Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations with Atrial Fibrillation

Yunju Yang; Traci M. Bartz; Michael R. Brown; Xiuqing Guo; Nuno R. Zilhão; Stella Trompet; Stefan Weiss; Jie Yao; Jennifer A. Brody; Christopher R. Defilippi; Ron C. Hoogeveen; Henry J. Lin; Vilmundur G. Guðnason; Christie M. Ballantyne; Marcus Dörr; J. Wouter Jukema; Astrid Petersmann; Bruce M. Psaty; Jerome I. Rotter; Eric Boerwinkle; Myriam Fornage; Goo Jun; Bing Yu

doi:10.1161/CIRCGEN.121.003460

Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations with Atrial Fibrillation

Yunju Yang
, Traci M. Bartz
, Michael R. Brown
, Xiuqing Guo
, Nuno R. Zilhão
, Stella Trompet
, Stefan Weiss
, Jie Yao
, Jennifer A. Brody
, Christopher R. Defilippi
, Ron C. Hoogeveen
, Henry J. Lin
, Vilmundur G. Guðnason
, Christie M. Ballantyne
, Marcus Dörr
, J. Wouter Jukema
, Astrid Petersmann
, Bruce M. Psaty
, Jerome I. Rotter
, Eric Boerwinkle

Myriam Fornage, Goo Jun, Bing Yu

Faculty of Medicine

University of Iceland

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive. METHODS: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI. RESULTS: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in PPFIA4 and 3 previously reported loci at NCOA2, TRAM1, and BCL2. One known locus at VCL was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6% increase in hs-cTnT levels (minor allele frequency, 0.18; P=2.80×10⁻⁹). We observed pleiotropic loci located at BAG3 and ANO5. The proportions of variances explained by single-nucleotide polymorphisms were 10.15% and 7.74% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with BCL2 expression in heart tissues and hs-cTnT and with ANO5 expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95% CI, 1.25-1.54] for hs-cTnT and 1.21 [95% CI, 1.06-1.37] for hs-cTnI). CONCLUSIONS: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.

Original language	English
Pages (from-to)	709-718
Number of pages	10
Journal	Circulation: Genomic and Precision Medicine
Volume	14
Issue number	6
DOIs	https://doi.org/10.1161/CIRCGEN.121.003460
Publication status	Published - 1 Dec 2021

Bibliographical note

Funding text 1 The AGES-Reykjavik study (Age, Gene/Environment Susceptibility) is funded by the National Institutes of Health contract N01-AG12100, the US National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The ARIC study (Atherosclerosis Risk in Communities) has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005—a component of the NIH and NIH Roadmap for Medical Research. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and 75N92021D00006; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from NIA. The provision of genotyping data was supported, in part, by the National Center for Advancing Translational Sciences, UCLA Clinical and Translational Science Institute grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The measurement of troponin T was funded by an investigator-initiated grant to the University of Maryland from Roche Diagnostics. MESA (Multi-Ethnic Study of Atherosclerosis) and the MESA contribution to the SNP Health Association Resource (SHARe) projects are conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org . The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Dr Jukema is an established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the Seventh Framework Program of the European Commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). SHIP (Study of Health in Pomerania) and SHIP TREND are part of the Community Medicine Research net (CMR) at the University of Greifswald, Germany. The CMR encompasses several research projects that share data from the population-based SHIP project ( http://ship.community-medicine.de ). Funding was provided by grants from the German Federal Ministry of Education and Research, the Ministry for Education, Research and Cultural Affairs (grants no. 01ZZ9603, 01ZZ0103, 01ZZ0403, and 03ZIK012), and the Ministry for Social Affairs of the Federal State of Mecklenburg–West Pomerania (grant 03IS2061A). Dr Yu was, in part, supported by NIH HL105756, HL141824, and HL148218. Dr Jun was, in part, supported by NIH DK118631 and HD098552. View less Funding text 2 The AGES-Reykjavik study (Age, Gene/Environment Susceptibility) is funded by the National Institutes of Health contract N01-AG12100, the US National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The ARIC study (Atherosclerosis Risk in Communities) has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005-a component of the NIH and NIH Roadmap for Medical Research. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, HHSN268201800001C, N01HC55222, N01HC 85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC 85086, and 75N92021D00006; and NHLBI grants U01HL080295, R01HL08 5251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from NIA. The provision of genotyping data was supported, in part, by the National Center for Advancing Translational Sciences, UCLA Clinical and Translational Science Institute grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The measurement of troponin T was funded by an investigator-initiated grant to the University of Maryland from Roche Diagnostics. MESA (Multi-Ethnic Study of Atherosclerosis) and the MESA contribution to the SNP Health Association Resource (SHARe) projects are conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Dr Jukema is an established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the Seventh Framework Program of the European Commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). SHIP (Study of Health in Pomerania) and SHIP TREND are part of the Community Medicine Research net (CMR) at the University of Greifswald, Germany. The CMR encompasses several research projects that share data from the population-based SHIP project (http://ship.community-medicine.de). Funding was provided by grants from the German Federal Ministry of Education and Research, the Ministry for Education, Research and Cultural Affairs (grants no. 01ZZ9603, 01ZZ0103, 01ZZ0403, and 03ZIK012), and the Ministry for Social Affairs of the Federal State of Mecklenburg-West Pomerania (grant 03IS2061A). Dr Yu was, in part, supported by NIH HL105756, HL141824, and HL148218. Dr Jun was, in part, supported by NIH DK118631 and HD098552. Publisher Copyright: © 2021 American Heart Association, Inc.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Other keywords

