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Research links genetic mutations to lupus

WINSTON-SALEM, N.C. – A gene discovered by scientists at Wake Forest University School of Medicine has been linked to lupus and related autoimmune diseases. The finding, reported in the current issue of Nature Genetics, is the latest in a series of revelations that shed new light on what goes wrong in human cells to cause the diseases.

“This research is a huge leap toward understanding the cause of lupus and related autoimmune diseases,” said Fred Perrino, Ph.D., a co-author on the paper and a professor of biochemistry at Wake Forest. “There had been few clues before now.”

Perrino, who discovered the gene in 1998, said he suspected it was involved in human disease, but it took a group of researchers from around the world collaborating to put the puzzle together.

“We’ve known that lupus was a complex disease, but now we have a specific protein and a particular cellular process that appears to be one of the causes,” said Perrino. “We’re connecting the dots to understand the biology of what’s going on with the disease.”

In Nature Genetics, lead author Min Ae Lee-Kirsch, M.D., from the Technische Universität Dresden in Dresden, Germany, and colleagues report finding variations of the TREX1 gene discovered by Perrino in patients with systemic lupus erythematosus. The study involved 417 lupus patients from the United Kingdom and Germany. Mutations were found in nine patients with lupus and were absent in 1,712 people without lupus.

“Our data identify a stronger risk for developing lupus in patients that carry variants of the gene,” said Lee-Kirsch.

In recent years, the gene was also linked to Aicardi-Goutieres syndrome, a rare neurological disease that causes death in infants, and to chilblain lupus, an inherited disease associated with painful bluish-red skin lesions that occur during cold weather and usually improve in summer. The current research also links it to Sjogren’s syndrome, a form of lupus.

The diseases are all autoimmuine diseases, which means that the body makes antibodies against itself. In lupus, these antibodies cause pain and inflammation in various parts of the body, including the skin, joints, heart, lungs, blood, kidneys and brain. The disease is characterized by pain, heat, redness, swelling and loss of function.

Perrino began studying the protein made by the gene more than 14 years ago.

“We basically cracked open cells to locate the protein and find the gene,” said Perrino. “In the 14 years since, we’ve learned a lot about the protein and how it functions.”

The gene manufactures a protein, also known as TREX1, whose function is to “disassemble” or “unravel” DNA, the strand of genetic material that controls processes within cells. The “unraveling” occurs during the natural process of cells dying and being replaced by new cells. If a cell’s DNA isn’t degraded or unraveled during cell death, the body develops antibodies against it.

“If the TREX1 protein isn’t working to disassemble the DNA, you make antibodies to your own DNA and can end up with a disease like lupus,” said Perrino.

Perrino and colleagues at Wake Forest have been studying the gene and its protein since 1993. Thomas Hollis, Ph.D., an assistant professor of biochemistry at Wake Forest, is credited with solving the structure of both TREX1 and a similar protein, TREX2. Perrino has also developed a way to measure the function of the proteins.

In a study reported in April in the Journal of Biological Chemistry, Hollis and Perrino found that three variations of the gene reduced the activity of the protein by four- to 35,000-fold.

“Now that we have the structure, we can understand how it disassembles DNA and how mutations in the gene may affect that process,” said Hollis.

The researchers hope that understanding more about the gene’s mutations and the structure of the protein may lead to drug treatments to help ensure that mutant copies of the gene are inactive.

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Media Contacts: Karen Richardson, krchrdsn@wfubmc.edu; Shannon Koontz, shkoontz@wfubmc.edu; at 336-716-4587.

Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university’s School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in primary care and 44th in research among the nation’s medical schools. It ranks 35th in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.

Contact: Karen Richardson
krchrdsn@wfubmc.edu
336-716-4453
Wake Forest University Baptist Medical Center

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July 29, 2007 Posted by | Alberta, Baltimore, Barcelona, Bethesda, Biological Sciences, Calgary, Canada, Clinical Trials, France, Genes, Genetic, Genetic Link, Genetic Marker C allele of rs10505477, Genetics, Genome, Genomic, Global, Global Health Vision, Global News, Health Canada, Human Genome, Italy, Japan, Lupus, Nature Genetics, Newfoundland, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, NIH, Nova Scotia, Nunavut, Osaka, Ottawa, Prince Edward Island, Public Health, Quebec, Research, RSS, RSS Feed, Slovakia, Spain, Toronto, UK, US, Virginia, Wake Forest University Baptist Medical Center, WASHINGTON, Washington DC, Washington DC City Feed, World Health Organisation, World News | 1 Comment

U-M, Israeli scientists report major advance in search for genes associated with colon cancer

Contact: Nicole Fawcett
nfawcett@umich.edu
734-764-2220
University of Michigan Health System

Single variation on chromosome 8 may account for sizable percentage of cases
ANN ARBOR, Mich. – A 10-year study involving thousands of Israeli Jews and Arabs, led by researchers from American and Israeli institutions, has yielded important new information in the search for the genes that make a person more likely to develop colon cancer.

In a paper to be published in the July issue of Cancer Biology and Therapy, the international research team reports finding a significant link between genetic variation in a single region of human chromosome 8 and the risk of colorectal cancer.

The link was found by detailed comparisons of genetic material from thousands of colon cancer patients and non-patients, and by evaluating the incidence of colon cancer among the immediate family members of colon cancer patients.

