TY - JOUR
T1 - Association of Thyroid Function Genetic Predictors with Atrial Fibrillation
T2 - A Phenome-Wide Association Study and Inverse-Variance Weighted Average Meta-analysis
AU - Salem, Joe Elie
AU - Shoemaker, M. Benjamin
AU - Bastarache, Lisa
AU - Shaffer, Christian M.
AU - Glazer, Andrew M.
AU - Kroncke, Brett
AU - Wells, Quinn S.
AU - Shi, Mingjian
AU - Straub, Peter
AU - Jarvik, Gail P.
AU - Larson, Eric B.
AU - Velez Edwards, Digna R.
AU - Edwards, Todd L.
AU - Davis, Lea K.
AU - Hakonarson, Hakon
AU - Weng, Chunhua
AU - Fasel, David
AU - Knollmann, Bjorn C.
AU - Wang, Thomas J.
AU - Denny, Joshua C.
AU - Ellinor, Patrick T.
AU - Roden, Dan M.
AU - Mosley, Jonathan D.
N1 - Funding Information:
Funding/Support: This study was supported by FRM (grant SPE20170336816, Dr Salem) and the American Heart Association (grant 16FTF30130005, Dr Mosley). Vanderbilt University Medical Center’s BioVU projects are supported by numerous sources: institutional funding, private agencies, and federal grants. These include the National Institutes of Health–funded Shared Instrumentation Grant S10RR025141 and Clinical and Translational Science Awards grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01LM010685, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711 and the following additional funding sources, accurate as of publication date: NIH K07 CA172294, AHA 14GRNT20460090, NIH P01 DK038226; NIH R24 DK 96527, NIH U01 HG004798, NIH R01 LM010685, NIH R01 NS032830, NIH R01 EY012118, NIH K12 HD043483, NIH R01 DK078616, NIH RC2 GM092618, NHMRC APP1064524, NIH R01 CA162433, NIH P01 HL056693, NIH P50 GM115305, NIH U01 HG006378, NIH U19 HL065962, NIH U01 HG004603, PCORI (private), NIH P50 CA09813, NIH R01 HD074711, NIH R03 HD078567, NIH R01 DK080007, and NIH P50 HL081009 (an updated list can be found at https:// victr.vanderbilt.edu/pub/biovu/?sid=229). The eMERGE (Electronic Medical Records and Genetics) Network was initiated and funded by National Human Genome Research Institute through grants from Children’s Hospital of Philadelphia (grant U01HG006830); Essentia Institute of Rural Health, Marshfield Clinic Research Foundation, and Pennsylvania State University (grant U01HG006389); Geisinger Clinic (grant U01HG006382); Kaiser Permanente/University of Washington (grant U01HG006375); Mayo Clinic (grant U01HG006379); Icahn School of Medicine at Mount Sinai (grant U01HG006380); Northwestern University (grant U01HG006388); Brigham and Women’s Hospital (grants U01HG006378 and U01HG8685); Vanderbilt University Medical Center (grant U01HG8672); and Vanderbilt University Medical Center serving as the Coordinating Center (grant U01HG006385); Center for Inherited Disease Research (grant U01HG004438) and the Broad Institute (grant U01HG004424) serve as genotyping centers. Dr Ellinor is supported by National Institutes of Health awards (grants 1RO1HL092577, R01HL128914, and K24HL105780) and by the Fondation Leducq (grant 14CVD01).
Funding Information:
Additional Contributions: We wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center and Vanderbilt Vision Center. We also wish to acknowledge Sara Van Driest, MD, PhD, Vanderbilt University Medical Center, for her editorial input. Dr Van Driest was not compensated outside of her standard salary.
Funding Information:
completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Salem reported grants from Fondation Recherche Medicale (SPE20170336816) during the conduct of the study. Dr Shoemaker reported a grant from the National Institutes of Health (grant K23HL127704) Dr Larson reported grants from National Institutes of Health/National Human Genome Research Institute during the conduct of the study. Dr Davis reported grants from Vanderbilt University Medical Center during the conduct of the study. Dr Ellinor reported grants from Bayer AG to the Broad Institute focused on the genetics and therapeutics of atrial fibrillation, personal fees from Novartis, and personal fees from Quest Diagnostics outside the submitted work. Dr Denny reported grants from National Institutes of Health during the conduct of the study. No other disclosures were reported.
Publisher Copyright:
© 2019 American Medical Association. All rights reserved.
