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January 2007 Posts
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Minnesota Gene Pool Blog

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January 31, 2007

Half of Americans Have Gene That Affects How Body Burns Sugar

This is a very interesting report. FABP2 is the gene for fatty acid binding protein 2 and a variant of this gene is associated with the increased risk for diabetes in Pima Indians. What this finding might mean at the population level is unclear at this point. It will aid in understanding more completely one pathway that leads to diabetes. It also may help us better understand why different people who look a lot alike on paper have different actual risks for developing insulin resistance and diabetes.

Here is link to the PubMed abstract

ST. LOUIS -- A recent study by a Saint Louis University researcher confirms findings that about half of the U.S. population has a version of a gene that causes them to metabolize food differently, putting them at greater risk of developing diabetes.

Edward Weiss, Ph.D., assistant professor of nutrition and dietetics at Doisy College of Health Sciences at Saint Louis University, looked at a relatively common version of a gene called FABP2, which is involved in the absorption of fat from food.

Those people with the variant gene processed fat differently than those who don't have it. They burned more fat, which may have hindered their ability to remove sugar from the blood stream and burn it. Diabetes is characterized by too much sugar in the blood.

"This study adds to what was previously known about this gene variant by showing that after consuming a very rich milkshake, people with the variant gene process the fat from the drink differently than other people," Weiss says.

That is not to say that half of U.S. residents are destined to get diabetes, he adds.

"While the variation of the gene appears to contribute to the diabetes risk, it does not cause diabetes by itself," Weiss says. "Many other genes, some known and some unknown, are involved in a person?s overall risk of developing diabetes. Those are things a person can?t control. But there are risk factors for diabetes that a person can change -- lifestyle factors, such as diet and exercise."

The study was published in the January issue of the American Journal of Clinical Nutrition.

Mental Abilities: Folic Acid May Improve Thinking Skills

Folic acid really IS the WD40 of biology. Now there is evidence that it can help us think better, as well.

Too Young for This: Facing Cancer Under 40

The New York Times reports today on the unique issues faced by people who are diagnosed with cancer in their young adult years. The number of people with cancer in their young adult years is trending upward and nobody really knows why or whether or not the treatments that are available for children and older adults with cancer are best for this population. Researchers and care providers suspect that both genetics and environmental factors are involved, but nobody knows for sure. Many of the young people who are diagnosed with cancer do not have a family history, but some do and this may be one important clue that would be a red flag, at least in some cases. Also, since no one expects cancer to occur in younger people, when the diagnosis is made, it is often at a later stage. In addition, it is not clear that cancer that occurs in young adults is the same disease as the cancer that is diagnosed in older patients. Whatever the particular situation might be, everyone agrees that we need to fill the gaps in our knowledge, there needs to be greater awareness amongst care providers and the public about this trend, and there needs to be more and better services and systems in place to meet the particular needs--many of which are psychosocial--of this group of cancer survivors.

So, what is the role for public health in this? Clearly, public health has a role in identify and characterize cases, do the population-based surveillance that may help identify the factors in the genome and in the environment are involved. Also, those who are looking at genes and those who are looking at environmental factors need to be talking to each other and integrating the knowledge that comes from both approaches because it is likely that it is at the point of interaction between the two that is responsible for this worrisome trend.

Public Health also has a role to educate the public and providers about this growing trend, encouraging doctors to consider placing cancer higher in the list of differential diagnoses. Even though a diagnosis of cancer may be the least likely situation, the consequences for the patient may be so grave that it may be appropriate to definitively rule out this situation, if at all possible. Public Health can have a role in collecting the perspectives of stakeholders in the medical and cancer survivor communities, along with data on the true prevalence of cancer in young adults and the cost / benefit ratios of such approaches to assure that our systems and providers have the evidence and tools they need to address this for the better health of their patients and the population as a whole.

More nformation on cancer in young adults can be found in a recent report that has been released by the National Cancer Institute and the Lance Armstrong Foundation last August.

January 20, 2007

Genetic signature predicts recurrence of breast, prostate and other cancers, Stanford researchers find

Researchers have discovered a pattern of expresson in 186 genes that predict the recurrence of malignancy for several types of cancer. The importance of this work is that it may lead to a test to help guide treatment for people with cancer and also be important in a more complete understanding of cancer biology. The next step is to learn how to integrate this new knowledge into determining what treatments would be most appropriate. There are many reports about genes associated with disease, but this finding may be a true breakthrough for cancer treatment and follow up for cancer surviors. The results are published in the January 18 issue of the New England of Medicine.

1/17/07 -- STANFORD, Calif. — Researchers working with breast cancer stem cells at the Stanford University School of Medicine have found 186 genes that together can predict the risk of recurrence in breast cancer patients.

Additionally, the same genes predict the recurrence of prostate cancer, lung cancer and medulloblastoma, the most common form of childhood brain cancer.

“These data suggest that there are some fundamental properties of the malignancy that are shared between many types of tumors,? said Michael Clarke, MD, the Karel H. and Avice N. Beekhuis Professor in Cancer Biology. He is the lead author of the study, which is published in the Jan. 18 issue of the New England Journal of Medicine.

Clarke and his colleagues also found they could predict aggressive cancers with even greater accuracy when they combined the 186-gene signature with another previously identified group of genes in the cells surrounding the tumor.

Stanford scientists say the findings are a significant step toward using insights from cancer stem cell research to develop better tools for diagnosing and treating the disease.

