associations near these genes with CAD, the suspected role of ARVCF and ATP1B1 in the development of atherosclerosis has not been well studied. ARVCF is a member of the catenin family, which plays an important role in cell adhesion and communication.…”

Section: Discussionmentioning

confidence: 99%

“…All CAD variants, except rs55730499 near LPA, have also previously been identified as associated with CAC in published CAC GWAS. 22,25,26 No SNVs met the Bonferroni-corrected threshold for significance in the interaction test, but 17 candidate variants were nominally significant (P int and P joint <0.05). Fifteen SNVs were in loci that had not previously been identified with CAC (Table 1).…”

Section: Study Populationmentioning

confidence: 99%

“…[11][12][13][14][15][16] While genome-wide association studies (GWASs) have identified hundreds of genetic loci associated with CAD, fewer GWAS-based discoveries have been observed for subclinical atherosclerosis measures despite their notable heritability and high genetic correlation with CAD. [17][18][19][20][21][22][23][24][25] Continuous subclinical atherosclerosis measures, such as CAC and CIMT, are particularly valuable in GWAS for measuring the early progression of atherosclerosis with greater statistical power than incident CAD. Furthermore, many studies have not considered the role of T2D in their analyses, which may differentially influence the way loci impact the development of atherosclerosis.…”

mentioning

confidence: 99%

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

Hasbani,

Westerman,

Kwak

et al. 2023

Circ: Genomic and Precision Medicine

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Study Populationmentioning

confidence: 99%

mentioning

confidence: 99%

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

Hasbani,

Westerman,

Kwak

et al. 2023

Circ: Genomic and Precision Medicine

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“…The modest added predictive value shown by recent studies such as by [Elliott et al, 2020] could partly be due to the missing genetic components hidden within the genetic architecture of intermediate phenotypes of CVD, such as coronary artery calcification (CAC), that are involved in the pathogenesis of CVD. Indeed, although there is shared etiology between CVD and CAC, a recent comprehensive GWAS study of CAC found several new CAC associated genes that have so far not been reported to be associated with CVD [Kavousi et al, 2023]. CAC score, a measure of the amount of calcified plaque in coronary arteries, is a highly reliable indicator of cardiovascular disease beyond the established CVD risk variables [Detrano et al, 2008; Greenland et al, 2018].…”

Section: Introductionmentioning

confidence: 99%

“…The main objective of the current study was to investigate whether GRS for CAC (CAC GRS) is associated with angiographically or morphometrically verified CAD in three European cohorts. The CAC GRS was calculated using genetic summary statistics from the most recent GWAS study of CAC [Kavousi et al, 2023]. We aimed to confirm the link between CAC associated SNPs and calcification by studying the association of CAC GRS with calcification areas measured in autopsy coronary arteries.…”

Section: Introductionmentioning

confidence: 99%

Genetic risk score for coronary artery calcification predicts coronary artery disease beyond traditional risk factors

Mishra,

Lyytikäinen

et al. 2024

Preprint

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Aim: The modest added predictive value of the existing genetic risk scores (GRSs) for coronary artery disease (CAD) could be partly due to missing genetic components, hidden in the genetic architecture of intermediate phenotypes such as coronary artery calcification (CAC). In this study, we investigated the predictive ability of CAC GRS for CAD. Materials and methods: We investigated the association of CAC GRSs with CAD and coronary calcification among the participants in the Ludwigshafen Risk and Cardiovascular Health study (LURIC) (n=2742), the Tampere Vascular Study (TVS) (n=133), and the Tampere Sudden Death Study (TSDS) (n=660) using summary data from the largest multiancestry GWAS metaanalysis of CAC to date. Added predictive value of the CAC GRS over the traditional CVD risk factors was tested with standard train-test machine learning approach using the LURIC data, which had the largest sample size. Results: CAC GRS was significantly associated with CAD in LURIC (OR=1.41, 95% CI [1.28-1.55]), TVS (OR=1.79, 95% CI [1.05-3.21]) as well as in TSDS (OR=4.20, 95% CI [1.74-10.52]). CAC GRS showed strong association with calcification areas in left (OR=1.78, 95% CI [1.16-2.74]) and right (OR=1.71, 95% CI [1.98-2.67]) coronary arteries. In addition, there was statistically significant added predictive value of the CAC GRS for CAD over the used traditional CVD risk factors (AUC 0.734 vs 0.717, p-value = 0.02). Conclusions: This study showed that CAC GRS is a new risk marker for CAD in three European cohorts, with added predictive value over the traditional CVD risk factors.

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Unraveling interindividual variation of trimethylamine N‐oxide and its precursors at the population level

Andreu‐Sánchez,

Ahmad,

Kurilshikov

et al. 2024

iMeta

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Trimethylamine N‐oxide (TMAO) is a circulating microbiome‐derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO‐to‐precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in‐depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome‐wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO‐to‐precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish‐TMAO, meat‐carnitine, and plant‐based food‐betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.

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Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification

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Cited by 23 publications

References 108 publications

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

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

Genetic risk score for coronary artery calcification predicts coronary artery disease beyond traditional risk factors

Unraveling interindividual variation of trimethylamine N‐oxide and its precursors at the population level

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