Cardiovascular diseases
Genome-wide association study
Heart failure
Mendelian randomization analysis
Troponin I
Troponin T

Access to Document

10.1161/CIRCGEN.121.003460

Cite this

Yang, Y., Bartz, T. M., Brown, M. R., Guo, X., Zilhão, N. R., Trompet, S., Weiss, S., Yao, J., Brody, J. A., Defilippi, C. R., Hoogeveen, R. C., Lin, H. J., Guðnason, V. G., Ballantyne, C. M., Dörr, M., Jukema, J. W., Petersmann, A., Psaty, B. M., Rotter, J. I., ... Yu, B. (2021). Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations with Atrial Fibrillation. Circulation: Genomic and Precision Medicine, 14(6), 709-718. https://doi.org/10.1161/CIRCGEN.121.003460

@article{b3b49cef5a5049ce99ac677db07e1aa8,

title = "Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations with Atrial Fibrillation",

abstract = "BACKGROUND: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive. METHODS: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI. RESULTS: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in PPFIA4 and 3 previously reported loci at NCOA2, TRAM1, and BCL2. One known locus at VCL was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6\% increase in hs-cTnT levels (minor allele frequency, 0.18; P=2.80×10−9). We observed pleiotropic loci located at BAG3 and ANO5. The proportions of variances explained by single-nucleotide polymorphisms were 10.15\% and 7.74\% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with BCL2 expression in heart tissues and hs-cTnT and with ANO5 expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95\% CI, 1.25-1.54] for hs-cTnT and 1.21 [95\% CI, 1.06-1.37] for hs-cTnI). CONCLUSIONS: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.",

keywords = "Cardiovascular diseases, Genome-wide association study, Heart failure, Mendelian randomization analysis, Troponin I, Troponin T",

author = "Yunju Yang and Bartz, \{Traci M.\} and Brown, \{Michael R.\} and Xiuqing Guo and Zilh{\~a}o, \{Nuno R.\} and Stella Trompet and Stefan Weiss and Jie Yao and Brody, \{Jennifer A.\} and Defilippi, \{Christopher R.\} and Hoogeveen, \{Ron C.\} and Lin, \{Henry J.\} and Gu{\dh}nason, \{Vilmundur G.\} and Ballantyne, \{Christie M.\} and Marcus D{\"o}rr and Jukema, \{J. Wouter\} and Astrid Petersmann and Psaty, \{Bruce M.\} and Rotter, \{Jerome I.\} and Eric Boerwinkle and Myriam Fornage and Goo Jun and Bing Yu",

