Dr. Michael Gotthardt and his co-workers at the Max Delbr ck Center for Molecular Medicine (MDC) Berlin-Buch, Germany, together with Professor Hendrikus Granzier from Washington State University in Pullman, USA, have been able to demonstrate that an elastic region of titin, N2B for short, is responsible for this filling process during the relaxing phase of the cardiac cycle, the diastole. The findings of the researchers in Berlin and Pullman have now been published in the Proceedings of the National Academy of Sciences (PNAS).

N2B is only present in cardiac titin and helps adjust the diastole to the heart rate. For example during physical exercise with an increased heart rate, there is less time for the heart muscle to relax and provide enough blood for the next heartbeat, unless the elastic properties of the heart change. Modulating titin based elasticity thus allows the adequate filling of the heart.

To be able to investigate the function of N2B in the heart muscle, the researchers created a knockout model that lacks only this region of the titin-gene. This results in expression of a shorter titin protein with a reduced heart size, and limited filling capacity. A healthy heart compensates such an insufficiency, by beating either faster or stronger. However, without N2B, the elastic properties and consequently relaxation of the heart muscle are disturbed. It is this malfunction that eventually leads to the development of heart disease.

Comprised of almost 30,000 building blocks (amino acids), titin is the biggest protein in humans. Found in the heart and skeletal muscle, it is an important part of the smallest mechanical unit of the muscle, the sarcomere. Only recently, Dr. Gotthardt and his collaborators where able to demonstrate that titin is involved in the contraction of muscles and the related signalling processes.

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Future studies will also investigate the biology of how variation in this gene may protect against the disease. The protein produced by the CASP8 gene participates in programmed cell death, or apoptosis, a defense mechanism that allows cells to commit suicide rather than develop into a tumor. DNA damage can trigger apoptosis, and one hypothesis is that the CASP8 SNP may enhance the body's ability to clear cancerous cells from the body and thereby lower the risk of breast cancer.

While mutations in some genes such as BRCA1 have previously been linked to cancer risk, the genetic variation found in the CASP8 gene is the first common variant to be definitively associated with breast cancer risk. In addition to this variant, the study found some support for an association with breast cancer risk for a variant in the gene TGFB1(Transforming Growth Factor Beta 1). Numerous other variants are likely to be identified in the coming years from genome-wide association studies, said Jeffery P. Struewing, M.D., senior investigator in the Laboratory of Population Genetics at NCI's Center for Cancer Research and a coauthor of the current study.

Effective strategies for finding variants in genes that contribute modestly to breast cancer risk are needed. Mutations in genes such as BRCA1 or BRCA2 account for less than 25 percent of the excess familial risk of breast cancer. Much of the remaining variation in genetic risk is likely to be explained by the cumulative effect of multiple variants in genes that individually confer relatively small amounts of risk.

"The SNPs in CASP8, and perhaps in TGFB1, are the first examples of such variants," said Douglas F. Easton, Ph.D. of Cancer Research United Kingdom Genetic Epidemiology Unit, one of the leaders of the BCAC. "Given that only a small number of genes have been investigated in this depth, the results suggest that large numbers of breast cancer susceptibility variants will eventually be found."

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