Photo Credit: Dikushin
Dr. Kathryn Kaiser explains the importance of investigating genetic associations within demographic groups to better understand and address health disparities.
A cross-sectional study by Kathryn Kaiser, PhD, her former PhD student Dr. Hairui Yu, and colleagues examined the association of FTO single-nucleotide variants (SNVs) with obesity and cardiometabolic diseases among older Black and White US adults. According to the study findings published online in JAMA Network Open, the researchers found some notable differences based on race and sex. Among 10,447 participants, FTO SNVs showed significant associations with obesity, hypertension, and diabetes in White individuals, while none were significantly associated with obesity in Black individuals. White males exhibited a higher risk of obesity, whereas White females had a higher risk of hypertension and diabetes. However, one FTO SNV (rs1121980) was directly associated with an increased risk of heart disease in Black participants, independent of obesity.
The study findings suggest that there may be sex-specific mechanisms for obesity risk and cardiometabolic diseases that may also differ by race. Physician’s Weekly (PW) spoke with Dr. Kaiser to better understand why this study underscores the importance of investigating genetic associations within specific demographic groups to better understand and address health disparities.
PW: Can you explain the significance of studying these associations in different racial and sex groups?
Dr. Kaiser: This gene creates a protein, as many genes do. It’s a complex, large gene as far as its sequence. So, there are a lot of places where variations in the structure of that gene product can be slightly different and, therefore, behave biologically somewhat differently. It’s been identified that this particular gene product works inside the cell. It’s not a cell signaling component; it operates inside cells. Based on experimentation of knocking that gene out in a mouse model, which is where this was first discovered to affect tissue modeling, it seems to be related to both fat mass and lean mass.
This spurred some investigations in genome-wide association studies into contributors to fat mass in humans, and it is routinely replicated across many genetic association studies to be the primary hitter. If you look at Manhattan plots, FTO is always there as far as being the biggest association with obesity risk, in concert with many others. Of course, the total genetic contribution is still a small percent of what explains a person’s obesity; however, we thought it would be interesting to see how human populations in different environments may have evolved with respect to FTO variations. In the study, we found that people of European ancestry had more of these high-risk gene variations than those of African ancestry.
How do you interpret the findings that show how FTO SNVs affect different demographic groups?
You can imagine that over much of human history on the African continent, the environment is different—from temperature, nutrient availability, and other things—compared to Northern Europe. Over many successive generations, with selective pressure genes do their own experiments, and these natural variants cause subtle modifications in organisms that may then prove to support reproductive ability, for example. For women, being able to have and maintain body fat is a reproductive advantage. Women can’t reproduce if they’re too thin, and one of the things that I noticed was there was a huge disparity between African Americans in terms of women being at much higher risk not only for obesity, but severe obesity, as compared to African American men. It made me wonder if there was environmental pressure with these genes taken from one continent and put in a different scenario that caused an interaction. This gene-environment interaction would exert selective pressure and a shift in the environment that would cause African Americans to be at a greater risk for obesity, given their genetic background. However, the results of our study do not show a greater obesity risk for people of African ancestry, at least related to this one gene.
How could this study impact clinical practice?
For clinicians, understanding how this gene works to drive eating behavior will help to educate parents as they prepare to become feeders of young children; parents need to understand that children are often good at regulating what they need and their way of managing energy as they grow. Parent training about feeding practices and routinely checking growth charts are important to ensure children are on a good trajectory, but not too high. My sense from looking at our population and the difficulty in treating obesity is such that prevention needs to be at the forefront. This is not to say that we shouldn’t treat obesity; we absolutely should treat obesity, but we also should think about how it can be managed or prevented if we understand how children can self-regulate in a good home environment where consumption matches physical activity.
What I learned from working with bariatric patients is that early life experiences, specifically adverse child experiences and trauma, hugely increased the odds ratios for many of the women to become severely obese. A common theme from the bariatric patients was that they reported early life trauma, neglect, abuse, and asking what does that do to one’s physiology in terms of detection of and response to threat, therefore accruing and keeping body fat? Again, the selective pressure is towards phenotypes that favor reproductive fitness. Until recently, a little extra fat was good for women’s reproductive fitness. Understanding a patient’s psychosocial history is important context for how obesity can be made manifest.
How should physicians integrate the study’s findings?
Sometimes, people hear the message from their physicians that obesity is a lifestyle problem and, therefore, the solution is lifestyle. My message would be that your frontal lobes cannot tell what the cells are shouting about and ignore them. Obesity happens over a lifespan or even inter-generationally at a level below conscious awareness. It happens for many people at what seems to be a cellular level—unless you have what’s known as ‘simple obesity’, which can be resolved by modifying diet and exercise.
Many people don’t have simple obesity; instead, they have a combination of factors that are difficult to tease apart. Physicians and patients should know that the ability to control this simply through lifestyle is difficult. Medicine and surgery are not “cheating”. You hear that attitude a lot that patients don’t want to “cheat.” They want to do it the “right” way. That assumes that a person’s obesity is simple obesity.
We should treat obesity seriously. It’s a lifelong challenge; physicians must have these conversations with their patients. Primary care physicians must also figure out how to get comfortable with patients early in adulthood by monitoring weight, seeing people every year, and conversing about weight management in a supportive way. They can’t just wait until a patient has diabetes or hypertension and treat the complications. More complex obesity becomes increasingly intractable. It starts in childhood with prevention and continues with monitoring and support in early adulthood to minimize this eventual epidemic we now see. Clearly, our genes and environment are interacting. More work is needed to understand the mechanisms.
