Daily Archives: February 9, 2017

Bloomberg

China Turns to Precision Medicine in Fight Against Cancer ... Bloomberg When Nisa Leung was pregnant with her first child in 2012, her doctor in Hong Kong offered her a choice. She could take a prenatal test that would require ... and more »

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China Turns to Precision Medicine in Fight Against Cancer ... - Bloomberg

February 8, 2017 Betty Pei-tie Tsao, Ph.D., is the Richard M. Silver Endowed Chair for Inflammation Research at the Medical University of South Carolina and senior author on the Nature Genetics article. Credit: Medical University of South Carolina

Investigators at the Medical University of South Carolina (MUSC) report pre-clinical research showing that a genetic variant encoded in neutrophil cystolic factor 1 (NCF1) is associated with increased risk for autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjgren's syndrome, in the January 2017 issue of Nature Genetics.

Data indicate that increased NCF1 protects against SLE while decreased NCF1 raises SLE risk and highlight the pathogenic role of reduced reactive oxygen species in autoimmune disease development.

Single-nucleotide polymorphisms (SNPs - pronounced 'snips') are the most common type of human genetic variation; each one represents a small difference in a nucleotide - the building blocks of our DNA. The Immunochip for fine-mapping is an important tool for conducting genome-wide association studies of the genetic components of disease. Researchers use the Immunochip to investigate DNA samples from people with a particular disease for linkage disequilibrium (LD) signals that illuminate associations between specific SNPs and the disease.

Autoimmune diseases such as SLE are known to have a strong genetic component and, to date, dozens of SNPs associated with SLE have been identified and included on the Immunochip. The Achilles heel is, of course, that the Immunochip cannot identify associations with SNPs that it does not include.

When MUSC researchers genotyped DNA samples from Chinese, European-American, and African-American SLE patients, they found a strong signal in the Chinese sample at the rs73366469 locus in the GTF2IRD1-GTF2I intergenic region at 7q11.23. This was puzzling because that locus was not consistent with SLE loci identified by other genome-wide association studies. Furthermore, the very strong signal in the Chinese sample appeared as a modest signal in the European-American sample and did not appear at all in the African-American sample.

"A true risk gene should be the same in all populations," explained Betty Pei-tie Tsao, Ph.D., Richard M. Silver Endowed Chair for Inflammation Research at MUSC and senior author on the article. "And for such a strong signal, we wondered, 'why hasn't anyone else seen it?' We wanted to find out if what we were seeing was true and explain it."

The team confirmed their finding using a different genotyping platform in an independent Asian sample provided by Nan Shen, M.D., Ph.D., professor of medicine and director of the Shanghai Institute of Rheumatology at Shanghai Jiao Tong University's School of Medicine. But, because rs73366469 did not show LD with any SNPs in the Immunochip, the researchers hypothesized that the SNP containing the true underlying risk factor was not included in it.

"We came into the study from our Asian samples and then started looking for this signal in other populations," said Tsao. "Every ethnic group has a different ancestral background and different LD patterns. We used the LD signal strength as a guide to find our way to the true risk gene - the particular variant that actually caused the increased risk for lupus."

Because the SNP they were looking for was most likely not included in the Immunochip, the team turned to the 1000 Genomes Project dataset, where they found two SNPs that were not only not on the Immunochip, but also produced stronger LD signals with rs73366469 in Asian patients than European or African patients. One of these two, rs117026326 located on intron 9 of GTF2I, showed a stronger association with SLE than either the original or the other locus from the 1000 Genomes Project.

As the researchers focused in on rs117026326, they saw that the NCF1 gene was nearby. This was important because NCF1, which encodes a subunit of NOX2, is thought to be related to SLE due to its role in activating the phagocytic complex NOX2.

Preclinical studies have shown that non-functional NOX2 exacerbates lupus in mice. Furthermore, NCF2, which encodes another subunit of NOX2, is associated with SLE risk in European Americans.

The strong association of rs117026326 with SLE and the functional implications of nearby NCF1 took the team to their next hypothesis: that the rs117026326 SNP might tag causal variants of NCF1 that were not present in the 1000 Genomes Project database.

But unraveling this mystery was not going to be easy.

"This is a very complex genomic region," explained Tsao. "The NCF1 gene has two nearly identical twins - NCF1B and NCF1C - that are 98% the same. But they are non-functional pseudo-genes. This makes working in this region of the human genome very difficult. That's why the next-generation sequencing method that the 1000 Genomes Project has been doing doesn't pertain to this region."

The researchers believed that mapping techniques commonly used by the larger projects, while efficient, limited their ability to find unique sequences among all the copies and duplications in this region. So, they decided to set up their own, novel PCR assay.

"You can't easily sequence this region using the next-generation techniques," said Tsao. "So, we had to do it the old-fashioned way, which was very time consuming and labor intensive. To genotype the region correctly, we used PCR to selectively amplify the NCF1 copies and conduct copy number variation tests. Then we only used samples with no copy number variation to examine the NCF1 variant. This method ensured that what we identified as an NCF1 variant was truly a variant."

Using this strategy, the team identified 67 SNPs, four of which had a strong association with rs117026326. After conducting a long series of multiple tests in samples from various ethnic populations, they gradually eliminated three of the four SNPs and determined that the one called p.Arg90His was the likely genetic variant causing SLE susceptibility across all populations.

In addition, p.Arg90His was associated with increased risk for other autoimmune diseases, including rheumatoid arthritis and Sjgren's syndrome.

