Genetic differences in the GLP‑1 and GIP receptors help explain why some people lose a great deal of weight—and others get severe nausea or barely respond—on the same obesity drugs.
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Two people start the same weight loss drug on the same day. One drops 25% of body weight. The other barely loses 5%, or gains weight. A new study now shows that part of the reason lies in the DNA, specifically in the gene the drug targets.
Roughly 4 in 10 American adults live with obesity, a condition that raises the risk of diabetes, heart disease and dozens of other serious illnesses. Drugs that mimic a natural gut hormone, known as GLP-1 drugs, transformed treatment. An estimated 1 in 8 American adults takes one of these medications. The results can be dramatic, but they vary widely from person to person.
Age, sex, starting weight, drug type, dose and time on treatment explain some of the variation. In clinical trials, the average person on semaglutide loses about 10% of their starting weight. Some lose more than a quarter of their weight. A full third lose less than 5%, or gain weight. People with Type 2 diabetes lose less weight on these drugs. Women lose more than men. These non-genetic factors, taken together, account for about 21% of the difference from person to person. That leaves a large share unexplained.
A series of genetic studies now sheds light on these differences. A genetic study of nearly 28,000 people taking these drugs now identifies a specific genetic variant tied to weight loss. A protein on the surface of cells called the receptor serves as the lock into which the drug fits. The variant sits in the gene that produces the receptor these drugs bind to on the surface of cells. It changes one amino acid in the receptor’s structure.
One specific variant changes a single amino acid at position seven of the receptor protein, from proline to leucine. This change sits in the signal peptide, the portion of the protein that guides the receptor to the cell surface. The substitution appears to enhance receptor trafficking, increasing the number of receptors available for drug binding.
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Each person carries two copies of this gene. A person with one copy of the variant loses roughly 1.7 pounds more than someone without it. A person with two copies loses about 3.3 pounds more. The variant is most common among people of European and Middle Eastern descent, occurring in roughly 40% of the population. It is less common in people of East Asian, South Asian, Latino and African ancestry. This distribution may help explain some of the differences in drug effectiveness observed across populations.
The same genetic region that influences weight loss also influences side effects. The signals for weight loss and for nausea or vomiting almost certainly trace to the same inherited variant. Greater weight loss and stronger side effects travel together, suggesting nausea reflects the drug working on the same pathway responsible for weight reduction. In some people, for reasons not yet fully explained, even a single copy of this variant gives rise to intense vomiting and a strong adverse reaction. These people cannot continue GLP-1 weight loss drugs.
A second genetic finding applies only to drugs that target two gut peptides: GLP-1 and GIP. A variant in the gene for the GIP receptor changes a single amino acid at position 354, from glutamic acid to glutamine. This change weakens the GIP receptor. The GIP component of these combination drugs normally buffers the nausea that the GLP-1 component causes.
When the GIP receptor carries this weakening variant, that protective buffer disappears. People carrying risk variants in the genes for the GLP-1 receptor and the GIP receptor face up to a 15-fold higher chance of severe vomiting on combination drugs, compared with people who carry neither.
The effects of these single variants do determine part of the outcome, but they are not the whole story. Other factors remain to be discovered. The study enrolled a relatively small number of people. Participants were mostly female, mostly of European descent and mostly middle-aged. The study also relied primarily on self-reported data, and self-reported weight loss consistently exceeded what medical records showed. Confirming these results requires broader studies, not only to verify the effect of this variant but to identify other variants in regulatory regions of the genome that control when and where genes are turned on.
The question of who benefits most from GLP-1 drugs, and who suffers the worst side effects, carries clinical weight. This study provides the first direct genetic evidence that variation in the drug target itself shapes how people respond. A person whose genetic profile suggests a high risk of severe nausea on a combination GLP-1 and GIP drug could start with a GLP-1-only drug instead. They could also adjust the pace of dose increases. A person whose profile predicts strong weight loss could begin treatment with greater confidence. As more data accumulate and additional genetic factors emerge, it may become possible to match each person with the drug, dose and approach most likely to work. The era of one-size-fits-all obesity treatment moves closer to its end.
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