“This paper demonstrates, for the first time, the clinical value of isolating pure human cancer stem cells,? said Irving Weissman, MD, director of the Stanford Institute for Stem Cell Biology and Medicine, who was not involved in the study. “Mike Clarke and his colleagues have now shown that the human breast cancer stem cell reveals information not evident when the whole tumor is analyzed. We plan to incorporate these findings in our approaches to the care of cancer patients, starting here at Stanford.?

Clarke has already begun working with surgeons to help translate these findings into tools that will help doctors zero in on the best treatment for individual cancer patients. For instance, he hopes that within five years a surgeon would be able to leave more breast tissue intact in a patient whose genetic profile showed that her tumor was unlikely to return. Likewise, a woman at high risk of relapse would get more aggressive treatment.

Frederick Dirbas, MD, an assistant professor of surgery at Stanford who was not involved in the study, said results such as these could have significant benefit to patients. “This work should lead to new opportunities for more accurate care of the individual patient,? he said.

Cancer stem cells are believed to be the cells that continually replenish cancer, like the spring at the source of a creek. Although other cancer cells can damage the body through sheer bulk, they can’t form new cancers.

Clarke found the first cancer stem cell in a solid tumor in 2003 while at the University of Michigan. Until he found the deadly cells in breast cancer, researchers had thought they might be restricted to blood cancers. Since then, other researchers have found the cells in brain and prostate cancer. Just this month Mark Prince, MD, an assistant professor at the University of Michigan, working with Stanford researchers including Clarke, Weissman and Laurie Ailles, PhD, reported finding cancer stem cells in head and neck cancers.

Clarke’s newest breast cancer study isn’t the first to identify a group of genes that can predict the risk of cancer recurrence. However, he said these genes are particularly effective at flagging risky cancers, especially when combined with a second group of genes originally identified by a team led by Patrick Brown, PhD, professor of biochemistry. These genes are active in the normal cells surrounding the tumor, called the stroma.

In essence, combining the two gene profiles is like examining both the soil (the stroma) and the seed (the cancer stem cells) to find out if the combination is likely to produce a tumor that can recur. Clarke said the finding shows that malignancy is the result of an interaction between the cancer cells in the tumor and the environment, as many researchers had previously surmised.

Although Clarke and his team identified the genetic pattern in breast cancer stem cells taken from tumors, they verified the results in a standard tumor biopsy containing a range of cell types. That same biopsy can also remove the stromal cells that are needed for the second genetic profile.

Over time, Clarke said, researchers will likely be able to refine the list of genes needed to most accurately determine a patient's risk of recurrence. A smaller list of genes could make a genetic profiling test more cost-effective for widespread use.

This work was supported by grants from the National Cancer Institute, the Breast Cancer Research Foundation and the Virginia and D.K. Ludwig Foundation.

Other Stanford researchers who contributed to this work include Piero Dalerba, MD, postdoctoral scholar, and Gavin Sherlock, PhD, assistant professor of genetics.


Norman Borlaug, Super Hero

Dr. Borlaug received a Nobel Prize in 1970 for his work in developing crops that would maximize food production across the globe. He did this through the classical approach of selective breeding of various grain species. He is credited with saving the lives of a billion people through his efforts.

See below this short clip on this truly great man to whom so much is owed and who is virtually unknown.

Thought to ponder: Are genetically modified crops always bad? Feel free to comment. The whole area of genetically modifying plants and animals is controversial for lots of reasons. Is it acceptable under any circumstances? If so, what might those be? If not, why not? What regulation needs to be in place to make the benefit worth the risk? What is the role for public health researchers and practitioners?

January 18, 2007

AHRQ Report on the use of CYP450 genetic tests in prescribing SSRI's in treating depression

The Agency for Healthcare Research and Quality (AHRQ) and the Centers for Disease Control and Prevention's (CDC) National Office of Public Health Genomics (NOPHG) have released a report examining the evidence for using Cytochrome P450 tests in prescribing selective serotonin reuptake inhibitors (SSRIs) for adults with depression.

The findings of this report are that there is insufficient information to support the use of this testing in clinical practice and that more well designed studies are needed to determine the clinical value for patients and the impact on outcomes. The process for producing this report is based on an exhaustive review of the literature to assess the evidence for analytical validity, clinical validity and clinical utility of the tests. Ethical, legal and social implications related to testing are also included in the assessment. The full report is available online. A news release that summarizes the major findings is also available.

Race: Are we so different?

Race is something that affects all of us, both in how we see ourselves and how we see each other. Race and genetics intersect in ways that are sometimes misunderstood. It is a fact that all of us are 99.99% the same at the DNA level, yet we also understand that there are genetic susceptibilities and even some genetically caused diseases that are much more common in people of one race than another. Cystic fibrosis is such a condition, being much more common in northern Europeans than in other racial groups. How do we sort it all out?

The Science Museum of Minnesota has the world premiere exhibit that explores the meanings and ramifications of race in peoples lives and their relationship with others. The exhibit opened on January 10 and will run through May 6, 2007.

If you go, please post a comment on what you learned and thought of the experience.

