Browsing by Author "Lusis, Aldons J"

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    ItemOpen Access
    Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.
    (European heart journal, 2021-03) Hartiala, Jaana A; Han, Yi; Jia, Qiong; Hilser, James R; Huang, Pin; Gukasyan, Janet; Schwartzman, William S; Cai, Zhiheng; Biswas, Subarna; Trégouët, David-Alexandre; Smith, Nicholas L; INVENT Consortium; CHARGE Consortium Hemostasis Working Group; GENIUS-CHD Consortium; Seldin, Marcus; Pan, Calvin; Mehrabian, Margarete; Lusis, Aldons J; Bazeley, Peter; Sun, Yan V; Liu, Chang; Quyyumi, Arshed A; Scholz, Markus; Thiery, Joachim; Delgado, Graciela E; Kleber, Marcus E; März, Winfried; Howe, Laurence J; Asselbergs, Folkert W; van Vugt, Marion; Vlachojannis, Georgios J; Patel, Riyaz S; Lyytikäinen, Leo-Pekka; Kähönen, Mika; Lehtimäki, Terho; Nieminen, Tuomo VM; Kuukasjärvi, Pekka; Laurikka, Jari O; Chang, Xuling; Heng, Chew-Kiat; Jiang, Rong; Kraus, William E; Hauser, Elizabeth R; Ferguson, Jane F; Reilly, Muredach P; Ito, Kaoru; Koyama, Satoshi; Kamatani, Yoichiro; Komuro, Issei; Biobank Japan; Stolze, Lindsey K; Romanoski, Casey E; Khan, Mohammad Daud; Turner, Adam W; Miller, Clint L; Aherrahrou, Redouane; Civelek, Mete; Ma, Lijiang; Björkegren, Johan LM; Kumar, S Ram; Tang, WH Wilson; Hazen, Stanley L; Allayee, Hooman

    Aims

    While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation.

    Methods and results

    We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro.

    Conclusions

    A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.
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    Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.
    (PLoS Genet, 2015-11) Kraus, William E; Muoio, Deborah M; Stevens, Robert; Craig, Damian; Bain, James R; Grass, Elizabeth; Haynes, Carol; Kwee, Lydia; Qin, Xuejun; Slentz, Dorothy H; Krupp, Deidre; Muehlbauer, Michael; Hauser, Elizabeth R; Gregory, Simon G; Newgard, Christopher B; Shah, Svati H
    Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6-2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.