In epidemiology, Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies: Wikipedia

Gene-Aided Research Finds Obesity a Disease

For years, the debate has raged whether fitness can override being fat. Early in 1999, Dr. Steven Blair, director of research at the Cooper Institute of Aerobics in Dallas, opined that fit and fat appears to be good enough. “In the men who are overweight or obese, but moderately or high-fit, we don’t see much increase in the risk of dying,” he told Nutrition Action Health Letter.

Harvard professor Frank Hu called that assertion “very misleading,” adding that “being physically active [does] not cancel out the increased mortality of overweight.”

While observational studies have consistently shown an association between obesity and mortality—24 years of weight history from the Framingham Heart Study, reported November 16, 2018, in JAMA Network Open, showed the lowest risk of mortality in normal-weight individuals—cause and effect has remained controversial.

Confounding influences such as external factors associated with both obesity and CVD, and diseases which lead to increased adiposity muddy the water. Interventions aimed at long term weight control to improve health and reduce mortality are, of course, difficult and impractical.

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Haris Riaz, MD, and colleagues from the Department of Cardiovascular Medicine at the Cleveland Clinic have entered the fray using a technique called Mendelian randomization (MR) to narrow the gap between association and causation. (Gregor Mendel, an Austrian friar whose pea plant experiments in the late 1800s established many of the rules of heredity, has come to be recognized as the founder of the modern science of genetics.)

Riaz and colleagues examined data on almost 900,000 individuals from five nonoverlapping studies, and used Mendelian randomization to reduce the effect of potential confounding factors. They concluded that obesity is associated with type 2 diabetes and coronary artery disease—and that MR is supportive of a causal association. (They found no strong evidence for an effect on stroke.)

“Mendelian randomization uses genetic variants to estimate the health consequences of phenotypes influenced by these genetic variants,” they wrote in introducing the study. “It is a relatively novel epidemiologic study design incorporating genetic information into standard epidemiologic methods. Mendelian randomization offers an opportunity to study associations without many of the typical biases that are inherent in traditional epidemiologic approaches. Thus, Mendelian randomization can fill the evidence gaps by minimizing confounding, if variables are randomly and equally distributed in the population of interest.”

Simply put, observational studies measure the correlation between body mass and health. Mendelian randomization adds genetic factors to lessen confounding and strengthen the correlation. While it doesn’t lock down causation, MR puts teeth in association.

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An editorial by British researchers Kaitlin H. Wade, BSc, PhD, and George Davie Smith, MD, DSc, FFPH, published along with the Riaz study, found it “compelling.”

They begin by explaining that “MR methodology exploits the properties of genetic inheritance to mimic a randomized clinical trial to improve causal influence.”

They devote practically the entire editorial to the careful and laborious effort devoted to selecting the five studies included in MR analysis. Of 4660 potentially relevant articles, 2511 titles were screened. Seven were included in systemic review, and 5 studies with 881,692 participants were found to be eligible to be included in the meta-analysis.

Four studies reported on type 2 diabetes in 461,871 individuals, of whom 66,341 were obese. All 5 studies reported on coronary artery disease in a total of 570,261 participants, of whom 100,103 were obese.

For all-cause stroke, 3 studies looked at the association in a total of 228,816 individuals, including 9774 who were obese.

Wade and Smith noted that the study is the first meta-analysis of MR studies assessing the association between obesity and cardiovascular disease, “reporting compelling evidence that each standard deviation higher BMI increased the risk of type 2 diabetes by 67% and coronary artery disease by 20% but no strong evidence for an effect on stroke.”

They concluded that the results warrant a “global effort” to reduce the trend toward excess weight—“and suggest that in most cases, any reduction in BMI is likely beneficial.”

Obesity Is a Disease

“This study is important because we can conclude that it is not solely factors like high blood pressure, high cholesterol, or lack of exercise that tend to come with obesity that are harmful, the excess fat itself is harmful,” senior author Haitham Ahmed, MD, stressed in a press release from the Cleveland Clinic.

He continued, “Patients may think their cardiovascular risk is mitigated if their other risk factors are normal or being treated, but this study suggests you cannot ignore the extra weight.”

“Physicians should take heed and make sure they are counseling their patients about weight loss in a comprehensive and collaborating manner.”

Dr. Ahmed added that it is “very important to recognize” that obesity is “not simply a lifestyle choice,” despite the contribution of lifestyle factors.

“[Obesity] is a disease, and there is large genetic influence on your weight; nearly 100 genetic variations” are associated with the development of obesity and subsequent heart disease risk.

You can read the entire study online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324374/

My Take

This is perhaps the most powerful hit ever on being overweight. Doctors and the health care system as a whole are confronted with a population that eats too much of the wrong food and moves too little. A study published online November 20, 2018, in JAMA found “a substantial prevalence of high sitting and physical inactivity among US adults.” We sit too much and don’t exercise. What’s more, the prevalence of inactivity increases with age. (And obesity?) The researchers urge healthcare providers to “support efforts to implement programs, practices, and policies where adults live, learn, work, and play to help them sit less and spend more time being physical active.”

The “global effort” called for by the British researchers.

Fine and good, but nothing works without self-help.

My father understood the dangers of being overweight. He always said that the Second World War saved his life. After a very active athletic career in high school and college, he let his weight get out of hand in the next decade or so. Important to remember that many men in his day judged success by the size of one’s waistline. Time on his hands on a hospital ship in WW2 gave him the opportunity to trim down. Ship-board movies show him on the high bar—he was a champion pole vaulter in HS and college—in terrific shape, lean and muscular. He let the pounds come back after his military service, but took the weight off again in the last decades of his life and never gained it back.

He had a chart in his examining room showing deep fat accumulating on the waistline. My guess that his patients were most receptive when he had his own weight under control.

My paternal grandmother let the weight pile on at midlife, but took if off with encouragement from my dad—and kept it off until her passing just short of 100.

My sense is that most current-day doctors consider it a waste of precious time urging patients to lose excess weight and keep it off. Few patients will listen and those that do rush the process and gain back any weight lost in short order. Most say “forget it” and eat what they want and can’t find time to exercise.

While I never considered myself fat, my first wife screamed when I hit 200.
I trimmed down after our divorce and have never gained the weight back.
This photo, taken by John Balik when I was 45, and many more on our “Training Pictorial from 15 to 81”
show the results of a lifetime of regular exercise and healthy eating.

In my experience, the only thing that will make and keep you lean is a balanced diet of whole foods and rewarding physical activity.

Regimens based on denial and torturous exercise are not sustainable. Any weight you lose rapidly is soon regained.

You must not rush the process. Take your time and build on success little by little.

See my FAQ on New Year’s resolutions for more details on what works: https://www.cbass.com/Faq(8).htm (scroll down)

May 1, 2019

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