January 17, 2007

Researchers find a common genetic risk factor for Parkinson's disease in Asians

Genetics is helping us begin to understand Parkinson Disease as well. Researchers from the Mayo Clinic in Jacksonville, Florida and Taiwan are reporting that they have discovered a particular variant of the LRRK2 gene that is associated with a two fold increased risk of developing Parkinson Disease. Like so many of these genetic associations, the presence of this variant is apparently not sufficient to cause this disease since many people who have the variant never develop Parkinson's and there are also people who have Parkinson's and do not have the gene. According to author Dr. Ruey-Meei Wu:

The G2385R mutation was first discovered in 2004 by Mayo and Taiwanese researchers in a family of ethnic Chinese decent. One of the study authors, Ruey-Meei Wu, M.D., Ph.D., and her group in Taiwan, went on to find the G2385R mutation in just over 22 percent of familial Parkinson's disease cases. "The findings that the frequency of LRRK2 G2385R is observed at 8 percent within ethnic Chinese patients, 4 percent in control subjects and 22 percent in familial patients strongly suggests the G2385R variant is an important genetic risk factor in the ethnic Chinese population," Dr. Wu says.

The full new release is below

Researchers find a common genetic risk factor for Parkinson's disease in Asians

JACKSONVILLE, Fla. -- January 16, 2007 -- Researchers at Mayo Clinic in Jacksonville, Fla. and the National Taiwan University Hospital in Taipei, Taiwan have discovered what to date appears to be the most common genetic risk factor for Parkinson's disease worldwide.

They believe the majority of people carrying this genetic mutation descend from a common ancestor about 4800 years ago. Their study was published Jan. 9 in the online edition of Parkinsonism and Related Disorders.

Researchers found that ethnic Chinese individuals carrying a mutation they identified in the LRRK2 gene are over two times more likely to develop the disease than non-carriers. Given the population of China and the number of ethnic Chinese worldwide, this mutation may predispose more people to developing Parkinson's disease than any other genetic factor. However, researchers say not everyone with the mutation develops the disease, and in those that do, other genetic and environmental factors are probably in play.

Mayo Clinic neuroscientist Matthew Farrer, Ph.D., lead author on the study, says this discovery is a small part of the ongoing genetic revolution in medicine. "Seemingly sporadic Parkinson's disease may be a familial disorder, and we're finding that the genetic risk factors for Parkinson's disease are population specific," he says.

In 2004 Mayo Clinic researchers were part of a team that discovered the LRRK2 gene and its role in Parkinson's disease. This group and others went on to find a number of mutations in LRRK2, a gene that codes for a poorly understood protein, leucine-rich repeat kinase 2. One of the mutations, G2019S, has been shown to cause Parkinson's disease in people with and without a family history of the disease. G2019S is an especially common cause of Parkinson's disease in Berber Arabs and Ashkenazi Jews.

However, in contrast to the G2019S mutation, which is considered a disease causing mutation because it is rarely found in healthy, elderly people without Parkinson's disease, the newly researched G2385R mutation, the subject of this study, does not always lead to disease. It is found in approximately 4 percent of the ethnic Chinese population without Parkinson's disease, which is why researchers consider it a risk factor rather than a causal mutation.

The G2385R mutation was first discovered in 2004 by Mayo and Taiwanese researchers in a family of ethnic Chinese decent. One of the study authors, Ruey-Meei Wu, M.D., Ph.D., and her group in Taiwan, went on to find the G2385R mutation in just over 22 percent of familial Parkinson's disease cases. "The findings that the frequency of LRRK2 G2385R is observed at 8 percent within ethnic Chinese patients, 4 percent in control subjects and 22 percent in familial patients strongly suggests the G2385R variant is an important genetic risk factor in the ethnic Chinese population," Dr. Wu says.

Due to these findings, Wu says it will be important to look at subtle signs of disease in asymptomatic carriers for clues about the mutation's penetrance, meaning the extent to which symptoms associated with disease will occur. "We can also evaluate the effect of neuroprotection in these carriers in a long-term follow up study," Wu says. "Epidemiology studies looking for other environmental risk factors and their interaction with genetic risk factors will provide clues to prevent the occurrence of this chronic and disabling disease in the future."

Other research groups also have found the G2385R mutation is at a higher frequency in Asian patients with Parkinson's disease, than in matched control subjects. These types of case and control genetic studies provide a powerful tool for researchers to find disease genes and risk factors in homogeneous or isolated populations where there has been little immigration.

Interestingly, the present paper's authors found evidence to suggest G2385R carriers share a common ancestor. They performed a genetic analysis looking at the inheritance pattern of a specific DNA sequence along chromosome 12 that includes the LRRK2 gene.

Examining known genetic markers, which are short stretches of repeated DNA subject to variation in the number of times they repeat, their analysis showed a unique pattern of these DNA sequence markers is almost always passed from generation to generation along with the G2385R variant.

Researchers used genetic theory to estimate the level of variation at these genetic markers between carriers and healthy non-carriers, and used that data along with the genetic distance the markers are away from the LRRK2 gene to estimate how many generations have been passing on this unique stretch of DNA. Their analysis concluded that the G2385R mutation arose approximately 4,800 years ago, corresponding with the rise of Chinese civilization and the reign of Yellow Emperor Huang Di, credited with inventing traditional Chinese medicine.

This mutation does not appear to play a role in Parkinson's disease within other racial groups. Studies to date have failed to find the mutation in Caucasian populations. Farrer says therapeutic interventions focused on LRRK2 will be very important to develop given the global population affected by all the LRRK2 mutations.

