Category Archives: Genetic Medicine

Public release date: 26-Mar-2012 [ | E-mail | Share ]

Contact: Karen N. Peart karen.peart@yale.edu 203-432-1326 Yale University

Obese youths with particular genetic variants may be more prone to fatty liver disease, a leading cause of chronic liver disease in children and adolescents in industrialized countries, according to new findings by Yale School of Medicine researchers.

The study, which focused on three ethnic groups, is published in the March issue of the journal Hepatology.

Led by Nicola Santoro, M.D., associate research scientist in the Department of Pediatrics at Yale School of Medicine, the authors measured the hepatic, or liver, fat content of children using magnetic resonance imaging. The study included 181 Caucasian, 139 African-American and 135 Hispanic children who were, on average, age 13.

"We observed that a common genetic variant known as Patatin-like phospholipase domain containing protein-3 (PNPLA3) working with a regulatory protein called glucokinase (GCKR), was associated with increased triglycerides, very low-density lipoproteins levels, and fatty liver," said Santoro.

Santoro explained that his observations could help unravel the genetic mechanisms that contribute to liver fat metabolism. "This may drive the decisions about future drug targets to treat hypertriglyceridemia and non-alcoholic fatty liver disease," he said.

Childhood obesity is a global health concern. Experts say nonalcoholic fatty liver disease is now the leading cause of chronic liver disease in children and adolescents in industrialized countries.

"Our findings confirm that obese youths with genetic variants in the GCKR and PNPLA3 genes may be more susceptible to fatty liver disease," said Santoro, who is cautious about automatically extending this observation to the overall population.

"Our data refer to a population of obese children and adolescents," he said. "I think that further studies in a larger sample size involving lean subjects and adults may help to further define in more details these associations."

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Researchers unravel genetic mechanism of fatty liver disease in obese children

- Human genome and mouse studies identify new precise genetic links

Newswise Working with genetically engineered mice and the genomes of thousands of people with schizophrenia, researchers at Johns Hopkins say they now better understand how both nature and nurture can affect ones risks for schizophrenia and abnormal brain development in general.

The researchers reported in the March 2 issue of Cell that defects in a schizophrenia-risk genes and environmental stress right after birth together can lead to abnormal brain development and raise the likelihood of developing schizophrenia by nearly one and half times.

Our study suggests that if people have a single genetic risk factor alone or a traumatic environment in very early childhood alone, they may not develop mental disorders like schizophrenia, says Guo-li Ming, M.D., Ph.D., professor of neurology and member of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. But the findings also suggest that someone who carries the genetic risk factor and experiences certain kinds of stress early in life may be more likely to develop the disease.

Pinpointing the cause or causes of schizophrenia has been notoriously difficult, owing to the likely interplay of multiple genes and environmental triggers, Ming says. Searching for clues at the molecular level, the Johns Hopkins team focused on the interaction of two factors long implicated in the disease: Disrupted-in-Schizophrenia 1 (DISC1) protein, which is important for brain development, and GABA, a brain chemical needed for normal brain function.

To find how these factors impact brain development and disease susceptibility, the researchers first engineered mice to have reduced levels of DISC1 protein in one type of neuron in the hippocampus, a region of the brain involved in learning, memory and mood regulation. Through a microscope, they saw that newborn mouse brain cells with reduced levels of DISC1 protein had similar sized and shaped neurons as those from mice with normal levels of DISC1 protein. To change the function of the chemical messenger GABA, the researchers engineered the same neurons in mice to have more effective GABA. Those brain cells looked much different than normal neurons, with longer appendages or projections. Newborn mice engineered with both the more effective GABA and reduced levels of DISC1 showed the longest projections, suggesting, Ming said, that defects in both DISC1 and GABA together could change the physiology of developing neurons for the worse.

Meanwhile, other researchers at University of Calgary and at the National Institute of Physiological Sciences in Japan had shown in newborn mice that changes in environment and routine stress can impede GABA from working properly during development. In the next set of experiments, the investigators paired reducing DISC1 levels and stress in mice to see if it could also lead to developmental defects. To stress the mice, the team separated newborns from their mothers for three hours a day for ten days, then examined neurons from the stressed newborns and saw no differences in their size, shape and organization compared with unstressed mice. But when they similarly stressed newborn mice with reduced DISC1 levels, the neurons they saw were larger, more disorganized and had more projections than the unstressed mouse neurons. The projections, in fact, went to the wrong places in the brain.

