Abstract
BackgroundIn animal models, lack of thyroid hormone is associated with cone photoreceptor preservation, while administration of high doses of active thyroid hormone leads to deterioration. The association between thyroid function and age-related macular degeneration (AMD) has not been investigated in the general population.MethodsParticipants of age ≥55 years from the Rotterdam Study with thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and AMD assessment were included. We conducted age- and sex-adjusted Cox proportional hazards models to explore the association of TSH or FT4 with AMD, in the full range and in those with TSH (0.4-4.0 mIU/L) and/or FT4 in normal range (11–25 pmol/L). Cox proportional hazards models were performed for the association of TSH or FT4 with retinal pigment alterations (RPA), as an early marker of retinal changes. Multivariable models additionally included cardiovascular risk factors and thyroid peroxidase antibodies positivity. We also performed stratification by age and sex. A bidirectional look-up in genome-wide association study (GWAS) data for thyroid parameters and AMD was performed. Single nucleotide polymorphisms (SNPs) that are significantly associated with both phenotypes were identified.ResultsWe included 5,573 participants with a median follow-up of 6.9 years (interquartile range 4.4-10.8 years). During follow-up 805 people developed AMD. TSH levels were not associated with increased risk of AMD. Within normal range of FT4, participants in the highest FT4 quintile had a 1.34-fold increased risk of developing AMD, compared to individuals in the middle group (95% confidence interval [CI] 1.07-1.66). Higher FT4 values in the full range were associated with a higher risk of AMD (hazard ratio 1.04, CI, 1.01-1.06 per 1 pmol/L increase). Higher FT4 levels were similarly associated with a higher risk of RPA. Restricting analyses to euthyroid individuals, additional multivariable models, and stratification did not change estimates. We found a SNP (rs943080) in the VEGF-A gene, associated with AMD, to be significant in the TSH GWAS (P = 1.2 x 10−4). Adding this SNP to multivariable models did not change estimates.ConclusionsHigher FT4 values are associated with increased risk of AMD - even in euthyroid individuals - and increased risk of RPA. Our data suggest an important role of thyroid hormone in pathways leading to AMD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0329-0) contains supplementary material, which is available to authorized users.
Highlights
In animal models, lack of thyroid hormone is associated with cone photoreceptor preservation, while administration of high doses of active thyroid hormone leads to deterioration
We looked at the association between age-related macular degeneration (AMD) and thyroid-stimulating hormone (TSH) or free T4 levels (FT4) both continuously and in quintiles, as well as overall and within the normal range of TSH
Association between thyroid function and AMD there was no association between TSH and AMD, the risk of AMD was significantly increased in those with higher FT4 levels (Table 2)
Summary
Lack of thyroid hormone is associated with cone photoreceptor preservation, while administration of high doses of active thyroid hormone leads to deterioration. The association between thyroid function and age-related macular degeneration (AMD) has not been investigated in the general population. Thyroid dysfunction and subclinical thyroid dysfunction are common in the general population, with a prevalence up to 10% [13,14,15,16] These thyroid disorders are associated with various cardiovascular risk factors, including alterations in lipid levels, atherosclerosis, and hypertension [17,18,19], which are known predisposing factors for development and progression of AMD [20,21]. There are no studies in the general population assessing the association between thyroid function and the risk of AMD. We aimed to assess the relation between thyroid-stimulating hormone (TSH), free thyroxine (FT4), and the risk of incident AMD in a prospective populationbased cohort study and to study possible underlying genetic pathways by investigating an overlap in genome-wide significant hits (that is, bidirectional genetic look-up)
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