note = "Funding text 1 The AGES-Reykjavik study (Age, Gene/Environment Susceptibility) is funded by the National Institutes of Health contract N01-AG12100, the US National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The ARIC study (Atherosclerosis Risk in Communities) has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005—a component of the NIH and NIH Roadmap for Medical Research. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and 75N92021D00006; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from NIA. The provision of genotyping data was supported, in part, by the National Center for Advancing Translational Sciences, UCLA Clinical and Translational Science Institute grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The measurement of troponin T was funded by an investigator-initiated grant to the University of Maryland from Roche Diagnostics. MESA (Multi-Ethnic Study of Atherosclerosis) and the MESA contribution to the SNP Health Association Resource (SHARe) projects are conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org . The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Dr Jukema is an established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the Seventh Framework Program of the European Commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). SHIP (Study of Health in Pomerania) and SHIP TREND are part of the Community Medicine Research net (CMR) at the University of Greifswald, Germany. The CMR encompasses several research projects that share data from the population-based SHIP project ( http://ship.community-medicine.de ). Funding was provided by grants from the German Federal Ministry of Education and Research, the Ministry for Education, Research and Cultural Affairs (grants no. 01ZZ9603, 01ZZ0103, 01ZZ0403, and 03ZIK012), and the Ministry for Social Affairs of the Federal State of Mecklenburg–West Pomerania (grant 03IS2061A). Dr Yu was, in part, supported by NIH HL105756, HL141824, and HL148218. Dr Jun was, in part, supported by NIH DK118631 and HD098552. View less Funding text 2 The AGES-Reykjavik study (Age, Gene/Environment Susceptibility) is funded by the National Institutes of Health contract N01-AG12100, the US National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The ARIC study (Atherosclerosis Risk in Communities) has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005-a component of the NIH and NIH Roadmap for Medical Research. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, HHSN268201800001C, N01HC55222, N01HC 85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC 85086, and 75N92021D00006; and NHLBI grants U01HL080295, R01HL08 5251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from NIA. The provision of genotyping data was supported, in part, by the National Center for Advancing Translational Sciences, UCLA Clinical and Translational Science Institute grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The measurement of troponin T was funded by an investigator-initiated grant to the University of Maryland from Roche Diagnostics. MESA (Multi-Ethnic Study of Atherosclerosis) and the MESA contribution to the SNP Health Association Resource (SHARe) projects are conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Dr Jukema is an established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the Seventh Framework Program of the European Commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). SHIP (Study of Health in Pomerania) and SHIP TREND are part of the Community Medicine Research net (CMR) at the University of Greifswald, Germany. The CMR encompasses several research projects that share data from the population-based SHIP project (http://ship.community-medicine.de). Funding was provided by grants from the German Federal Ministry of Education and Research, the Ministry for Education, Research and Cultural Affairs (grants no. 01ZZ9603, 01ZZ0103, 01ZZ0403, and 03ZIK012), and the Ministry for Social Affairs of the Federal State of Mecklenburg-West Pomerania (grant 03IS2061A). Dr Yu was, in part, supported by NIH HL105756, HL141824, and HL148218. Dr Jun was, in part, supported by NIH DK118631 and HD098552. Publisher Copyright: {\textcopyright} 2021 American Heart Association, Inc.",

year = "2021",

month = dec,

day = "1",

doi = "10.1161/CIRCGEN.121.003460",

language = "English",

volume = "14",

pages = "709--718",

journal = "Circulation: Genomic and Precision Medicine",

issn = "1942-325X",

publisher = "Lippincott Williams and Wilkins",

number = "6",

}

Yang, Y, Bartz, TM, Brown, MR, Guo, X, Zilhão, NR, Trompet, S, Weiss, S, Yao, J, Brody, JA, Defilippi, CR, Hoogeveen, RC, Lin, HJ, Guðnason, VG, Ballantyne, CM, Dörr, M, Jukema, JW, Petersmann, A, Psaty, BM, Rotter, JI, Boerwinkle, E, Fornage, M, Jun, G & Yu, B 2021, 'Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations with Atrial Fibrillation', Circulation: Genomic and Precision Medicine, vol. 14, no. 6, pp. 709-718. https://doi.org/10.1161/CIRCGEN.121.003460

TY - JOUR

T1 - Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations with Atrial Fibrillation

AU - Yang, Yunju

AU - Bartz, Traci M.

AU - Brown, Michael R.

AU - Guo, Xiuqing

AU - Zilhão, Nuno R.

AU - Trompet, Stella

AU - Weiss, Stefan

AU - Yao, Jie

AU - Brody, Jennifer A.

AU - Defilippi, Christopher R.

AU - Hoogeveen, Ron C.

AU - Lin, Henry J.

AU - Guðnason, Vilmundur G.

AU - Ballantyne, Christie M.

