The cholesterol drug statin could protect many against colorectal cancer too, but Caucasians are out of its reach. A gene variant in them somehow renders them impervious to statin effect, as many as 44 per cent of them in a recent study.
In the May issue of Cancer Prevention Research, researchers at NewYork-Presbyterian Hospital/Weill Cornell Medical Center say this finding might help personalize the use of statins, both by offering patients a test to determine if they have the "right" gene to benefit from current statin drugs, and by providing insight into how to create a new class of statins for those who have the "wrong" gene profile.
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The other lead author is Dr. Stephen B. Gruber, professor of internal medicine, epidemiology and human genetics at the University of Michigan Medical School. The research team also includes scientists from the University of Barcelona, the National Cancer Institute and the Israel Institute of Technology.
The researchers tested their hypothesis that people who don't respond well to the cholesterol-lowering ability of statins also do not benefit from recently documented protective effects of statins against colorectal cancer, and that the difference was in genetic variation that led to a different response to the drug.
In this study, the research team genotyped 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.
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Dr. Lipkin estimates that, in this Caucasian population, 56 percent had at least one A allele in that HMGCR genomic position.
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Statins Offer No Protection Against Colorectal Adenoma
Statins did not protect patients against colorectal adenomas, which are benign precursors of colorectal cancer, according to results of a secondary analysis of the
Statins did not protect patients against colorectal adenomas, which are benign precursors of colorectal cancer, according to results of a secondary analysis of the
"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. That is especially true if a person has two A alleles," says Dr. Lipkin. "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."
Dr. Lipkin believes most of the many statin drugs on the market work by binding on to the HMGCR protein. Most of the participants in this study used simvastatin (marketed under the trade names Zocor, Simlup, Simcard, Simvacor, and others), and pravastatin (marketed as Pravachol or Selektine).
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