Next, to see if their results in mice correlated to suspected human schizophrenia risk factors, the researchers compared the genetic sequences of 2,961 schizophrenia patients and healthy people from Scotland, Germany and the United States. Specifically, they determined if specific variations of DNA letters found in two genes, DISC1 and a gene for another protein, NKCC1, which controls the effect of GABA, were more likely to be found in schizophrenia patients than in healthy individuals. They paired 36 DNA letter changes in DISC1 and two DNA letter variations in NKCC1 one DNA letter change per gene in all possible combinations. Results showed that if a persons genome contained one specific combination of single DNA letter changes, then that person is 1.4 times more likely than people without these DNA changes to develop schizophrenia. Having these single DNA letter changes in either one of these genes alone did not increase risk.

Now that we have identified the precise genetic risks, we can rationally search for drugs that correct these defects, says Hongjun Song, Ph.D., co-author, professor of neurology and director of the Stem Cell Program at the Institute for Cell Engineering.

Other authors of the paper from Johns Hopkins are Ju Young Kim, Cindy Y. Liu, Fengyu Zhang, Xin Duan, Zhexing Wen, Juan Song, Kimberly Christian and Daniel R. Weinberger. Emer Feighery, Bai Lu and Joseph H. Callicott from the National Institute of Mental Health, Dan Rujescu of Ludwig-Maximilians-University, and David St Clair of the University of Aberdeen Royal Cornhill Hospital are additional authors.

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Genetic Risk and Stressful Early Infancy Join to Increase Risk for Schizophrenia

When driving of flying with the kids, I hear "Are we there yet?" It has to be one of the most annoying things these little angels do.


I had a wonderful patient. A fantastic friend. He was diagnosed with AML. 21 days later he died.


The family, upon learning the diagnosis said, "Is he going to do ok?" Sadly, given his age, I said probably not. But......his cytogenetics looked good. 


Way back when, we classified this disease according to microscopic morphology. It was classified on how it looked visually. This led to some good, albeit not perfect classification.


We then used our rudimentary cytogenetics studies. This led to some helpful poor and good prognostic help. Again, not perfect, but better. Well, my friend's cytogenetics were great. So I suggested that, we may be surprised........


Despite this, he died. 21 Days later. Why? Was there something else? Perhaps some genetic alteration that was not screened for. Could I have had some better prognostic tools?


Well, we sent for some experimental marker, which returned too late. NEJM has recently published  a study on these markers. Yes, I did something experimentally. Why? My friend was dying and I needed some insight.


"We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 andPHF6 were associated with reduced overall survival (P=0.001 forFLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival"


Despite good cytogenetics, my friend died, 21 days after diagnosis.


FLT3-ITD positive.........results returned 5 days after death.


Why can't we do these faster? Why didn't it get sent right away? I should have forced the provincial Oncologist to send ASAP. 


I will from now on. In remembrance of my friend.


The Sherpa Says: We have to get these studies out in publication quicker. We can't move the ship of personalized medicine forward without quicker peer review and publication!

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22-03-2012 12:29 Dr. Rebecca Carley talks about the vast dangers of vaccines and other AMA-approved treatments that actually do greater harm. website: drcarley.com (expand for more info) "The only safe vaccine is one that is never used." (Dr.James R. Shannon, former Director National Institute of Health) Vaccine Ingredients - Formaldehyde, Aspartame, Mercury + more The numbers of microbes, antibiotics, chemicals, heavy metals and animal byproducts is staggering. Would you knowingly inject these materials into your children? This following list of common vaccines and their ingredients should shock anyone --- eye-opening list here http://www.rense.com (page xcerpt) Acel-Immune DTaP - Diphtheria-Tetanus-Pertussis Wyeth-Ayerst 800.934.5556 * diphtheria and tetanus toxoids and acellular pertussis adsorbed, formaldehyde, aluminum hydroxide, aluminum phosphate, thimerosal, and polysorbate 80 (Tween-80) gelatin Act HIB Haemophilus - Influenza B Connaught Laboratories 800.822.2463 * Haemophilus influenza Type B, polyribosylribitol phosphate ammonium sulfate, formalin, and sucrose Attenuvax - Measles Merck & Co., Inc. 800-672-6372 * measles live virus neomycin sorbitol hydrolized gelatin, chick embryo Biavax - Rubella Merck & Co., Inc. 800-672-6372 * rubella live virus neomycin sorbitol hydrolized gelatin, human diploid cells from aborted fetal tissue BioThrax - Anthrax Adsorbed BioPort Corporation 517.327.1500 * nonencapsulated strain of Bacillus anthracis aluminum hydroxide, benzethonium chloride, and ...

