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

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.

Figure 1.

Cross-sectional association of the GRS with TPOAbs, TH markers and clinical outcomes. A, Association of TPOAb concentrations and GRS (GRS distribution in the background). B, Association of TPOAb positivity and GRS. C, Association of TSH concentrations and GRS (GRS distribution in the background). D, Association of elevated TSH concentrations and GRS. E, Association of FT4 concentrations and GRS (GRS distribution in the background). F, Association of over hypothyroidism and GRS.