'Lucky Genes' May Protect Against Some Obesity-Related Diseases

People with obesity who have inherited "lucky genes" for a favorable distribution of body fat had a lower risk of 11 diseases related to the metabolic effects of fat compared with people who had inherited "unlucky genes," in a large new genetics study.

That is, people with unfavorable adiposity gene variants had fat stored under the skin throughout the body, but they also had more ectopic fat (fat in the "wrong place") surrounding the pancreas and liver, which is associated with a higher risk of metabolic diseases such as heart disease and type 2 diabetes.

In contrast, people with favorable adiposity gene variants had more subcutaneous fat (such as a paunch or a double chin).

The study by Susan Martin, PhD, a postdoctoral research associate at the University of Exeter, UK, and colleagues, was recently published in eLife.

"Some people have 'unlucky fat genes,' meaning they store higher levels of fat everywhere, including under the skin [and around the] liver and pancreas. That's associated with a higher risk of diseases such as type 2 diabetes," senior author Hanieh Yaghootkar, MD, PhD, summarized in a press release from the University of Exeter.

"Others are luckier and have genes that mean higher fat under the skin but lower liver fat and a lower risk of diseases like type 2 diabetes," added Yaghootkar, from Brunel University London, UK.

Among 37 chronic diseases that are associated with obesity, the researchers found the metabolic effects of adiposity are likely the main cause of the following 11: type 2 diabetes, polycystic ovary syndrome, coronary artery disease, peripheral artery disease, hypertension, stroke, heart failure, atrial fibrillation, chronic kidney disease, renal cancer, and gout.

On the other hand, excess weight itself (such as a heavy load on the joints) rather than a metabolic effect is associated with nine other obesity-related diseases: osteoarthritis, rheumatoid arthritis, osteoporosis, gastro-esophageal reflux disease, gallstones, adult-onset asthma, psoriasis, deep vein thrombosis, and venous thromboembolism.

Good Genes No Substitute for a Healthy Lifestyle

"People with more favorable adiposity gene variants are still at risk of the nine diseases" that are not caused by metabolic effects — such as osteoarthritis — but are caused by the effect of excess weight on the joints, another author, Timothy M. Frayling, PhD, stressed.

"People with obesity and unfavorable adiposity gene variants are at higher risk of all 20 diseases because they have the double hit of the excess mechanical effects and the adverse metabolic effects," Frayling, University of Exeter, told Medscape Medical News in an email.

The main clinical message, he said, is that "this research helps inform which conditions may respond better to therapies that lower the adverse effects" of risk factors such as high cholesterol and blood glucose levels, "and high blood pressure, even with no weight loss."

"In contrast, other conditions really require the weight loss."

"These results emphasize that many people in the community who are of higher body mass index (BMI) are at risk of multiple chronic conditions that can severely impair their quality of life or cause morbidity or mortality, even if their metabolic parameters appear relatively normal," the researchers conclude.

"Whilst it's important that we identify the causes of obesity-related disease, good genes [are] still no substitute for a healthy lifestyle," Martin stressed.

"A favorable adiposity will only go so far. If you're obese, the advice is to still try and shift the excess weight where you can," she said.

"The authors have conducted a robust and very comprehensive study using Mendelian randomization to disentangle metabolic and nonmetabolic effects of overweight on a long list of disease outcomes," reviewing editor Edward D. Janus, MD, PhD, University of Melbourne, Australia, summarized.

"This is an important topic and can help us better understand how overweight influences risk of several important outcomes."

Metabolic and Nonmetabolic Diseases Caused by Obesity

The researchers aimed to investigate the effects of adiposity on metabolic and nonmetabolic diseases caused by obesity.

They used data from 176,899 individuals in the FinnGen project in Finland and from over 500,000 individuals in the UK Biobank database.

They performed Mendelian randomization studies to investigate the causal association between BMI, body fat percentage, favorable adiposity alleles, and unfavorable adiposity alleles with 37 disease outcomes.

Of these 37 chronic diseases associated with obesity, 11 diseases were directly related to the metabolic effect of adiposity (where favorable adiposity or unfavorable adiposity gene variants had opposite effects). Nine other diseases were unrelated to the metabolic effects of adiposity.

For most of the remaining diseases — for example, Alzheimer's disease and different cancers — it was difficult to draw firm conclusions about the respective roles of favorable adiposity and unfavorable adiposity gene variants.

The study was funded by Diabetes UK, the UK Medical Research Council, the World Cancer Research Fund, and the National Cancer Institute. Author disclosures are listed with the article.

eLife. Published online January 25, 2022. Full Text

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