Another study author, Mayo Clinic neuroscientist Owen A. Ross, Ph.D., says although the group's findings point toward one of the most important genetic risk factor for Parkinson's disease, he agrees with Wu that there is still much to understand about which carriers will develop the disease and at what age their symptoms begin. "There are going to be other significant disease modifiers," he says. "The age of onset for disease is variable in G2385R carriers and for LRRK2-parkinsonism in general. Not only may there be environmental factors, but also other genetic factors acting on this genomic background which determines disease presentation."

As the G2385R mutation dates so far back and is now so prevalent; researchers have an opportunity to assess thousands of carriers and treat them as members of one distantly related family in order to find other genetic and environmental factors that act with G2385R to trigger Parkinson's disease.

The study was supported by Mayo Clinic's National Institute of Neurological Disorders and Stroke Morris K. Udall Center of Excellence for Parkinson's Disease Research and the Taiwan National Science Council.

Authors on the paper are: Matthew J. Farrer; Jeremy T. Stone; Justus C. Dachsel; Mary M. Hulihan; Kristoffer Haugarvoll; and Owen A. Ross from the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA; Chin-Hsien Lin; and Ruey-Meei Wu from the Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.


Another major gene variant that predisposes to Alzheimer disease in several different ethnic groups

Alzheimer disease is one of the most difficult common diagnoses that can befall a person and their family. Studies identifying genetic links have thus far shed some light into possible mechanisms by which this devastating disease progresses, but has not significantly impacted treatment or prevention. A variant of the gene SORL1 is being reported in Nature Genetics to be associated with Alzheimer Disease.

Money quote from the news release from Columbia University:

“The importance of the finding is that it opens new pathways to explore the cause and as well as potential targets for treatment of this devastating disease,? said Dr. Mayeux. “SORL1 represents another critical piece of the Alzheimer’s disease puzzle. This appears to be the fifth Alzheimer’s disease gene, and there are likely to be other important genetic variants that need to be identified before the entire picture is complete.?

Read the whole news release below.

Findings Replicated in Four Different Ethnic Groups: Caribbean-Hispanics, Northern Europeans, African-Americans & Israeli-Arabs

DNA from 6,000 Volunteers Analyzed in Multi-Center Study

New York (January 14, 2007) -- An international team of researchers, led by Columbia University Medical Center, Boston University School of Medicine and the University of Toronto, has uncovered a major new gene – SORL1 – implicated in late-onset Alzheimer’s disease.

Replicated in four distinct ethnic groups, SORL1 is only the second genetic variant for late-onset Alzheimer’s, the type of Alzheimer’s found in 90 percent of people with this devastating disease. ApoE4, the first, was identified in 1993.

In an article published in the Jan. 14 advance on-line edition of Nature Genetics (February print edition), researchers describe how variants in the SORL1 gene were found to be more common in people with late-onset Alzheimer’s than in healthy people the same age. The authors believe that these genetic variants alter the normal function of SORL1, sending amyloid precursor protein (APP) down a pathway that increases the production of the toxic amyloid beta (Aβ) peptides in the brain resulting in Alzheimer’s. When the SORL1 gene works properly, it sends APP along recycling pathways – preventing it from being cut into toxic Aβ forms.

People with these genetic variants may not produce normal amounts of SORL1, suggesting that this gene has protective function when working properly. The researchers believe that the reduction of SORL1 in the brain increases the likelihood of developing Alzheimer’s disease.

An important aspect of their findings was that the association between Alzheimer’s disease and SORL1 was replicated in four distinct ethnic groups: Caribbean-Hispanics, North Europeans, African-Americans and Israeli-Arabs. Many previous studies on the genetics of Alzheimer’s used data from mostly white populations of American and European ancestry. In total, the five-year federally- and internationally-funded study involved DNA samples from 6,000 volunteers.

The research team at Columbia University Medical Center was led by Richard Mayeux, M.D., co-director of the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain. The team at the University of Toronto was led by Peter St. George-Hyslop, M.D., director of the Centre for Research in Neurodegenerative Diseases, and the Boston University team by Lindsay Farrer, Ph.D., chief of the Genetics Program. Steven Younkin, M.D., Ph.D., chair of Department of Pharmacology at the Mayo Clinic College of Medicine in Jacksonville, Fla. also provided DNA samples from the Mayo’s respective unique populations for the study.

“The importance of the finding is that it opens new pathways to explore the cause and as well as potential targets for treatment of this devastating disease,? said Dr. Mayeux. “SORL1 represents another critical piece of the Alzheimer’s disease puzzle. This appears to be the fifth Alzheimer’s disease gene, and there are likely to be other important genetic variants that need to be identified before the entire picture is complete.?

“Instead of scanning all the genes in the entire genome, we had an idea of what an Alzheimer’s disease-causing gene would look like based on past discoveries,? said Dr. St. George-Hyslop. “We knew that the abnormalities in APP processing and the accumulation of its toxic amyloid beta (Aβ) peptide derivative cause Alzheimer’s, so we hypothesized that other genes associated with APP regulation might also cause the disease.?

Genetic Homogeneity of Dominican Population Informs Discovery

In 1994, Dr. Mayeux noticed, upon studying elderly residents of Washington Heights, a predominantly Hispanic neighborhood in Northern Manhattan where Columbia University Medical Center is located, that Dominicans have about three times the rate of Alzheimer’s disease compared to individuals of different ethnic backgrounds in the community. Dr. Mayeux decided to find out why this population has such a high incidence of Alzheimer’s, so he and his Columbia team began visiting Dominican families living in both Washington Heights and the Dominican Republic to collect blood samples of entire families in order to look for similar gene variations in relatives diagnosed with Alzheimer’s.

