Genetic basis of obesity supports weight

There are probably many factors that come into a person's weight. A new report from Sekar lab Kathiresan, MD, director of the Massachusetts General Hospital's Genomic Medicine Center (MGH), documents a clear biological basis for predisposition to obesity. More specifically, this genetics plays a role in the weight of a person.

The study used polygenic risk scores (PRS) to stratify patients into risk categories based on their genetic mutations. It is rare that a disease is caused by mutations of a single gene. More generally, diseases (including cardiovascular diseases, type 2 diabetes, and certain brain disorders) are mediated by a set of common and low-frequency genetic variants, most of which remain unknown. Each variant has a small effect but, taken together, they could indicate the overall risk of a person.

Severe obesity affects 8% of adults in the United States. Although this figure is much lower (about 1%) in countries such as India and China, the prevalence of severe obesity has been multiplied by 100 in recent years. 30 years. It also shows "no sign of slowing down," the authors said.

It is also known that obesity has a hereditary component, "which suggests that innate DNA variation confers increased susceptibility to some individuals and protection to others." Hereditary susceptibility to obesity may, in rare cases, be the result of melanocortin 4 receptor (MC4R), which have a significant effect, but for most people with severe obesity, it is not possible to have a significant effect. There is no single genetic cause. The researchers pointed out that, in these cases and as with other complex diseases, "genetic susceptibility may rather result from the cumulative effects of many variants with individually modest effects, namely a polygenic model".

Kathiresan's group developed the PRS for obesity using the same approach that it used previously for diseases such as coronary artery disease: extracting information from millions of genome sites whose genetic code varies in size. single digit that reflects inherited risk. The dataset used to construct the predictor is based on a large GWAS published in a 2015 report. Nature article entitled "Genetic studies of body mass index provide new information on the biology of obesity". The polygenic predictor quantified the relationship between each of over 2.1 million common genetic variants and BMI in more than 300,000 people.

The study using the predictor of obesity revealed that some people are much more likely than others to be obese. Those who were among the richest 10% averaged 29 pounds more than the lowest 10% and 25 times more likely to develop severe obesity.

It is interesting to note that the data show that the impact of the score begins to manifest itself as the children enroll in kindergarten, which surprised Amit Khera, MD, associate director of the Precision Medicine at the Center for Genomics Medicine at London General Hospital. paper. In addition, their weight trajectories continue to diverge over the years, Kathiresan calling ages 0 to 8 years the "Golden Age of Susceptibility".

"The score is only associated with minimal differences in birth weight, but it predicts net weight differences during infancy and profound differences in weight trajectory and risk of pregnancy." severe obesity in the coming years, "said Kathiresan.

The research is published in Cell in an article titled "Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood".

"The power to identify people at high risk of obesity at birth is striking," said Ali Torkamani, PhD, director of genomics and genomic informatics at Scripps Research Translational Institute. "However, he added, the genetic risk of obesity seems to be mainly expressed when people reach the age of 8 years." Torkamani said, "It remains to be seen if and how people could use this information earlier in life to prevent obesity throughout life. The commentary accompanying Torkamani's study appears in the research article of the Cell.

Khera said GEN that many people are stigmatized for severe obesity on the premise that this is due to a lack of will or wrong choice. This result can begin to de-stigmatize obesity in society in addition to providing important health information to people with high scores of polygenic obesity who are also at a higher risk of developing many other health complications. This also suggests how some people's DNA greatly increases the risk of obesity, which helps answer the following question: "Is there a genetic reason why I have so many difficulty in keeping the weight? "Finally, and in a prognostic way, the score identifies a subset of increased risk of developing severe obesity, which increases the potential for a targeted intervention.

However, the score simply predicts a risk – no more than that. In fact, 17% of people with a high risk score maintained a normal weight. "What's really important here is that we have a new approach to" genome interpretation "that can be applied anytime after birth," Khera noted. He added that "for diseases such as coronary artery disease and breast cancer," we have clearly shown that these high-risk individuals – who are at four times higher risk – go unnoticed in our clinical practice. " individuals is a major goal for years to come.

"The ability to identify people at high risk from birth can facilitate the implementation of targeted obesity prevention strategies, with increased impact or increased profitability," Khera said.

Khera noted that "evidence that genetics is starting to manifest early in life highlights the critical importance of public health interventions that begin at a young age. It will take a lot of work to be optimized, but healthier foods in our schools, education, creating a safe environment for children – these will all be important parts of the puzzle. "