Investigation of potential causal associations and mechanisms between vitamin D, hypertension and atrial fibrillation

Executive summary

The prevalence of hypertension and atrial fibrillation (AF, an abnormal heart rhythm) in Norway is among the highest in the world. Prevention of hypertension and AF are important to reduce serious consequences such as severe cardiovascular diseases and death. To achieve a successful prevention, identification of causal risk factors and mechanisms is essential. Meanwhile, vitamin D insufficiency is widespread globally. Insufficient vitamin D status was present in about 60% of the Norwegian HUNT population. It is unknown if low vitamin D leads to increased risk of hypertension and AF at population level and what are the linking pathways.

We will apply updated Mendelian randomization (MR) methods (both univariable and multivariable MR) to assess the causal relationships between vitamin D, hypertension and AF. An MR study uses genetic variants as instruments to reflect a long-term exposure to low vitamin D, high blood pressure and high risk for AF. The MR approach mimics a randomized controlled trial and can largely avoid methodological problems (confounding and reverse causation) that are common in observational studies. Evidence from the MR studies can be used to predict the outcome of the future intervention studies. We will use individual-level data from the large and homogenous Norwegian HUNT and UK Biobank populations and the summary-level data from publicly available genome-wide association studies.

This is a collaborative project between NTNU and St. Olavs Hospital. We have a multidisciplinary research group consisting of national and international experts on genetic epidemiology and cardiology. If the causal associations are established, targeting insufficient vitamin D can be an effective way to reduce the risk of both hypertension and AF.

Primary and secondary objectives

Primary objective: We aim to clarify causal associations and the underlying pathway between vitamin D, hypertension and AF risk. We hypothesize that low vitamin D leads to a higher risk of hypertension which further leads to a higher risk of AF (low vitamin D → hypertension → AF).

Specific objectives:

1)         To study if vitamin D status is causally associated with the risk of hypertension;

2)         To investigate if there is a bidirectionally causal association between hypertension and AF;

3)         To explore if vitamin D status is a risk and causal factor for the development of AF: a prospective cohort study and Mendelian randomization analysis.

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