In all, people who carry the specific genetic variation, called a marker, were found to be 23 percent more likely to have colon cancer than individuals without the marker. The researchers estimate that this single genetic variation might account for 14 percent of colorectal cancer cases in Israel, where colon cancer is the leading cause of cancer deaths. The specific marker is called the C allele of rs10505477.

Three other research teams are reporting similar findings today in the journal Nature Genetics, having simultaneously found their way to the same small area of chromosome 8, called 8q24, in the search for colon cancer genetic links. The fact that these studies were performed among other populations around the world suggests that this one genetic marker is highly influential across ethnic groups.

The new Cancer Biology and Therapy paper is by an international group of scientists from the University of Michigan Medical School and U-M School of Public Health, the Catalan Institute of Oncology in Spain, the CHS National Israeli Cancer Control Center and Technion – the Israel Institute of Technology.

It’s the product of an ongoing Michigan-Israel collaboration, the Molecular Epidemiology of Colorectal Cancer project, which for 10 years has searched for clues to colon cancer’s genetic roots using samples from large numbers of people in Israel with known ancestral heritage. The project is funded by the National Cancer Institute, with additional funding from the Irving Weinstein Foundation.

The researchers compared the genetic makeup and family history of more than 1,800 colorectal cancer patients with that of 1,900 healthy people with the same breakdown of age, gender and ethnicity – either Ashkenazi Jew, Sephardic Jew or Arab/non-Jew. Samples of tumor tissue from many cancer patients were also tested. The genetic link between the marker and colon cancer was especially strong among patients diagnosed with colon cancer at a young age, under 50 years.

Stephen Gruber, M.D., Ph.D., the co-leader of the Michigan-Israeli team and first author of the new paper, says that the new finding is particularly interesting when considered alongside recent discoveries in the genetics of prostate and breast cancer.

“The same genetic region that predisposes to colon cancer has also recently been shown to be an important region predisposing to breast cancer and prostate cancer,” he says. “The specific genetic cause for this joint susceptibility to three different cancers has not yet been discovered, but several groups are working to close in on the mechanism that might cause these cancers.”

Gruber is an associate professor of internal medicine and of human genetics in the U-M Medical School, and of epidemiology in the U-M School of Public Health. He directs the Cancer Genetics program in the U-M Comprehensive Cancer Center, which focuses on inherited cancer risks.

Genetic discovery in Israel through MECC has already proven highly informative. Senior author Gad Rennert M.D., Ph.D., of the Carmel Medical Center and the B. Rappaport Faculty of Medicine at Technion in Haifa, Israel, says “The study of populations in Israel has been shown to be exceptionally fruitful in contributing to knowledge about the genetics of leading cancers. This is due to the unique characteristics of the population and our ability to study it in a representative manner.”

Unraveling the mysteries of the susceptibility to disease is moving rapidly since the publication of the complete sequence of the human genome in 2003. Says Gruber, “The mystery of the relationship between our genetic code and disease is now starting to become clear, and many scientists are turning to the same chapter to find important clues to colorectal cancer.” He and his colleagues plan to continue their effort to zero in on the genetic variations involved in cancer.

While there is not yet a screening test for the genetic variation that was pinpointed in the study, Gruber and his co-authors emphasize that genetic testing is available for other known genetic variations linked to colorectal cancer. People with a strong family history of colon cancer, especially cases that began when relatives were younger than age 50, should get genetic counseling and have colonoscopies or other screening tests starting earlier in life than age 50.

“Colon cancer is one of the most common cancers in the United States, and the good news is that it’s largely preventable with early screening,” says Gruber. The American Cancer Society estimates that some 150,000 new cases of colon cancer will be diagnosed in 2007, and more than 50,000 deaths from colorectal cancer will occur.

Although most cancers are not “inherited,” some families are particularly susceptible to cancer and may benefit from early detection or other risk reduction strategies. People concerned about a family history of cancer, or those who have been diagnosed with colon cancer before age 50 or after having two or more relatives diagnosed with the disease, should talk to their doctor about the possible benefits of genetic counseling, Gruber says. Counseling can be done for both patients and family members.

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In addition to Gruber and Rennert, the new paper’s co-authors are Victor Moreno of U-M and the Catalan Institute of Oncology in Spain, Laura S. Rozek of U-M Hematology/Oncology, Hedy Rennert and Flavio Lejbkowicz of CHS National Cancer Control Center and Technion, Joseph D. Bonner, formerly of U-M and now at Michigan State University, and Joel K. Greenson, Thomas J. Giordano and Eric R. Fearon of the U-M Department of Pathology.

For more information, contact:

Nicole Fawcett
nfawcett@umich.edu

Kara Gavin
kegavin@umich.edu
734-764-2220

For more information on colon cancer, genetic counseling for cancer and colonoscopy, call the U-M Cancer AnswerLine toll-free at 800-865-1125 or visit http://www.mcancer.org.

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July 8, 2007 Posted by | Ancestral Heritage, B. Rappaport Faculty of Medicine at Technion in Haifa, Bethesda, Calgary, Cancer, Cancer Biology and Therapy, Catalan Institute of Oncology in Spain, Chromosome 8, CHS National Cancer Control Center and Technion, CHS National Israeli Cancer Control Center, Genetic Marker C allele of rs10505477, Irving Weinstein Foundation, journal Nature Genetics, Molecular Epidemiology, National Cancer Institute, the Israel Institute of Technology | 2 Comments