AU - Dörr, Marcus

AU - Jukema, J. Wouter

AU - Petersmann, Astrid

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Boerwinkle, Eric

AU - Fornage, Myriam

AU - Jun, Goo

AU - Yu, Bing

N1 - Funding text 1 The AGES-Reykjavik study (Age, Gene/Environment Susceptibility) is funded by the National Institutes of Health contract N01-AG12100, the US National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The ARIC study (Atherosclerosis Risk in Communities) has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005—a component of the NIH and NIH Roadmap for Medical Research. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and 75N92021D00006; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from NIA. The provision of genotyping data was supported, in part, by the National Center for Advancing Translational Sciences, UCLA Clinical and Translational Science Institute grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The measurement of troponin T was funded by an investigator-initiated grant to the University of Maryland from Roche Diagnostics. MESA (Multi-Ethnic Study of Atherosclerosis) and the MESA contribution to the SNP Health Association Resource (SHARe) projects are conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org . The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Dr Jukema is an established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the Seventh Framework Program of the European Commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). SHIP (Study of Health in Pomerania) and SHIP TREND are part of the Community Medicine Research net (CMR) at the University of Greifswald, Germany. The CMR encompasses several research projects that share data from the population-based SHIP project ( http://ship.community-medicine.de ). Funding was provided by grants from the German Federal Ministry of Education and Research, the Ministry for Education, Research and Cultural Affairs (grants no. 01ZZ9603, 01ZZ0103, 01ZZ0403, and 03ZIK012), and the Ministry for Social Affairs of the Federal State of Mecklenburg–West Pomerania (grant 03IS2061A). Dr Yu was, in part, supported by NIH HL105756, HL141824, and HL148218. Dr Jun was, in part, supported by NIH DK118631 and HD098552. View less Funding text 2 The AGES-Reykjavik study (Age, Gene/Environment Susceptibility) is funded by the National Institutes of Health contract N01-AG12100, the US National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The ARIC study (Atherosclerosis Risk in Communities) has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005-a component of the NIH and NIH Roadmap for Medical Research. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, HHSN268201800001C, N01HC55222, N01HC 85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC 85086, and 75N92021D00006; and NHLBI grants U01HL080295, R01HL08 5251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from NIA. The provision of genotyping data was supported, in part, by the National Center for Advancing Translational Sciences, UCLA Clinical and Translational Science Institute grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The measurement of troponin T was funded by an investigator-initiated grant to the University of Maryland from Roche Diagnostics. MESA (Multi-Ethnic Study of Atherosclerosis) and the MESA contribution to the SNP Health Association Resource (SHARe) projects are conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Dr Jukema is an established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the Seventh Framework Program of the European Commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). SHIP (Study of Health in Pomerania) and SHIP TREND are part of the Community Medicine Research net (CMR) at the University of Greifswald, Germany. The CMR encompasses several research projects that share data from the population-based SHIP project (http://ship.community-medicine.de). Funding was provided by grants from the German Federal Ministry of Education and Research, the Ministry for Education, Research and Cultural Affairs (grants no. 01ZZ9603, 01ZZ0103, 01ZZ0403, and 03ZIK012), and the Ministry for Social Affairs of the Federal State of Mecklenburg-West Pomerania (grant 03IS2061A). Dr Yu was, in part, supported by NIH HL105756, HL141824, and HL148218. Dr Jun was, in part, supported by NIH DK118631 and HD098552. Publisher Copyright: © 2021 American Heart Association, Inc.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - BACKGROUND: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive. METHODS: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI. RESULTS: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in PPFIA4 and 3 previously reported loci at NCOA2, TRAM1, and BCL2. One known locus at VCL was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6% increase in hs-cTnT levels (minor allele frequency, 0.18; P=2.80×10−9). We observed pleiotropic loci located at BAG3 and ANO5. The proportions of variances explained by single-nucleotide polymorphisms were 10.15% and 7.74% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with BCL2 expression in heart tissues and hs-cTnT and with ANO5 expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95% CI, 1.25-1.54] for hs-cTnT and 1.21 [95% CI, 1.06-1.37] for hs-cTnI). CONCLUSIONS: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.

AB - BACKGROUND: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive. METHODS: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI. RESULTS: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in PPFIA4 and 3 previously reported loci at NCOA2, TRAM1, and BCL2. One known locus at VCL was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6% increase in hs-cTnT levels (minor allele frequency, 0.18; P=2.80×10−9). We observed pleiotropic loci located at BAG3 and ANO5. The proportions of variances explained by single-nucleotide polymorphisms were 10.15% and 7.74% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with BCL2 expression in heart tissues and hs-cTnT and with ANO5 expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95% CI, 1.25-1.54] for hs-cTnT and 1.21 [95% CI, 1.06-1.37] for hs-cTnI). CONCLUSIONS: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.

KW - Cardiovascular diseases

KW - Genome-wide association study

KW - Heart failure

KW - Mendelian randomization analysis

KW - Troponin I

KW - Troponin T

UR - https://www.scopus.com/pages/publications/85122355046

U2 - 10.1161/CIRCGEN.121.003460

DO - 10.1161/CIRCGEN.121.003460

M3 - Article

C2 - 34732054

SN - 1942-325X

VL - 14

SP - 709

EP - 718

JO - Circulation: Genomic and Precision Medicine

JF - Circulation: Genomic and Precision Medicine

IS - 6

ER -

Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations with Atrial Fibrillation

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