“The Dominican population is very concerned about the increased frequency of disease and was very helpful in forming the basis of this study. From a genetic perspective, Dominicans are a relatively homogenous population, and follow similar diet and living patterns,? said Dr. Mayeux. “Because individuals within families stay in touch and remain close to one another even after migrating to the United States, we were able to identify families in this large population that were very similar genetically.?

To confirm their preliminary findings, Drs. Mayeux and St. George-Hyslop, his collaborator of more than 25 years, reached out to other colleagues who tapped genetic records of people of from even more diverse ethnic backgrounds.

In total, the initial discovery group included 350 families (representing a total of 1,800 people, half of whom had Alzheimer’s), from Columbia University Medical Center and the University of Toronto. The group was divided into two parts: one that was analyzed to help with the discovery of SORL1, and a second that was analyzed to confirm the role of the gene. To this collection, Dr. Farrer, from Boston University School of Medicine, added 500 African-American sibling pairs (representing a total of 1,000 people), where one sibling was diagnosed with Alzheimer’s and the other was not. Farrer also enabled the researchers to reconfirm their findings in an examination of data from Israeli-Arabs, while Younkin’s data from mostly white Alzheimer’s patients provided by the Mayo Clinic also confirmed the findings. Interestingly, the same variant was found in both the Israeli-Arab and Caribbean-Hispanic groups, which indicates that generations ago these two groups may have been genetically or geographically linked.

Seeking Pathogenesis of SORL1 & Attributable Risk of SORL1 Variants

“Now that we know that variants in SORL1 are associated with late-onset Alzheimer’s disease and we know the specific regions of the gene involved, our next step is to determine which of the variants contain the specific disease causing alteration,? said Dr. Mayeux.

Another next step is to determine how many cases of late-onset Alzheimer’s are caused by these SORL1 variants; it is known that ApoE4 explains approximately 20 percent of all cases of late-onset Alzheimer’s. Studies are planned to investigate how many Alzheimer’s cases are attributable to SORL1. The hope is that this information will help develop accurate screening for this gene.

Study Funding

This research was funded by the National Institute on Aging of the National Institutes of Health, the Alzheimer’s Association of the United States, the Canadian Institutes of Health Research, Howard Hughes Medical Institute, the Alzheimer Society of Ontario, the Canada Foundation for Innovation, the Ontario Research and Development Challenge Fund, Genome Canada and the Banbury Fund.

Facts about Alzheimer’s Disease

Alzheimer’s disease, which affects 4.5 million Americans, is differentiated as either early-onset or late-onset. The early-onset form is rare and tends to affect those between the ages of 30-60. Most cases of early-onset are genetic, caused by a mutation of the APP gene. The late-onset form is much more common – accounts for 90 percent of all cases of Alzheimer’s – and tends to affect those aged 65 and older. With aging baby boomers, the prevalence of late-onset Alzheimer’s is expected to double in the next 25 years as the population ages.


January 12, 2007

Researchers Identify Gene Associated with Severe Kidney Failure in Diabetes

This is a very interesting report that could have an impact on identifying and intervening with diabetics who are most likely to have kidney failure.

Take home summary:

1. The gene (CNDP1) codes for an enzyme (carnosinase 1) that deactivates a substance (carnosine) that protects the kidneys from scarring. Carnosine is also a free radical scavenger.

2. A variant of the carnosinase gene is associated with lower risk of kidney failure in diabetes and is found in a proportion of Caucasians (Europeans, American whites and Arabs), but not in African Americans. Authors speculate that kidney failure in blacks may be due to differences in carnosine metabolism or a different mechanism or pathway.

3. Implications are that individuals with diabetes who have the greatest risk for kidney failure may be identified and interventions developed to prevent or ameliorate kidney damage, either by increasing carnosine levels or by interfering with the enzyme that deactivates it.

This research was done at Wake Forst Unversity and the University of Heidelberg. It is published online as an article in Nephrology Dialysis Transplantation. See below for the full press release from Wake Forest University.

Researchers Identify Gene Associated with Severe Kidney Failure in Diabetes

WINSTON-SALEM, N.C. - A research team at Wake Forest University Baptist Medical Center and the University of Heidelberg has proven that a gene protects some people with diabetes from developing severe kidney failure or "end-stage renal disease."

Diabetes is the leading cause of end-stage kidney disease worldwide, an illness that requires either kidney dialysis treatments or a kidney transplant for survival.

The carnosinase 1 gene, located on human chromosome 18, produces the protective factor, said Barry I. Freedman, M.D., the John H. Felts III Professor and head of the Section on Nephrology, in an article in Nephrology Dialysis Transplantation published online.

This is a major gene that appears to be associated with development of severe diabetic kidney disease, he said.

The research team evaluated 858 subjects, including diabetic patients with end-stage kidney failure on dialysis, diabetic patients with normal kidney function, and healthy non-diabetic individuals. They confirmed that a protective form of the carnosinase 1 gene was present in greater frequency among both healthy individuals and diabetic subjects without kidney disease, compared to the diabetic patients on dialysis who more commonly had forms of the gene that were not protective.

This discovery may lead to novel treatment strategies in susceptible diabetic patients to protect them from kidney failure may provide a marker to determine which diabetic patients are at increased risk for future kidney disease, Freedman said.

