Identification of pathways associated with thyroid hormones and their molecular regulators by integrated OMICs analyses of cross-sectional and longitudinal studies in the general population and selected patients

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Thyroid hormones (THs) play a key role in cellular growth, development and metabolism. Changes in thyroid function caused by thyroid disorders affect many tissues and metabolism in general. Circulating thyroid hormones are tightly regulated by thyrotropin, which is the most important marker for thyroid function. Recently, thyronamines (TAMs) emerged as a new class of regulators probably antagonizing the effects of TH. They constitute metabolites of the THs and their molecular structure differs from the thyroid pro-hormones. All studies revealed physiological effects opposite to those of classical THs, including a rapid and profound hypothermia and bradycardia upon administration of TAMs. However, up to now, the precise mechanisms of action and regulation of THs and TAMs are poorly understood.Already published data indicate a strong genetic influence on TH levels; a large portion of heritability is supposed to be under polygenic control, but the genes responsible and affected pathways are mostly unknown. Within the framework of the Priority Programme “THYROID TRANS ACT” (SPP 1629) we now propose an integrated multi-OMICs analysis of a combination of a cross sectional and longitudinal population based study (Study of Health in Pomerania – SHIP and SHIP-TREND) and selected patient cohorts to reveal new facets of the action of THs and TAMs.As preliminary work we provide to the consortium genome-wide individual genotyping data (N= 4105 probands of SHIP and 998 probands of SHIP-TREND), genome-wide whole blood expression data (N=998 probands SHIP-TREND) and metabolome data (N=1000 SHIP-TREND, N=7400 SHIP-0/1 samples). Using these data and miRNA, metabolome and proteome data sets generated within the project we will address in SHIP and SHIP-TREND how these complex data correlate to variations in TH (T3, T4)- and TAM (T1AM,)-levels. These new findings from the epidemiological analyses will be followed-up by studies of patients with overt hyper- or hypothyroidism (N=400) ex vivo. Here, we will investigate the regulatory impact of THs and TAMs on the gene expression pattern, metabolom activity and selected protein candidates to validate our findings of the population based study in a cohort of patients with overt hyper- and hypothyroidism and to explore the impact of normalisation of thyroid function by therapy. A specific focus will be the distinction of TH and TAM related alterations. The generated data will also be a resource for other groups of the priority program to validate hypotheses generated in the specific projects.