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Exploring the genetic determinants of serum phosphate through large-scale GWAS Biobank approach: towards the elucidation of the genetic architecture of human serum phosphate

Exploring the genetic determinants of serum phosphate through large-scale GWAS Biobank approach: towards the elucidation of the genetic architecture of human serum phosphate

Principal Investigator: Mrs Natalia Campos-Obando
Approved Research ID: 48264
Approval date: March 4th 2020

Lay summary

We plan to perform a large-scale study to find the genetic determinants of serum phosphate levels. We consider this an important research project because P has been related to increased adverse consequences in public health.

Research aims: we plan to perform a large-scale study to find the genetic determinants of P and increase the current explained variance. We aim to study the epidemiology of P within UKBB, to assess statistical evidence of gender-interaction between P genetic determinants, and to test if there is evidence of causality -through Mendelian Randomization- between P and two important clinical outcomes specifically described within Rotterdam Study, namely COPD and fracture risk.

Scientific rationale: phosphorus is one of the most common elements, being involved in several homeostatic and structural processes. Phosphorus exists in tissues as phosphate. Despite these key roles, clinical settings characterized by a marked increase in P levels - or in P accumulation -without frank hyperphosphatemia- such as chronic kidney disease (CKD), are related to high morbidity and mortality. A linear relation between P and adverse events has been reported. Additionally, an increasing epidemiological evidence has shown that even normal P levels are related with several adverse outcomes in the general population, such as in mortality risk (all-cause, CVD and COPD) and in morbidity (fracture risk, atherosclerosis and CKD progression). Simultaneously, a clear gender difference has become consistently evident, with stronger associations in men than women. From a cardiovascular perspective, high P is able to induce vascular calcification through trans-differentiation of vascular smooth muscle cells; from a pulmonary perspective, high P is related to severe emphysema that is rescued when P normalizes. High P induces a phenotype of premature ageing, leading to the concept of phosphotoxicity. Yet, the adverse effects with increasing -but normal- P are worrisome and raise the question if there is a threshold above which P is toxic.

Project duration: approximately 24 months.

Public health impact: the discovery of P genetic determinants within a large dataset enriched with low frequency and rare variants allows the elucidation of P genetic architecture and potential gender differences, as suggested by epidemiologic studies.  If P homeostasis truly differs by gender, it has an important impact in public health measurements undertaken to decrease the risk associated with increasing P in the general population. The discovery of P determinants increases the power of future Mendelian Randomization studies testing for causality.