The carnosinase 1 gene produces an enzyme called carnosinase. Carnosinase inactivates the protective substance carnosine. Carnosine appears to prevent scarring from developing in kidney tissue and serves as a scavenger of damaging oxygen-free radicals.

Prior to these genetic analyses, kidney doctors were unaware that this pathway played an important role in diabetic kidney disease, Freedman said.

He added that the groups at Wake Forest and in Germany had been looking for the gene or genes after concluding that a region on chromosome 18 was important in predisposing people who have type 2 diabetes (adult onset diabetes) to the development of severe kidney failure. Freedman said the actions of this gene apply to Europeans, American whites and Arabs.

When his group repeated the analysis in black Americans, there was no evidence that the carnosinase pathway was involved in their kidney failure.

It is possible that American blacks have different carnosine metabolism, making them less susceptible to alterations in carnosinase gene activity. Analyses are currently under way, said Freedman. It is also possible that an additional gene or genes on chromosome 18 is associated with susceptibility to end-stage kidney disease in black Americans, and our group is actively trying to identify them.

Freedman said that among people who are susceptible to kidney failure, it will be important to evaluate whether the administration of carnosine or agents that inhibit carnosinase activity will protect diabetic individuals from the development of progressive kidney disease.

He said that while carnosine is available over the counter in health food stores, it is possible that excessive carnosinase enzyme activity could prevent carnosine supplementation from protecting the kidney. As such, carnosinase blockers may prove to be more important.

Freedman noted that Wake Forest researchers "have one of the largest existing collections of DNA samples from black and white families with multiple members having end-stage kidney disease. We have been evaluating these families since 1991.

Besides Freedman, the research team includes Donald W. Bowden, Ph.D., Pamela J. Hicks, B.S., Michele M. Sale, Ph.D., Eric F. Pierson, M.D., Carl D. Langefield, Ph.D., Stephen S. Rich, Ph.D., Jianzhao Xu, B.S., and Caitrin McDonough, B.S., all from Wake Forest, Bart Janssen, M.D., and Benito A. Yard, M.D., from the Institute of Human Genetics in Heidelberg, Germany, and Fokko J. van der Woude from Fifth Medical Department, University Clinic (Universitätsklinikum), Mannheim Germany.

Source: ( )

January 10, 2007

What will the $1000 genome bring?

In their question of the year for 2007, the editors of Nature Genetics ask some eminent scientists this question. Read their answers here.

Genetic variant raises risk for cerebral infarction by 40%

The New York Times reported today that a variant of the PRKCH gene are associated with an increased risk for strokes due to cerebral infarction. The variant reportedly leads to increased enzymatic activity and is found most commonly in people of Asian descent. This discovery may be important for identifying people who are at risk for strokes and for understanding how strokes might be prevented. The research is published online as a letter in Nature Genetics.

PRKCH codes for protein kinase C and is mapped to human chromosome 14.

January 8, 2007

Politics, science and sexual orientation

Andrew Sullivan muses on the underlying etiologies of sexual orientation in an essay in the Sunday Times of London. Powerful information is a double-edged sword, with potential for good and ill, depending on how it is applied and what your viewpoint is. This may be especially true for something as basic and intrinsic as sexual orientation, where the potential for eugenic applications is very real. Mr. Sullivans highlights the issues, considers the implications and asks many of the right questions. It's worth a read.

January 6, 2007

Obesity and genetics

The developed world is floundering in a rising tide of fat. Reading the literature or listening to the news, several villians are blamed for this intensifying problem. If it is not the soft drink companies, then it is the fast food industry. Or, the city planners who design neighborhoods that are not walkable. Or the increasing crime in our inner cities or the lack of accessible fresh foods and vegetables. In addition, our faster-than-the-speed-of-thought lifestyles do not leave room for regular trips to the gym to work off the extra calories we are taking in. The calculus is somewhat different for each of us, but the outcome is the same: We are literally too big for our britches.

Genes as a causative factor are hardly ever included in the long list of obesity antecedents. This emerging field of obesity genetics is providing new insights on the mechanisms of how and why both individuals and populations respond to obesogenic environmental and behaviorial factors. If public health professionals are to get a handle on the obesity epidemic and come up with better and more complete interventions for prevention, we cannot continue to ignore genetics in our understanding of and approaches to the problem and the solutions.

The first step in integrating genetics is to learn about what genetics is showing us about obesity. The Public Library of Science Genetics has just published a short (8 pages) accessible review on the genetics of obesity by David Mutch and Karine Clement. This review provides a brief overview of what is known about the role of genes in obesity, from single gene causes of obesity, genetic syndromes that include obesity and, most important from the population-based perspective, genetic susceptibility and gene-environment interaction that contribute to common types of obesity. This review is freely accessible and does not require registration or membership or a subscription.

Scientists Discover How Maternal Smoking Can Cause Cleft Lip and Palate

Maternal smoking during pregnancy is a known risk factor for cleft lip and palate in offspring. Research funded by the National Institute of Dental and Craniofacial Research and done at the University of Iowa by Dr. Jeff Murray's group could be an important discovery to better understand the pathways and processes involved in the development of this common birth defect. Ultimately, this information might be used to identify pregnancies that are at greatest risk of being affected and may also lead to strategies (in addition to not smoking) of preventing this condition.

The following announcement was released by the NIH and the research was published in the January 2007 issue of the American Journal of Human Genetics. The abstract is indexed in PubMed.