PY - 2019/2
Y1 - 2019/2
N2 - Importance: Thyroid hormone levels are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland. Hyperthyroidism is overwhelmingly due to thyroid disorders and is well recognized to contribute to a wide spectrum of cardiovascular morbidity, particularly the increasingly common arrhythmia atrial fibrillation (AF). Objective: To determine the association between genetically determined thyrotropin levels and AF. Design, Setting, and Participants: This phenome-wide association study scanned 1318 phenotypes associated with a polygenic predictor of thyrotropin levels identified by a previously published genome-wide association study that included participants of European ancestry. North American individuals of European ancestry with longitudinal electronic health records were analyzed from May 2008 to November 2016. Analysis began March 2018. Main Outcomes and Measures: Clinical diagnoses associated with a polygenic predictor of thyrotropin levels. Exposures: Genetically determined thyrotropin levels. Results: Of 37154 individuals, 19330 (52%) were men. The thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR], 1.10; 95% CI, 1.07-1.14; P = 5 × 10 -11 ) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 × 10 -8 for toxic multinodular goiter). Among nonthyroid associations, the top association was AF/flutter (OR, 0.93; 95% CI, 0.9-0.95; P = 9 × 10 -7 ). When the analyses were repeated excluding 9801 individuals with any diagnoses of a thyroid-related disease, the AF association persisted (OR, 0.91; 95% CI, 0.88-0.95; P = 2.9 × 10 -6 ). To replicate this association, we conducted an inverse-variance weighted average meta-analysis using AF single-nucleotide variant weights from a genome-wide association study of 17931 AF cases and 115142 controls. As in the discovery analyses, each SD increase in predicted thyrotropin was associated with a decreased risk of AF (OR, 0.86; 95% CI, 0.79-0.93; P = 4.7 × 10 -4 ). In a set of AF cases (n = 745) and controls (n = 1680) older than 55 years, directly measured thyrotropin levels that fell within the normal range were inversely associated with AF risk (OR, 0.91; 95% CI, 0.83-0.99; P =.04). Conclusions and Relevance: This study suggests a role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for AF. The clinical decision to treat subclinical thyroid disease should incorporate the risk for AF as antithyroid medications to treat hyperthyroidism may reduce AF risk and thyroid hormone replacement for hypothyroidism may increase AF risk.
AB - Importance: Thyroid hormone levels are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland. Hyperthyroidism is overwhelmingly due to thyroid disorders and is well recognized to contribute to a wide spectrum of cardiovascular morbidity, particularly the increasingly common arrhythmia atrial fibrillation (AF). Objective: To determine the association between genetically determined thyrotropin levels and AF. Design, Setting, and Participants: This phenome-wide association study scanned 1318 phenotypes associated with a polygenic predictor of thyrotropin levels identified by a previously published genome-wide association study that included participants of European ancestry. North American individuals of European ancestry with longitudinal electronic health records were analyzed from May 2008 to November 2016. Analysis began March 2018. Main Outcomes and Measures: Clinical diagnoses associated with a polygenic predictor of thyrotropin levels. Exposures: Genetically determined thyrotropin levels. Results: Of 37154 individuals, 19330 (52%) were men. The thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR], 1.10; 95% CI, 1.07-1.14; P = 5 × 10 -11 ) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 × 10 -8 for toxic multinodular goiter). Among nonthyroid associations, the top association was AF/flutter (OR, 0.93; 95% CI, 0.9-0.95; P = 9 × 10 -7 ). When the analyses were repeated excluding 9801 individuals with any diagnoses of a thyroid-related disease, the AF association persisted (OR, 0.91; 95% CI, 0.88-0.95; P = 2.9 × 10 -6 ). To replicate this association, we conducted an inverse-variance weighted average meta-analysis using AF single-nucleotide variant weights from a genome-wide association study of 17931 AF cases and 115142 controls. As in the discovery analyses, each SD increase in predicted thyrotropin was associated with a decreased risk of AF (OR, 0.86; 95% CI, 0.79-0.93; P = 4.7 × 10 -4 ). In a set of AF cases (n = 745) and controls (n = 1680) older than 55 years, directly measured thyrotropin levels that fell within the normal range were inversely associated with AF risk (OR, 0.91; 95% CI, 0.83-0.99; P =.04). Conclusions and Relevance: This study suggests a role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for AF. The clinical decision to treat subclinical thyroid disease should incorporate the risk for AF as antithyroid medications to treat hyperthyroidism may reduce AF risk and thyroid hormone replacement for hypothyroidism may increase AF risk.
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U2 - 10.1001/jamacardio.2018.4615
DO - 10.1001/jamacardio.2018.4615
M3 - Article
C2 - 30673079
AN - SCOPUS:85060638987
SN - 2380-6583
VL - 4
SP - 136
EP - 143
JO - JAMA Cardiology
JF - JAMA Cardiology
IS - 2
ER -