A team from NewYork-Presbyterian Hospital/Weill Cornell Medical Center reports that it has figured out why statins work for some people but not for all. Consequently, the researchers believe that their findings also explain why some people on statins are protected against colorectal cancer.
The study is published in the May issue of Cancer Prevention Research. The research team also included scientists from the University of Michigan Medical School, University of Barcelona, NCI, and the Israel Institute of Technology.
The researchers set out to test their hypothesis that people who don't respond well to the cholesterol-lowering ability of statins also do not benefit from the recently documented protective effects of statins against colorectal cancer. They believed that the difference was in genetic variations that led to a different response to the drug.
They genotyped 40 candidate genes known to be important for synthesis and metabolism of cholesterol in participants of a case-control colorectal cancer study in northern Israel. Included in the 40 genes were six SNPs within the HMGCR gene, which produces a critical enzyme involved in formation of cholesterol. The study's co-lead author, Steven M. Lipkin, M.D., Ph.D., believes that most statins on the market work by binding to the HMGCR protein.
The study involved 1,780 colon cancer patients and 1,863 people who did not have colorectal cancer. Many of the participants, who were predominantly Caucasian, had used either simvastatin or pravastatin for a long time.
The scientists initially 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 compared with people who had a "T" variant. 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, with levels varying between that seen for A/A and T/T genotypes.
The investigators then tested, in laboratory colorectal cancer cells, why the T allele might not work well with statins. They found that the protein produced by this HMGCR gene variant does not bind on the statin like the A allele does due to alternative splicing.
"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 colorectal cancer risk reduction associated with long-term use,” explains Dr. Lipkin. “That is especially true if a person has two A alleles.
“Carriers of the T allele are less sensitive to statins because they are missing part of the protein that binds to statins. A protective effect against colorectal cancer development is largely absent from people who have two T alleles.
"Together, these studies provide strong evidence that these two alleles play an important role in modulation of HMGCR activity for colorectal risk reduction,” Dr. Lipkin says. "We anticipate that genotyping for these alleles in patients may help identify those who are most likely to benefit from statins and spare others who will not respond from any side effects of the drugs."