Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets

Virtual Patients and Sensitivity Analysis of the Guyton Model of Blood Pressure Regulation: Towards Individualized Models of Whole-Body Physiology

Mathematical models that integrate multi-scale physiological data can offer insight into physiological and pathophysiological function, and may eventually assist in individualized predictive medicine. We present a methodology for performing systematic analyses of multi-parameter interactions in such complex, multi-scale models. Human physiology models are often based on or inspired by Arthur Guyton's whole-body circulatory regulation model. Despite the significance of this model, it has not been the subject of a systematic and comprehensive sensitivity study. Therefore, we use this model as a case study for our methodology. Our analysis of the Guyton model reveals how the multitude of model parameters combine to affect the model dynamics, and how interesting combinations of parameters may be identified. It also includes a “virtual population” from which “virtual individuals” can be chosen, on the basis of exhibiting conditions similar to those of a real-world patient. This lays the groundwork for using the Guyton model for in silico exploration of pathophysiological states and treatment strategies. The results presented here illustrate several potential uses for the entire dataset of sensitivity results and the “virtual individuals” that we have generated, which are included in the supplementary material. More generally, the presented methodology is applicable to modern, more complex multi-scale physiological models

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Evaluation of Three Current Methods for the Determination of Creatine Kinase-MB Catalytic Activity

Peer Reviewe

Acute Myocardial Infarction Size and Myoglobin Release into Serum

Peer Reviewe