New cholesterol disorder discovered As predicted from g...( ation that knocked out this gene would ...)

ation 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 double their family's average, putting them at extreme risk for coronary heart disease. Two of the three brothers had elevated triglycerides and premature gallstone disease, as predicted.

Even family members with a mutation in just one of the two copies of the gene had significantly elevated cholesterol levels, the scientists f
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Contact: Wallace Ravven
wravven@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
26-Jun-2002

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