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Dr. Rebecca Carley : Vaccines

What: Honors Forum on Faith and Intellect; topic is bioethics

When: Noon to 1 p.m. today

Where: Hardin-Simmons University, in the multipurpose room of the Johnson Building.

Keynote speaker: Dr. Peter Dysert II, chief of pathology, Baylor University Medical Center

Topic: "Precision Medicine: A Technology-driven Revolution"

Registration fees: $20 for conference and all meals ($10 for HSU employees and students); $5 each for keynote address and meal; no charge for presentations only.

Photo by Joy Lewis

Joy Lewis/Reporter-News Dr. James Denison, director of the Denison Forum on Truth and Culture, talks with guests before his keynote address, "Precision Medicine: Ethical Imperatives and Challenges" at Hardin-Simmons University on Thursday.

The day may come when some diseases are greatly diminished or even eliminated through genetic testing before people are even conceived that's the good news.

But what if that same testing can predict a child's future capabilities when conception occurs? Will that knowledge affect a couple's decision to have a child or even to marry?

Originally posted here:
Ethics questions posed by 'precision medicine' are weighty, speaker tells HSU forum

Public release date: 23-Mar-2012 [ | E-mail | Share ]

Contact: Dawn Peters healthnews@wiley.com 781-388-8408 Wiley-Blackwell

New research found the genetic variant Patatin-like phospholipase domain containing protein-3 (PNPLA3) acting in conjunction with the glucokinase regulatory protein (GCKR) is associated with increased susceptibility to fatty liver disease in obese children. The study, published in the March issue of Hepatology, a journal of the American Association for the Study of Liver Diseases, determined the PNPLA3 and GCKR single nucleotide polymorphisms (SNPs) were responsible for up to 39% of the hepatic fat content in this pediatric population.

Obesity is a global health concern and children are not unscathed by this epidemic. As a result, experts say nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease in children and adolescents in industrialized countries. Previous studies indicate genetics significantly impacts the susceptibility of developing fatty liver and nonalcoholic steatohepatitis (NASH), particularly in early-onset disease, which places greater interest on childhood obesity.

For the current study, a team led by Dr. Nicola Santoro from Yale University School of Medicine in New Haven, Connecticut recruited 455 obese children and adolescents who underwent genotyping and fasting triglycerides and lipoprotein particles testing. Participants in this pediatric cohort had a mean age of 13 years with 181 Caucasian, 139 African American and 135 Hispanic children. Researchers measured hepatic fat content (HFF%) using magnetic resonance imaging (MRI) in a subset of 142 children.

Study findings show that rs1260326 in the GCKR gene is associated with higher triglycerides levels and higher levels of very-low-density lipoproteins (VLDL) in Caucasian and African American children. The GCKR SNP was associated with fatty liver in each of the three ethnic groups. A joint effect between PNPLA3 and GCKR SNPs was responsible for 32% of the HFF% in Caucasian, 39% in African American and 15% of Hispanic children. "Our findings confirm that obese youths with genetic variants in the GCKR and PNPLA3 genes may be more susceptible to fatty liver disease. We need to be cautious, though, and refrain to automatically extend this observation to the overall population. In fact, our data refer to a population of obese children and adolescents. I think that further studies involving lean subjects and adults may help to further define in more details these associations," said Dr. Santoro.

In a related editorial, Valerio Nobili with "Bambino Gesu" Children's Hospital and Research Institute in Italy concurs, "Dr. Santoro and colleagues determined the additive effect of PNPLA3 and GCKR variants explained over one third of hepatic fat content variance in obese children." He recommends that ethnicity data be replicated in larger study cohorts due to the small number of participants in each of the three groups.

The study authors suggest that the GCKR variant may lead to accumulation of fat in the liver through an increase in hepatic triglyceride production and further research is warranted to confirm their results. Dr. Santoro concludes, "While the small sample size raises the possibility of false negative results in our study, the presence of both GCKR and PNLPA3 genetic variants acting in combination confers susceptibility to fatty liver disease in obese children."

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This study and editorial are published in Hepatology. Media wishing to receive a PDF of the articles may contact healthnews@wiley.com.

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Study identifies genetic variants linked to fatty liver disease in obese children