Extracting Evidence for Causation from the Correlation Between Excess Fat Tissue and Risk of Cardiovascular Disease

Given a good enough data set, there are ways to produce evidence for causation in the observed relationships between patient characteristics and risk of age-related disease. While it is well accepted by now that being overweight does in fact cause a raised risk of all the common age-related diseases, a shorter life expectancy, and a raised lifetime medical expenditure, more data never hurts. Researchers have a good understanding of the mechanisms involved in these relationships. In particular, visceral fat tissue around the abdominal organs generates chronic inflammation, which acts to accelerate tissue decline and age-related dysfunction. This inflammation is perhaps largely produced through the creation of increased numbers of senescent cells, but there are numerous described mechanism with the same outcome.

Mendelian randomisation is a way of showing whether or not individual risk factors actually cause disease, rather than just being associated with it. It uses genetic variants that are already known to be associated with potential risk factors, such as body mass index (BMI) and body fat, as indirect indicators or "proxies" for these risk factors. This enables researchers to discover whether the risk factor is the cause of the disease (rather than the other way around), and reduces bias in results because genetic variants are determined at conception and cannot be affected by subsequent external or environmental factors, or by the development of disease.

Researchers studied 96 genetic variants associated with BMI and body fat mass to estimate their effect on 14 cardiovascular diseases in 367,703 participants of white-British descent in UK Biobank - a UK-based national and international resource containing data on 500,000 people, aged 40-69 years. Using Mendelian randomisation they found that higher BMI and fat mass are associated with an increased risk of aortic valve stenosis and most other cardiovascular diseases, suggesting that excess body fat is a cause of cardiovascular disease.

People who had genetic variants that predict higher BMI were at increased risk of aortic valve stenosis, heart failure, deep vein thrombosis, high blood pressure, peripheral artery disease, coronary artery disease, atrial fibrillation, and pulmonary embolism. For every genetically-predicted 1kg/m2 increase in BMI, the increased risk ranged from 6% for pulmonary embolism to 13% for aortic valve stenosis. (Above a BMI that is considered "healthy" (20-25 kg/m2) every 1 kg/m2 increase in BMI for someone who is 1.7 metres tall (5'7") corresponds to a weight gain of nearly 3 kg)

Link: https://www.eurekalert.org/pub_releases/2019-06/esoc-ewa061219.php

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