<Graphical Abstract. Association between adiposity and cardiovascular outcomes: an umbrella review and meta-analysis of observational and Mendelian randomization studies. Eur Heart J. 2021>

A research team led by Professor Hong-Hee Won (first author: Minseo Kim, and corresponding author: Hong-Hee Won) of the Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, and Samsung Genome Institute (SGI), Samsung Medical Center, conducted a comprehensive analysis on adiposity and cardiovascular disease events and mortality, and published results in one of the most prestigious cardiology journals, European Heart Journal (Impact Factor 29.98)'.

This study performed a meta-analysis of more than 500 cohorts to comprehensively analyze the effects of adiposity on the risk of nine cardiovascular diseases and mortality. The study design presented in this study enables a higher-resolution analysis for complex epidemiological topics by examining associations using a cohort study and causality through a genomic study.

The relationship between adiposity and cardiovascular disease has been continuously studied for a long time, and it is known that adiposity increases the risk of cardiovascular disease. However, each study showed very heterogeneous results according to obesity metrics, ancestry, and cohort characteristics. In addition, obesity has a unique feature that it has a bidirectional interaction with the disease. That is, although the risk of cardiovascular disease is increased by obesity, conversely, the possibility that obesity is increased due to the occurrence of cardiovascular disease cannot be excluded. In the case of such a complex epidemiologic relationship, there is a limitation in that it is difficult to confirm the exact causality or direction of interaction only through observational studies.

In interventional studies such as drug research, causality can be confirmed through a study design called a randomized controlled trial. In the case of obesity and cardiovascular disease, however, research mainly relies on observational studies because it is unethical to induce obesity through intervention. Due to the nature of observational studies, it is difficult to fundamentally exclude confounding variables, and in the case of the bidirectional phenotype such as obesity, it becomes more difficult to identify the relationship.

To solve this problem, this research team grafted genome-based research to confirm causality to observational research for the first time. Mendelian randomization study used in this study is based on the fact that genetic variants are randomly assigned during meiosis to form groups with high or low genetic risk of obesity. Comparing the difference in the risk of cardiovascular disease for these two groups can evaluate whether obesity causes the disease without intervention. Mendelian randomization studies have the advantage of being able to obtain independent results from confounding variables and reverse causation caused by the environment because groups are randomly divided at the stage of meiosis. This is in contrast to the weakness of epidemiological studies that they can be often affected by confounding factors or reverse causation. This study presents new high-level evidence for the relationship between obesity and cardiovascular disease, which has been studied for a long time, by utilizing both the strength of large-scale observational studies (association confirmation), and the strength of genome-based research (causality confirmation).

A researcher, Minseo Kim (graduated from Korea University College of Medicine and a M.A. student at SAIHST, Sungkyunkwan University), said, “There were weaknesses in clinical research while conducting clinical research. We devised a new research design that could augment clinical research with genomic approaches. This was possible because he learned both clinical research and genomics. It is expected that more sophisticated studies will be possible by using this research methodology for many epidemiological research topics in the future.”

Professor Hong-Hee Won said, “This study is meaningful that it systematically presented scientific evidence for causality between obesity and the risk of cardiovascular disease by integrating large-scale epidemiological and genomic studies. As obesity has been shown to be responsible for various cardiovascular diseases and mortality risk, it is important to maintain ideal body weight and to adhere to healthy lifestyles to lower the risk of cardiovascular disease."

The results of this study, which was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (Information and Communication Technologies) of the Korea government, were published in one of the most prestigious cardiology journals, 'European Heart Journal (Impact Factor 29.98)'.

▲ Prof. Hong-Hee Won, Ph.D. (corresponding author) ▲ Minseo Kim, M.D. (first author)

▲ A research team led by Professor Hong-Hee Won at SAIHST, Sungkyunkwan University, Samsung Medical Center