Milkshake study reveals how gene variants affect cholesterol

In a bid to better understand the effects of human genetics on cholesterol, a team of scientists had 800 people drink a fatty milkshake, take a drug for three weeks, then drink another milkshake. Sequencing their genes turned up a trio of uncommon variants that governed a patient's response to the cholesterol treatment fenofibrate.

"Triglyceride and cholesterol levels are influenced by what people eat and whether they take drugs to lower fat and cholesterol," said lead author Xin Geng, a postdoctoral fellow at the University of Texas Health Science Center at Houston, in a statement. "We know, however, that not everyone's triglyceride and cholesterol levels respond the same to diet and drugs. Previous research suggests that these differences in response to diet and drugs may be caused by genetic factors inherited from parents."

Participants of the Genetics of Lipid-lowering Drugs and Diet Network (GOLDN) came to the lab with an empty stomach. Scientists drew their blood before and after they drank the milkshake. The team measured the HDL cholesterol, LDL cholesterol and triglyceride levels in their blood and sequenced the genes in the blood cells. They sent the patients home to take fenofibrate for three weeks before coming back for another milkshake and more blood tests.

"We found that variants in one gene, called SIPA1L2, predicted triglyceride level changes after consuming the milkshake. Variants in another gene, ITGA7, predicted LDL-cholesterol level ("bad" cholesterol) changes after taking the drug. And variants in a third gene, CEP72, predicted triglyceride response when comparing the pre-fenofibrate milkshake experiment to the post-fenofibrate milkshake experiment," said Ryan Irvin of the University of Alabama at Birmingham. The findings appear in the Journal of Lipid Research.

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Common genetic variants were thought to be responsible for the differences in people's triglyceride and cholesterol levels, but they only explained less than a quarter or inherited variability, the team said. "Our hypothesis was that at least some of the 48% of unexplained variability could be driven by rare genetic variants, those that occur in less than 5% of the population," said Degui Zhi, of the UTHSC at Houston.

Genetic variants have been fingered elsewhere as culprits in cardiovascular and neurological diseases. For example, a variant on the chromosome 6p24 was implicated in migraines, heart disease and hypertension. It was also found to raise the risk of cervical artery dissection, a blood-vessel tear that can lead to stroke and fibromuscular dysplasia, a condition marked by abnormal cells in artery walls.

Amgen's Repatha and Sanofi's Praluent, the subjects of a fierce patent battle, target the enzyme PCSK9, which helps regulate the amount of cholesterol in the bloodstream. Now a group of scientists in Europe, along with Affiris, are working on a vaccine to inhibit the enzyme, coded by the PCSK9 gene, and immunize people against developing high cholesterol and atherosclerosis.

The milkshake study will no doubt spark interest in the gene variants that were turned up, though more research will be needed to determine the true role these abnormalities play in driving heart disease. The GOLDN population is not diverse—most of the program's participants are white—so more population studies would be needed to determine how the variants affect other demographic groups. Future studies could reveal additional rare variants, or a role for genes that do not code for proteins, which were excluded from this study.

"Future studies can begin where we left off by trying to uncover exactly how the metabolic pathways and mechanisms these genes are part of interact with dietary fat and fenofibrate to change triglyceride and cholesterol levels," said Donna Arnett, dean of the U.K. College of Public Health and the GOLDN principal investigator. "Armed with this knowledge, we will be one step closer to finding new ways to prevent and/or treat unhealthy triglyceride and cholesterol levels."

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