January 3, 2007 -- Scientists supported by the National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health, report that women who smoke during pregnancy and carry a fetus whose DNA lacks both copies of a gene involved in detoxifying cigarette smoke substantially increase their baby's chances of being born with a cleft lip and/or palate.

According to the scientists, about a quarter of babies of European ancestry and possibly up to 60 percent of those of Asian ancestry lack both copies of the gene called GSTT1. Based on their data, published in the January issue of the American Journal of Human Genetics, the scientists calculated that if a pregnant woman smokes 15 cigarettes or more per day, the chances of her GSTT1-lacking fetus developing a cleft increase nearly 20 fold. Globally, about 12 million women each year smoke through their pregnancies.

Dr. Jeff Murray, a scientist at the University of Iowa and senior author of the study, noted that parents who are considering having a child and need added motivation for the mother to quit smoking might one day be tested to determine their GSTT1 status. Because the fetus inherits its genes from both mother and father, the test would determine the likelihood of the baby developing without the GSTT1 gene to detoxify the cigarette smoke.

"A test that indicates the GSTT1 gene is present certainly would not eliminate a baby's risk of a cleft because many other genetic and environmental factors can be involved." said Murray. "But the opposite result would give the mother one more compelling reason to quit smoking for her own health and for the sake of her child."

In the United States, about one in every 750 babies is born with isolated, also called nonsyndromic, cleft lip and/or palate. The condition is correctable but typically requires several surgeries. Families often undergo tremendous emotional and economic hardship during the process, and children frequently require many other services, including complex dental care and speech therapy.

According to Murray, researchers have built a strong statistical case over the past several years that pregnant women who smoke put their unborn babies at greater risk of developing a cleft. The data raised two related questions. "Do genetic variations in the mother influence her own metabolism of the cigarette smoke and its byproducts, thus setting in motion developmental changes that cause the cleft in the fetus? Or do genetic variations in the fetus itself compromise its ability to metabolize the cigarette smoke and cause the cleft?" said Dr. Min Shi, now a scientist at NIH's National Institute of Environmental Health Sciences and a lead author of the paper.

To find the answers, Murray's group teamed with colleagues in Denmark to perform a large, complex, and possibly first-of-its-kind international study. The group first assembled a list of 16 genes of interest, each of which encode proteins that plug into various pathways in the body involved in detoxifying dangerous chemicals. "We picked genes that previous evidence shows either are directly involved in cigarette smoke toxicity or are major players in general toxicity management in people," said Dr. Kaare Christensen, a scientist at the University of Southern Denmark in Odense and an author on the paper.

"These genes tend to be quite variable from person to person in their precise DNA structure, or spelling," Christensen added. "We wanted to see if any of these variations might adversely affect a person's ability to break down the toxic products of cigarette smoke."

Christiansen and his colleagues then turned to their existing database of kids with clefts, their parents, and siblings. In all, the scientists analyzed 5,000 DNA samples from both continents — including 1,244 from children born with clefts. Importantly, the families in Denmark and Iowa provided the opportunity to independently confirm the findings in two distinct populations.

In addition, they had free public access to the NIDCR-funded COGENE project, a comprehensive online database of genes expressed throughout the various stages of development. Working closely with Dr. Mike Lovett at Washington University in St. Louis, one of COGENE's founders, the database proved especially helpful because cleft lip and/or palate occurs during the first 5-to-12 weeks of development. This meant the scientists had to be sure not only that their genes of interest are expressed during this vital period but are switched on in fetal craniofactial structures. If the genes met both criteria, the investigators said they hoped their subsequent data might point them to a gene-environment interaction.

As reported, the scientists determined from their analyses that the mother provides the toxic environmental exposure, which then can be greatly amplified by the genetics of the fetus to produce the cleft. This marks the first time a gene-environment interaction in clefting has been documented at a molecular level. The data also point the way for future studies to define the specific molecular chain of events that lead to the cleft, vital information to understand and hopefully one day prevent the process.

While sifting through the data, the researchers took particular note of the GSTT gene and its contribution to clefting. The gene encodes one of the body's approximately 20 different glutathione S-transferase enzymes. These enzymes collectively play roles in common detoxification processes, ranging from chemically altering drugs and industrial chemicals to detoxifying polycyclic aromatic hydrocarbons, a key component of cigarette smoke.

The scientists found that pregnant women who smoked and also carried fetuses that lacked the GSTT1 enzyme were much more likely to give birth to a baby with a cleft. This finding was true in Iowa and Denmark, and they noted in the COGENE database that the gene is highly expressed in developing craniofacial structures. "It may be that be that the lip and palate can form normally without GSTT1," said Murray. "But if the chemicals in cigarette smoke challenge the normal development of these structures, fetuses that lack the gene are at a distinct disadvantage."

Murray and his collaborators continue their genetic analyses. "We now have data from about 350 genes on this cohort of families," he said. "It's certainly a more complicated analysis to perform, but we're working our way through it and hope to have some very interesting data in the months ahead."

The article is titled "Orofacial Cleft Risk is Increased with Maternal Smoking and Specific Detoxification-Gene Variants," and is published in the January 2007 issue of the American Journal of Human Genetics. The authors are Min Shi, Kaare Christensen, Clarice R. Weinberg, Paul Romitti, Lise Bathum, Anthony Lozada, Richard W. Morris, Michael Lovett, and Jeffrey C.Murray.

