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-1$\beta$ (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.
%0 Journal Article
%1 Hartiala2021-le
%A Hartiala, Jaana A
%A Han, Yi
%A Jia, Qiong
%A Hilser, James R
%A Huang, Pin
%A Gukasyan, Janet
%A Schwartzman, William S
%A Cai, Zhiheng
%A Biswas, Subarna
%A Trégouët, David-Alexandre
%A Smith, Nicholas L
%A INVENT Consortium,
%A CHARGE Consortium Hemostasis Working Group,
%A GENIUS-CHD Consortium,
%A Seldin, Marcus
%A Pan, Calvin
%A Mehrabian, Margarete
%A Lusis, Aldons J
%A Bazeley, Peter
%A Sun, Yan V
%A Liu, Chang
%A Quyyumi, Arshed A
%A Scholz, Markus
%A Thiery, Joachim
%A Delgado, Graciela E
%A Kleber, Marcus E
%A März, Winfried
%A Howe, Laurence J
%A Asselbergs, Folkert W
%A van Vugt, Marion
%A Vlachojannis, Georgios J
%A Patel, Riyaz S
%A Lyytikäinen, Leo-Pekka
%A Kähönen, Mika
%A Lehtimäki, Terho
%A Nieminen, Tuomo V M
%A Kuukasjärvi, Pekka
%A Laurikka, Jari O
%A Chang, Xuling
%A Heng, Chew-Kiat
%A Jiang, Rong
%A Kraus, William E
%A Hauser, Elizabeth R
%A Ferguson, Jane F
%A Reilly, Muredach P
%A Ito, Kaoru
%A Koyama, Satoshi
%A Kamatani, Yoichiro
%A Komuro, Issei
%A Biobank Japan,
%A Stolze, Lindsey K
%A Romanoski, Casey E
%A Khan, Mohammad Daud
%A Turner, Adam W
%A Miller, Clint L
%A Aherrahrou, Redouane
%A Civelek, Mete
%A Ma, Lijiang
%A Björkegren, Johan L M
%A Kumar, S Ram
%A Tang, W H Wilson
%A Hazen, Stanley L
%A Allayee, Hooman
%D 2021
%I Oxford University Press (OUP)
%J Eur. Heart J.
%K Genetic Genome-wide Meta-analysis; Myocardial SLC44A3 association factors; infarction; study; topic_lifescience
%N 9
%P 919--933
%T Genome-wide analysis identifies novel susceptibility loci for myocardial infarction
%V 42
%X 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-1$\beta$ (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.
@article{Hartiala2021-le,
abstract = {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-1$\beta$ (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.},
added-at = {2024-09-10T11:54:51.000+0200},
author = {Hartiala, Jaana A and Han, Yi and Jia, Qiong and Hilser, James R and Huang, Pin and Gukasyan, Janet and Schwartzman, William S and Cai, Zhiheng and Biswas, Subarna and Tr{\'e}gou{\"e}t, David-Alexandre and Smith, Nicholas L and {INVENT Consortium} and {CHARGE Consortium Hemostasis Working Group} and {GENIUS-CHD Consortium} and Seldin, Marcus and Pan, Calvin and Mehrabian, Margarete and Lusis, Aldons J and Bazeley, Peter and Sun, Yan V and Liu, Chang and Quyyumi, Arshed A and Scholz, Markus and Thiery, Joachim and Delgado, Graciela E and Kleber, Marcus E and M{\"a}rz, Winfried and Howe, Laurence J and Asselbergs, Folkert W and van Vugt, Marion and Vlachojannis, Georgios J and Patel, Riyaz S and Lyytik{\"a}inen, Leo-Pekka and K{\"a}h{\"o}nen, Mika and Lehtim{\"a}ki, Terho and Nieminen, Tuomo V M and Kuukasj{\"a}rvi, Pekka and Laurikka, Jari O and Chang, Xuling and Heng, Chew-Kiat and Jiang, Rong and Kraus, William E and Hauser, Elizabeth R and Ferguson, Jane F and Reilly, Muredach P and Ito, Kaoru and Koyama, Satoshi and Kamatani, Yoichiro and Komuro, Issei and {Biobank Japan} and Stolze, Lindsey K and Romanoski, Casey E and Khan, Mohammad Daud and Turner, Adam W and Miller, Clint L and Aherrahrou, Redouane and Civelek, Mete and Ma, Lijiang and Bj{\"o}rkegren, Johan L M and Kumar, S Ram and Tang, W H Wilson and Hazen, Stanley L and Allayee, Hooman},
biburl = {https://puma.scadsai.uni-leipzig.de/bibtex/2fcd97222e4225ff991f398fec7cf29bf/scadsfct},
copyright = {https://academic.oup.com/journals/pages/open\_access/funder\_policies/chorus/standard\_publication\_model},
interhash = {15bde84fa05cf440d52b9c78a76cd9e7},
intrahash = {fcd97222e4225ff991f398fec7cf29bf},
journal = {Eur. Heart J.},
keywords = {Genetic Genome-wide Meta-analysis; Myocardial SLC44A3 association factors; infarction; study; topic_lifescience},
language = {en},
month = mar,
number = 9,
pages = {919--933},
publisher = {Oxford University Press (OUP)},
timestamp = {2024-09-10T12:00:15.000+0200},
title = {Genome-wide analysis identifies novel susceptibility loci for myocardial infarction},
volume = 42,
year = 2021
}
