TY - JOUR
T1 - A Genetic Risk Score for Thyroid Peroxidase Antibodies Associates With Clinical Thyroid Disease in Community-Based Populations
AU - Schultheiss, UT
AU - Teumer, A
AU - Medici, Marco
AU - Li, Y
AU - Daya, N
AU - Chaker, Layal
AU - Homuth, G
AU - Uitterlinden, André
AU - Nauck, M
AU - Hofman, Bert
AU - Selvin, E
AU - Volzke, H
AU - Peeters, Robin
AU - Kottgen, A
PY - 2015
Y1 - 2015
N2 - 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 T-4), 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 T-4 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.
AB - 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 T-4), 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 T-4 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.
U2 - 10.1210/jc.2014-4352
DO - 10.1210/jc.2014-4352
M3 - Article
C2 - 25719932
SN - 0021-972X
VL - 100
SP - E799-E807
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 5
ER -