Garver said he was among the first discoverers of an “obesity gene” known as the Niemann-Pick C1 (NPC1) gene. Certain variations in this gene are strongly associated with developing obesity and/or diabetes — variations that a large amount of people have.
The NPC1 gene is a small segment of DNA that provides instructions for making the NPC1 protein, which helps the body process cholesterol and fatty acids. Variations in the NPC1 gene change the way the NPC1 protein is made and interferes with its function, he said.
NPC1 was first identified as the gene that, when mutated, results in Niemann-Pick C1 disease — a disorder Garver has studied for nearly two decades.
For a child to develop NPC1 disease they must have two copies of a rare NPC1 gene variant, meaning that both of their parents were “carriers.” The carrier parents have no symptoms. In his research, Garver regularly bred two carrier mice to get offspring with NPC1 disease. However, it was while working with these mice that he made an unexpected observation.
“I was looking at them and I noticed they were gaining weight — they were chubby, the parent mice,” explained Garver. “I knew this 10 years earlier, but I never thought about it. They were chubby; that’s all we said, and we continued studying the rare disease.”
Eventually he succumbed to curiosity and tracked weight gain in his carrier mice on different diets. Garver said he was astonished to find that these mice gained weight on a high-fat diet much quicker and more dramatically than normal mice.
“Every time I presented this, people laughed and said, ‘no way, this is not happening,’” Garver said. “Well, about that time the first genome-wide association study was performed in Europe. They found that the NPC1 gene was associated with extreme obesity (in humans).”
Since being among the first people to identify NPC1’s role in obesity, Garver has studied the different variations of the gene, which is turning out to be very complicated, he said. Certain extremely rare variants are associated with the NPC1 disease, while other, more common variants are associated with either obesity or diabetes, independent of body weight. According to Garver, roughly 30 percent of the population has the more common variants, including himself.
Garver and his graduate student, Joseph Castillo, are in the process of sampling a large number of New Mexicans and testing to see how many people locally have the more common NPC1 variations. So far, they have collected data from 700 to 800 people, Castillo said.
Castillo said he hopes that they can use this information to help combat the obesity epidemic.
“Maybe we have something here that we can one day, if not treat, then at least be able to help people with,” Castillo said. “We can genotype them and then give them specific interventions, a diet regimen specific to their needs. If they’re at risk to become obese we can give them lifestyle coaching. That would be a pretty nice end goal.”
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Garver became director of the National NPC1 Disease Database with information from all of the patients in the United States. He noticed that, surprisingly, Hispanics living along the Rio Grande Valley region in New Mexico all had the same mutation in NPC1.
In Arizona, Garver worked closely with Dr. Randall Heidenreich, now the division chief of pediatric genetics at UNM hospital. As NPC1 disease had no available treatment options, Heidenreich spent much of his time developing one, he said.
“I’m a physician — I want to treat people. So I said ‘okay, we know that cholesterol is accumulating in the cells of these children and these mice,’” Heidenreich said. “‘Can I find any medicines or compounds that help get rid of cholesterol from the cells?’”
He said he eventually identified a compound called cyclodextrin — interestingly, the active ingredient in Febreze — that sequesters cholesterol and slowed the progression of the disease in his mice.
The compound is now in human clinical trials, and is a promising therapeutic treatment, he said.
Lauren Topper is a freelance reporter at the Daily Lobo. She can be reached at news@dailylobo.com, or on Twitter @lauretopps.