The National Institute of Dental and Craniofacial Research (NIDCR) ( is the nation's leading funder of research on oral, dental, and craniofacial health.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

January 5, 2007

Sea slug offers clues to human brain disorders

Sea slugs are a well characterized model system for studying the functions of the nervous system. It's nervous system is relatively simple, compared to humans, but the connections between nerves and the mechanisms by which neurons communicate with each other is similar. Also, the neural mechanisms used in learning and memory can be studied in this organism.

Up until now, the study of the sea slug's nervous system has been limited due to a lack of genetic and genomic information. No more. Researchers from Columbia University and the University of Florida have characterized up to 70% of the sea slug's neuronal transcriptome by sequencing neuronal cDNA libraries. This provides a new database resource for studying the functions of sea slug's nervous system, including the processes involved in behavior, learning and memory, but also allows comparative analyses with other species, including humans. As a first indicator of the importance of this new resource, many of the genes that have been implicated in important human maladies such as Parkinson Disease and Alzheimer Disease have been shown to be conserved and expressed within the sea slug's nervous system.

You can get more information on this important work. The full report was published in the Dec 29, 2006 issue of Cell. The PubMed abstract is available online. An accessible summary of this work is available via LiveScience.

January 3, 2007

ACOG calls for screening all pregnancies for Down Syndrome

This represents a paradigm shift in screening for Down Syndrome and other conditions due to chromosomal aberrations. For more than a generation, one of the leading criteria for offering prenatal testing for Down Syndrome was maternal age over 35 years at delivery and the standard of care was to offer every pregnant women over 35 years an invasive test to evaluate the fetal chromosomes.

In the last few years, new tools including biomarkers in maternal serum and on ultrasound have made the risk assessment for chromosome abnormalities more focused and precise. As it was, increasing maternal age has been useful for predicting risk to individual pregnancies, but since the great majority of pregnancies occur in younger women, most of the pregnancies with Down syndrome occurred in younger women. Maternal age will still be a factor in assessing risk, but these additional tools will make risk assessment more accurate and will also make prenatal diagnosis available for more pregnancies. This appears to be a rational approach aimed at improving practice and for providing better information and services in this area of reproductive health.

See below for the American College of Obstetricians and Gynecologists' press release:

Washington, DC -- All pregnant women, regardless of their age, should be offered screening for Down syndrome, according to a new Practice Bulletin issued today by The American College of Obstetricians and Gynecologists (ACOG).

Previously, women were automatically offered genetic counseling and diagnostic testing for Down syndrome by amniocentesis or chorionic villus sampling (CVS) if they were 35 years and older.

The new ACOG guidelines recommend that all pregnant women consider less invasive screening options for assessing their risk for Down syndrome, a common disorder that is caused by an extra chromosome and can result in congenital heart defects and mental retardation. Screening for Down syndrome should occur before the 20th week of pregnancy.

"This new recommendation says that the maternal age of 35 should no longer be used by itself as a cut-off to determine who is offered screening versus who is offered invasive diagnostic testing," noted Deborah Driscoll, MD, a lead author of the document and vice chair of ACOG's Committee on Practice Bulletins-Obstetrics, which developed the Practice Bulletin with ACOG's Committee on Genetics and the Society for Maternal-Fetal Medicine.

ACOG also advises that all pregnant women, regardless of their age, should have the option of diagnostic testing. ACOG recognizes that a woman's decision to have an amniocentesis or CVS is based on many factors, such as a family or personal history of birth defects, the risk that the fetus will have a chromosome abnormality or an inherited condition, and the risk of pregnancy loss from an invasive procedure.

According to the new guidelines, the goal is to offer screening tests with high detection rates and low false positive rates that also provide patients with diagnostic testing options if the screening test indicates that the patient is at an increased risk for having a child with Down syndrome. Because of the number of multiple screening strategies currently available, the document provides ob-gyns with some suggested screening strategies that they can choose to offer in their practice to best meet the needs of their patients. The guidelines discuss the advantages and disadvantages of each screening test and some of the factors that determine which screening test should be offered, including gestational age at first prenatal visit, number of fetuses, previous obstetrical and family history, and availability of various screening tests.

The following ACOG recommendations are based on good and consistent scientific evidence:

· First-trimester screening using both nuchal translucency (NT), an ultrasound exam that measures the thickness at the back of the neck of the fetus, and a blood test is an effective screening test in the general population and is more effective than NT alone.

· Women found to be at increased risk of having a baby with Down syndrome with first-trimester screening should be offered genetic counseling and the option of CVS or mid-trimester amniocentesis.

· Specific training, standardization, use of appropriate ultrasound equipment, and ongoing quality assessment are important to achieve optimal NT measurement for Down syndrome risk assessment, and this procedure should be limited to centers and individuals meeting this criteria.

· Neural tube defect screening should be offered in the mid-trimester to women who elect only first-trimester screening for Down syndrome.

Practice Bulletin #77, "Screening for Fetal Chromosomal Abnormalities," is published in the January 2007 issue of Obstetrics & Gynecology.

Studies and articles published in Obstetrics & Gynecology, the peer-reviewed scientific journal of The American College of Obstetricians and Gynecologists (ACOG), do not necessarily reflect the policies, opinions, or recommendations of ACOG. ACOG is the national medical organization representing over 51,000 members who provide health care for women.

Source: The American College of Obstetricians and Gynecologists