A genetic risk score for thyroid peroxidase antibodies associates with clinical thyroid disease in community-based populations.

Pubmed ID: 25719932

Pubmed Central ID: PMC4422885

Journal: The Journal of clinical endocrinology and metabolism

Publication Date: May 1, 2015

MeSH Terms: Humans, Male, Female, Risk Factors, Genetic Predisposition to Disease, Middle Aged, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Prospective Studies, Iodide Peroxidase, Thyroid Diseases, Thyrotropin, Thyroxine

Grants: HHSN268201100005C, HHSN268201100007C, HHSN268201100008C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, U01 HG004402, R01 DK089174, R01DK089174, R01 HL059367, UL1RR025005, R01HL59367, UL1 RR025005, R01 HL086694, HHSN268200625226C, HSN268201100006C, U01HG004402, R01HL087641, R01 HL087641, HSN268201100009C, R01HL086694, HHSN268201100005G, HHSN268201100008I, HHSN268201100011I, HHSN268201100005I, HHSN268201100007I

Authors: Völzke H, Hofman A, Li Y, Selvin E, Schultheiss UT, Teumer A, Medici M, Daya N, Chaker L, Homuth G, Uitterlinden AG, Nauck M, Peeters RP, Köttgen A

Cite As: Schultheiss UT, Teumer A, Medici M, Li Y, Daya N, Chaker L, Homuth G, Uitterlinden AG, Nauck M, Hofman A, Selvin E, Völzke H, Peeters RP, Köttgen A. A genetic risk score for thyroid peroxidase antibodies associates with clinical thyroid disease in community-based populations. J Clin Endocrinol Metab 2015 May;100(5):E799-807. Epub 2015 Feb 26.

Studies:

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.