Ulla T Schultheiss1, Alexander Teumer, Marco Medici, Yong Li, Natalie Daya, Layal Chaker, Georg Homuth, Andre G Uitterlinden, Matthias Nauck, Albert Hofman, Elizabeth Selvin, Henry Völzke, Robin P Peeters, Anna Köttgen. 1. Renal Division (U.T.S., Y.L., A.K.), Department of Medicine IV, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Department of Internal Medicine and Rotterdam Thyroid Center (M.M., L.C., A.G.U., R.P.P.) and Department of Epidemiology (L.C., A.H.), Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands; Institute for Community Medicine (A.T., H.V.), Interfaculty Institute for Genetics and Functional Genomics (G.H.), and Institute of Clinical Chemistry and Laboratory Medicine (M.N.), University Medicine Greifswald, 17475 Greifswald, Germany; and Department of Epidemiology (N.D., E.S., A.K.), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
Abstract
CONTEXT: Antibodies against thyroid peroxidase (TPOAbs) are detected in 90% of all patients with Hashimoto thyroiditis, the most common cause of hypothyroidism. Hypothyroidism is associated with a range of adverse outcomes. The current knowledge of its genetic underpinnings is limited. OBJECTIVE: The purpose of this study was to identify novel genetic variants associated with TPOAb concentrations and positivity using genome-wide association data and to characterize their association with thyroid function and disease. DESIGN, SETTING, AND PARTICIPANTS: We studied European ancestry participants of 3 independent prospective population-based studies: Atherosclerosis Risk In Communities study (n = 7524), Study of Health in Pomerania (n = 3803), and Study of Health in Pomerania-TREND (n = 887). EXPOSURE: Single nucleotide polymorphisms (SNPs), individually and combined into a genetic risk score (GRS), were examined. MAIN OUTCOMES: The main outcomes were TPOAb concentrations and positivity, thyroid hormone concentrations (TSH, free T4), and clinical thyroid diseases (subclinical and overt hypothyroidism and goiter). RESULTS: Significantly associated single nucleotide polymorphisms (P < 5 · 10(-8)) mapped into 4 genomic regions not previously implicated for TPOAbs (RERE, extended HLA region) and into 5 previously described loci. A higher Genetic Risk Score (GRS) based on these 9 SNPs showed strong and graded associations with higher TPOAb, TSH, and lower free T4 concentrations (P < .001). Compared with individuals in the lowest GRS quartile, those in the highest quartile had 1.80-fold higher odds of subclinical hypothyroidism (95% confidence interval, 1.27-2.55) and 1.89-fold higher odds of overt hypothyroidism (95% confidence interval, 1.24-2.87). CONCLUSION: The identification of 4 novel genetic loci associated with TPOAb concentrations and positivity gives further insight into the genetic underpinnings of hypothyroidism. A GRS showed strong and graded associations with markers of thyroid function and disease in independent population-based studies.
CONTEXT: Antibodies against thyroid peroxidase (TPOAbs) are detected in 90% of all patients with Hashimoto thyroiditis, the most common cause of hypothyroidism. Hypothyroidism is associated with a range of adverse outcomes. The current knowledge of its genetic underpinnings is limited. OBJECTIVE: The purpose of this study was to identify novel genetic variants associated with TPOAb concentrations and positivity using genome-wide association data and to characterize their association with thyroid function and disease. DESIGN, SETTING, AND PARTICIPANTS: We studied European ancestry participants of 3 independent prospective population-based studies: Atherosclerosis Risk In Communities study (n = 7524), Study of Health in Pomerania (n = 3803), and Study of Health in Pomerania-TREND (n = 887). EXPOSURE: Single nucleotide polymorphisms (SNPs), individually and combined into a genetic risk score (GRS), were examined. MAIN OUTCOMES: The main outcomes were TPOAb concentrations and positivity, thyroid hormone concentrations (TSH, free T4), and clinical thyroid diseases (subclinical and overt hypothyroidism and goiter). RESULTS: Significantly associated single nucleotide polymorphisms (P < 5 · 10(-8)) mapped into 4 genomic regions not previously implicated for TPOAbs (RERE, extended HLA region) and into 5 previously described loci. A higher Genetic Risk Score (GRS) based on these 9 SNPs showed strong and graded associations with higher TPOAb, TSH, and lower free T4 concentrations (P < .001). Compared with individuals in the lowest GRS quartile, those in the highest quartile had 1.80-fold higher odds of subclinical hypothyroidism (95% confidence interval, 1.27-2.55) and 1.89-fold higher odds of overt hypothyroidism (95% confidence interval, 1.24-2.87). CONCLUSION: The identification of 4 novel genetic loci associated with TPOAb concentrations and positivity gives further insight into the genetic underpinnings of hypothyroidism. A GRS showed strong and graded associations with markers of thyroid function and disease in independent population-based studies.
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