Obesity is causally linked to so many diseases - what are your risks?
At a population level, the prevention of childhood and adolescent obesity may lower the incidence of MS by as much as 15-20%. The challenge is how do we prevent childhood and adolescent obesity?
Mendelian randomization or MR is a method used to measure variation or polymorphisms in genes that are associated with a specific phenotype to imply causal effects of an exposure on an outcome. For example, genomic variants associated with say obesity and/or a raised body mass index are substituted for actual obesity or BMI. MR is meant to reduce so-called reverse causation and confounding.
Despite this assumption, there is a tautology that underpins all MR studies in that the genetic variants associated with a specific phenotype were discovered and validated using case-control studies using the phenotype. What is often under-appreciated is that the phenotype may only express itself in the context of a specific environment or microenvironment. It is often assumed that because cases and controls are selected from the same population that there are no biases. However, this does not necessarily mean the exposure(s), be a qualitative or quantitative exposure(s), are necessarily similar. For example, the microbiome or infection with an agent that may cause obesity cannot be controlled for in these studies.
Saying this MR is one way of getting to potential causal factors in complex diseases, which is why the review below linking a high body index to multiple chronic diseases, including multiple sclerosis, is so important. The question I ask is is the biology associated with these diseases similar or is it different?
A high body mass index is associated with metabolic syndrome, which is driven by chronically raised insulin levels and the many metabolic perturbations that occur downstream of hyperinsulinaemia. At the same time increased adiposity, particularly visceral or centripetal obesity, is associated with a proinflammatory state. Adipose tissue is also a source of hormones and cytokines and a sink for lipid-soluble mediators, for example, vitamin D. It is, therefore, important to try and pin down the biological pathways associated with obesity that are driving the risk of these individual chronic diseases.
Despite trying to make the case for causation based on biological plausibility the final proof that obesity causes disease X will require an interventional study, i.e. by preventing or successfully treating obesity does it reduce the risk of getting the disease in question and by how much.
It is quite clear that childhood and adolescent obesity is a risk factor for developing MS. However, as it is not necessary for getting the disease most people don’t think it is a modifiable risk factor. I disagree. At a population level, the prevention of childhood and adolescent obesity may lower the incidence of MS by as much as 15-20%. The challenge is how do we prevent childhood and adolescent obesity from occurring in the first place?
Larsson & Burgess. Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies. BMC Med. 2021 Dec 15;19(1):320.
Background: Obesity is a worldwide epidemic that has been associated with a plurality of diseases in observational studies. The aim of this study was to summarize the evidence from Mendelian randomization (MR) studies of the association between body mass index (BMI) and chronic diseases.
Methods: PubMed and Embase were searched for MR studies on adult BMI in relation to major chronic diseases, including diabetes mellitus; diseases of the circulatory, respiratory, digestive, musculoskeletal, and nervous systems; and neoplasms. A meta-analysis was performed for each disease by using results from published MR studies and corresponding de novo analyses based on summary-level genetic data from the FinnGen consortium (n = 218,792 individuals).
Results: In a meta-analysis of results from published MR studies and de novo analyses of the FinnGen consortium, genetically predicted higher BMI was associated with increased risk of type 2 diabetes mellitus, 14 circulatory disease outcomes, asthma, chronic obstructive pulmonary disease, five digestive system diseases, three musculoskeletal system diseases, and multiple sclerosis as well as cancers of the digestive system (six cancer sites), uterus, kidney, and bladder. In contrast, genetically predicted higher adult BMI was associated with a decreased risk of Dupuytren's disease, osteoporosis, and breast, prostate, and non-melanoma cancer, and not associated with Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson's disease.
Conclusions: The totality of the evidence from MR studies supports a causal role of excess adiposity in a plurality of chronic diseases. Hence, continued efforts to reduce the prevalence of overweight and obesity are a major public health goal.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.