4.6 Article

Association of Thyroid Function Genetic Predictors With Atrial Fibrillation A Phenome-Wide Association Study and Inverse-Variance Weighted Average Meta-analysis

期刊

JAMA CARDIOLOGY
卷 4, 期 2, 页码 136-143

出版社

AMER MEDICAL ASSOC
DOI: 10.1001/jamacardio.2018.4615

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资金

  1. FRM [SPE20170336816]
  2. American Heart Association [16FTF30130005]
  3. National Institutes of Health [S10RR025141, UL1TR002243, UL1TR000445, UL1RR024975, 1R01HL092577, R01HL128914, K24HL105780, P50 GM115305, U01 HG006378, U19 HL065962, U01 HG004603, P50 CA09813, R01 HD074711, R03 HD078567, R01 DK080007, P50 HL081009]
  4. NIH [K07 CA172294, P01 DK038226, R24 DK 96527, U01 HG004798, R01 LM010685, R01 NS032830, R01 EY012118, K12 HD043483, R01 DK078616, RC2 GM092618, R01 CA162433, P01 HL056693]
  5. AHA [14GRNT20460090]
  6. NHMRC [APP1064524]
  7. PCORI
  8. National Human Genome Research Institute from Children's Hospital of Philadelphia [U01HG006830]
  9. Essentia Institute of Rural Health
  10. Marshfield Clinic Research Foundation
  11. Pennsylvania State University [U01HG006389]
  12. Geisinger Clinic [U01HG006382]
  13. Kaiser Permanente/University of Washington [U01HG006375]
  14. Mayo Clinic [U01HG006379]
  15. Icahn School of Medicine at Mount Sinai [U01HG006380]
  16. Northwestern University [U01HG006388]
  17. Brigham and Women's Hospital [U01HG006378, U01HG8685]
  18. Vanderbilt University Medical Center [U01HG8672]
  19. Vanderbilt University Medical Center serving as the Coordinating Center [U01HG006385]
  20. Center for Inherited Disease Research [U01HG004438]
  21. Broad Institute [U01HG004424]
  22. Fondation Leducq [14CVD01]
  23. [U01HG004798]
  24. [R01LM010685]
  25. [R01NS032830]
  26. [RC2GM092618]
  27. [P50GM115305]
  28. [U19HL065962]
  29. [R01HD074711]

向作者/读者索取更多资源

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 37 154 individuals, 19 330 (52%) were men. The thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR] 1.10; 95% CI, 1.07-114; P = 5 x 10(-11)) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 x 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 x 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 x 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 17 931AF 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 x 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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