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

ABSTRACT: Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

SUBMITTER: Kavousi M

PROVIDER: S-EPMC10601987 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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

Kavousi Maryam M Bos Maxime M MM Barnes Hanna J HJ Lino Cardenas Christian L CL Wong Doris D Lu Haojie H Hodonsky Chani J CJ Landsmeer Lennart P L LPL Turner Adam W AW Kho Minjung M Hasbani Natalie R NR de Vries Paul S PS Bowden Donald W DW Chopade Sandesh S Deelen Joris J Benavente Ernest Diez ED Guo Xiuqing X Hofer Edith E Hwang Shih-Jen SJ Lutz Sharon M SM Lyytikäinen Leo-Pekka LP Slenders Lotte L Smith Albert V AV Stanislawski Maggie A MA van Setten Jessica J Wong Quenna Q Yanek Lisa R LR Becker Diane M DM Beekman Marian M Budoff Matthew J MJ Feitosa Mary F MF Finan Chris C Hilliard Austin T AT Kardia Sharon L R SLR Kovacic Jason C JC Kral Brian G BG Langefeld Carl D CD Launer Lenore J LJ Malik Shaista S Hoesein Firdaus A A Mohamed FAAM Mokry Michal M Schmidt Reinhold R Smith Jennifer A JA Taylor Kent D KD Terry James G JG van der Grond Jeroen J van Meurs Joyce J Vliegenthart Rozemarijn R Xu Jianzhao J Young Kendra A KA Zilhão Nuno R NR Zweiker Robert R Assimes Themistocles L TL Becker Lewis C LC Bos Daniel D Carr J Jeffrey JJ Cupples L Adrienne LA de Kleijn Dominique P V DPV de Winther Menno M den Ruijter Hester M HM Fornage Myriam M Freedman Barry I BI Gudnason Vilmundur V Hingorani Aroon D AD Hokanson John E JE Ikram M Arfan MA Išgum Ivana I Jacobs David R DR Kähönen Mika M Lange Leslie A LA Lehtimäki Terho T Pasterkamp Gerard G Raitakari Olli T OT Schmidt Helena H Slagboom P Eline PE Uitterlinden André G AG Vernooij Meike W MW Bis Joshua C JC Franceschini Nora N Psaty Bruce M BM Post Wendy S WS Rotter Jerome I JI Björkegren Johan L M JLM O'Donnell Christopher J CJ Bielak Lawrence F LF Peyser Patricia A PA Malhotra Rajeev R van der Laan Sander W SW Miller Clint L CL

Nature genetics 20230928 10

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ance ...[more]

PMID: 37770635

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Project description:Many GWAS have identified novel loci associated with common diseases, but have focused only on main effects of individual genetic variants rather than interactions with environmental factors (GxE). Identification of GxE interactions is particularly important for coronary heart disease (CHD), a major preventable source of morbidity and mortality with strong non-genetic risk factors. Atherosclerosis is the major cause of CHD, and coronary artery calcification (CAC) is directly correlated with quantity of coronary atherosclerotic plaque. In the current study, we tested for genetic variants influencing extent of CAC via interaction with smoking (GxS), by conducting a GxS discovery GWAS in Genetic Epidemiology Network of Arteriopathy (GENOA) sibships (N = 915 European Americans) followed by replication in Framingham Heart Study (FHS) sibships (N = 1025 European Americans). Generalized estimating equations accounted for the correlation within sibships in strata-specific groups of smokers and nonsmokers, as well as GxS interaction. Primary analysis found SNPs that showed suggestive associations (p≤10(-5)) in GENOA GWAS, but these index SNPs did not replicate in FHS. However, secondary analysis was able to replicate candidate gene regions in FHS using other SNPs (+/-250 kb of GENOA index SNP). In smoker and nonsmoker groups, replicated genes included TCF7L2 (p = 6.0×10(-5)) and WWOX (p = 4.5×10(-6)); and TNFRSF8 (p = 7.8×10(-5)), respectively. For GxS interactions, replicated genes included TBC1D4 (p = 6.9×10(-5)) and ADAMTS9 (P = 7.1×10(-5)). Interestingly, these genes are involved in inflammatory pathways mediated by the NF-κB axis. Since smoking is known to induce chronic and systemic inflammation, association of these genes likely reflects roles in CAC development via inflammatory pathways. Furthermore, the NF-κB axis regulates bone remodeling, a key physiological process in CAC development. In conclusion, GxS GWAS has yielded evidence for novel loci that are associated with CAC via interaction with smoking, providing promising new targets for future population-based and functional studies of CAC development.

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

Publications

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

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