Causal links established between obesity and 14 major diseases

The findings, which represent the strongest causal links shown to date, are from a new Lancet Digital Health study led by Professor Elina Hyppönen from the Australian Centre for Precision Health at the University of South Australia.
 
The hypothesis-free, data-driven phenome-wide association study (PHeWAS) analysed genetic data from more than 330,000 people, using UK Biobank data to analyse associations between body mass index (BMI) and disease outcomes.
 
‘In this study we used a genetic approach to seek evidence for true health effects associated with higher body mass index, which assesses our weight against our height and is commonly used to measure obesity,’ Professor Hyppönen said.
 
The study used a genetic risk score of 76 BMI-related genetic variants to approximate high BMI when testing for its associations with multiple disease outcomes.
 
A key finding bolsters concerns held by health professionals around the link between obesity and diabetes, with many of the diseases related to high BMI known to be commonly associated with poorly controlled diabetes.
 
The study also found evidence supporting a link between obesity and type 1 diabetes.
 
‘We saw evidence for effects on peripheral nerve disorders, chronic leg and foot ulcers, and even gangrene and kidney failure, which are all known to be diabetic complications,’ Professor Hyppönen said.
 
‘This suggests a key aspect to reduce comorbidity risk in obesity is careful monitoring of blood sugar and effective control of diabetes and its complications.’
 
The study found that in addition to ischaemic heart disease and hypertension, the downstream consequences of high BMI include increases in the risks of cardiomegaly, dysrhythmias, and heart failure.
 
‘We also showed evidence supporting not only the well-known association between high BMI and type 2 diabetes, but also the less well established association with type 1 diabetes,’ the study states.
 
‘We provided novel evidence for the role of high BMI as a risk factor for – rather than a consequence of – hypothyroidism.’
 
Researchers also discovered causal evidence between obesity and inflammatory conditions like cellulitis and bronchitis, retinal dystrophies, hypothyroidism, chronic ulcers of leg and foot, gangrene, and structural problems such as hernias and knee derangement.
 
Previous research has suggested higher BMI is associated with increased risk of chronic diseases such as type 2 diabetes and cancer, but the difficulty of conducting clinical trials around obesity has made it hard to prove causation.
 
Professor Hyppönen and her collaborators developed a multi-dimensional analysis in which genetic data was put through a series of examinations to deliver high confidence of causality.
 
‘We compared evidence from five different statistical approaches to establish how strong the evidence for causal effect actually is,’ she said.
 
‘Fully consistent evidence across all approaches was seen for 14 different diseases, and for 26 different diseases evidence was obtained by at least four of the five methods used.
 
‘What increases the confidence that these associations are largely reflective of real effects is the fact that those effects which came across with consistent evidence are also ones for which we have previous clinical evidence.’
 
Professor Hyppönen said these type of genetic studies will hopefully lead to new strategies for prevention.
 
‘We know that obesity has a strong genetic basis, which can make weight management very difficult to some of us and the same strategies for prevention may also not work for all,’ she said.

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