New Cholesterol Disorder Discovered – As Predicted From Gene's Role

Discovery of the disorder started from a deduction: Researchers knew the gene's function, so they hypothesized how mutations would affect cholesterol levels, vulnerability to gallstones and other factors. They then searched a genetic database of some 12,000 patients and identified a number of people who had mutations in that gene. They studied the family of one patient and found that carriers of mutations in the gene did indeed have elevated cholesterol, including three siblings with dangerously elevated levels.

"We went from a hypothesis to identifying the disorder in patients, rather than the more conventional route of seeing a disorder in patients and searching for the cause," said John Kane, MD, PhD, UCSF professor of medicine and senior author of a report on the findings in the July issue of The Journal of Clinical Investigation.

"Our finding adds to the roster of genes that can cause a disorder of cholesterol in the blood and increase the risk of heart disease and stroke," Kane said. "By understanding the mechanism – how this gene affects cholesterol regulation– we can diagnose those at risk earlier and choose better treatments for them."

The research is highlighted in an accompanying editorial in the journal by scientists from the Gladstone Institute of Cardiovascular Disease, UCSF and UC San Diego.

The discovery is the fifth gene known to cause elevated cholesterol when it is defective. The gene's product is an enzyme called cholesterol 7-alpha hydroxylase (CYP7A1), and it is essential for the normal elimination of cholesterol. The enzyme initiates the primary conversion of cholesterol into bile acids in the liver.

The researchers hypothesized that a mutation that knocked out this gene would lead to an accumulation of cholesterol in the liver as the primary route of converting cholesterol to bile acids is blocked. The liver responds to excessive cholesterol by reducing the amount of receptors available to take up low density lipoprotein, or LDL, -- the "bad" cholesterol – from the blood. A mutation in the gene, they reasoned, would result in an accumulation of LDL.

The team also predicted higher triglyceride levels in the blood as well, because lower bile acid levels are known to lead to greater triglyceride production. Triglycerides, like LDL cholesterol, are major risk factors in atherosclerosis and other arterial disease. The scientists also predicted the presence of gallstones because inadequate bile acid levels would allow the cholesterol to crystallize into gallstones.

When the team identified their candidate patients, all their predictions were confirmed. Their search utilized a repository of DNA samples from more than 12,000 patients, along with their blood samples and clinical data which make up the Genomic Resource in Atherosclerosis of the UCSF Cardiovascular Research Institute (CVRI).

The team predicted the clinical effects of having a mutated CYP7A1 gene and then identified several hundred people who fit the profile. Using a sensitive technique to search for mutations in the DNA of these people, they found mutations in 11 people. Of 37 people in the family of one patient, nine carried the same mutation. Three were siblings with defects in both their maternal and paternal copies of the gene. Their cholesterol levels were above 300 mg/dl -- nearly d