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Research team discovers genetic variance in cancer protection from statin drugs
Date:4/21/2010

40 candidate genes known to be important for synthesis and metabolism of cholesterol in people who participated in a population case-control study of colorectal cancer in northern Israel. Included were 1,780 colon cancer patients and 1,863 people who did not have colorectal cancer, and many of the participants, who were predominantly Caucasian, had used statins for a long time. In the initial study, statin use was associated with a 50 percent relative risk of developing colorectal cancer in this population.

Included in the 40 genes were six SNPs, or DNA sequences, within the HMGCR gene, which produces a critical enzyme involved in formation of cholesterol.

They found one SNP within HMGCR that was associated with statin protection against colorectal cancer. A follow-up pharmacogenetic analysis showed that the protective association was significantly stronger among individuals with what they dubbed the "A" SNP allele, or variant, compared with people who had a "T" variant. Because a person inherits two variants, one from each parent, the stronger colorectal cancer protection came from individuals with the A/A HMGCR genotype, compared with those with the T/T genotype. Individuals with an A/T genotype had intermediate protection against colorectal cancer -- levels that varied between that seen for A/A and T/T genotypes.

Dr. Lipkin estimates that, in this Caucasian population, 56 percent had at least one A allele in that HMGCR genomic position.

They then tested, in laboratory colorectal cancer cells, why the T allele might not work well with statins, and found that the protein produced by this HMGCR gene variant does not bind on to the statin like the A allele does, due to "alternative splicing" -- the production of a protein that is slightly altered.

"Carriers of the A allele express more of the full-length protein that binds statins, and are therefore more sensitive to statins and are more likely to experience the colorect
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Contact: Andrew Klein
ank2017@med.cornell.edu
212-821-0560
New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College
Source:Eurekalert

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