The team also found that having only one copy of NCF1 was associated with a higher SLE risk, but having three or more NCF1 copies was associated with reduced SLE risk. Finally, while the underlying mechanism is unclear, the team found that having reduced NOX2-derived reactive oxygen species also raised the risk for these autoimmune diseases.

Tsao notes that perseverance was a critical component of this work. This work was started years ago when the team was at the University of California Los Angeles and was completed after moving to MUSC.

"We just stuck with it as a labor of love. Our lead author, Jian Zhao, devoted several years of his life to this project," explained Tsao." At the time we started, we didn't know it was going to be so complex. We just wanted to explain what we were seeing. It turned out to be quite a chase and very interesting and rewarding to finally bring this project to this point."

This work also points out an important unmet need in the field of genetic mapping.

"We need a more efficient platform to screen complex genome regions for variants. For a lot of diseases we've identified some, but not all, of the variants. There may be more variants hiding in these complex regions," said Tsao. "You have to sort it out like a puzzle. Autoimmune diseases share certain risk factors but also have unique genetic variants that drive the molecular pathogenesis of the disease. Each time you find a variant, you get more puzzle pieces and you can start to understand more about that disease and other autoimmune diseases as well."

Explore further: Genome study identifies risk genes in African Americans with inflammatory bowel disease

More information: Jian Zhao et al, A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases, Nature Genetics (2017). DOI: 10.1038/ng.3782

In the first genome-wide association study (GWAS) of genetic risk factors for inflammatory bowel disease in African Americans, a research team has identified two regions of the genome (loci) associated with ulcerative colitis ...

Researchers from Boston University's Slone Epidemiology Center have found four new genetic variants in the major histocompatibility complex (MHC) that confer a higher risk of systemic lupus erythemathosus ("lupus") in African ...

A person's DNA sequence can provide a lot of information about how genes are turned on and off, but new research out of Case Western Reserve University School of Medicine suggests the 3-D structure DNA forms as it crams into ...

Researchers have newly identified three genetic regions associated with primary biliary cirrhosis (PBC), the most common autoimmune liver disease, increasing the number of known regions associated with the disorder to 25.

A genetic study of Chinese patients reveals a prevalent risk factor for certain blood cancers not detected in European patients.

Investigators at the Medical University of South Carolina (MUSC) report pre-clinical research showing that a genetic variant encoded in neutrophil cystolic factor 1 (NCF1) is associated with increased risk for autoimmune ...

Geneticists from Trinity College Dublin have used our evolutionary history to shine light on a plethora of neurodevelopmental disorders and diseases. Their findings isolate a relatively short list of genes as candidates for ...

It's been more than 10 years since Japanese researchers Shinya Yamanaka, M.D., Ph.D., and his graduate student Kazutoshi Takahashi, Ph.D., developed the breakthrough technique to return any adult cell to its earliest stage ...

Two Princeton University studies are opening important new windows into understanding an untreatable group of common genetic disorders known as RASopathies that are characterized by distinct facial features, developmental ...

The world's biggest study into an individual's genetic make-up and the risk of developing lung disease could allow scientists to more accurately 'predict' - based on genes and smoking - your chance of developing COPD, a deadly ...

A poor diet during pregnancy can cause biological changes that last throughout life, according to research from Imperial College London.

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Study of complex genetic region finds hidden role of NCF1 in ... - Medical Xpress

Science Daily

Overcoming hurdles in CRISPR gene editing to improve treatment ... Science Daily The new gene-editing tool CRISPR/Cas9 holds promise for new treatment of such genetic diseases as cystic fibrosis, muscular dystrophy and hemophilia. But to ... and more »

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Overcoming hurdles in CRISPR gene editing to improve treatment ... - Science Daily

A pediatrician decides a struggling teen with mental illness needs hospitalization to neutralize psychologic demons impacting their personal and social life.

A workers compensation doctor requests a neck MRI in a powerline worker with growing right arm numbness and weakness to search for potential paralyzing nerve impingement.

An orthopedist orders special testing to determine if an elder patient with right hip pain which limits walking and driving might need surgery to improve her quality of life.

Physicians are rigorously trained to make decisions in the best interest of their patients. Even after medical school and residency, doctors must follow the challenges of evidence-based medicine, standard of care, peer review, and muster the time for continuing medical education and certification.

Doctors are not only held accountable by their peers, but also legally, as they could be subject to lawsuits. Additionally, state licensing agencies that oversee medical professionals can discipline them, should they not practice medicine up to the standards of quality medical decision-making.

However, what if the teens pediatrician feels hospitalization is acutely needed for mental illness, but it is denied by the insurance company? What if the workers comp physician orders an MRI for the powerline workers ailing right arm, but it is denied? Or, if special testing to evaluate grandmas worsening mobility and pain is turned down by the HMO? Who is held accountable?

To justify requests for specific patient care, physicians are forced to have peer-to-peer phone discussions with doctors employed by insurance companies, workers comp and HMOs. Frequently, these conversations result in denial of further care without medical justification.

A controversial question arises: Are denials by these company doctors considered medical decisions?

They are not. These decisions are considered utilization review. What does this mean? They are making decisions based on controlling costs, which is in the financial interest of the for-profit agencies they serve but not necessarily in the best interest of the patient.

Even though they are licensed doctors practicing medicine, their role in patient care is under the guise of utilization review and therefore not under the scrutiny of state licensing agencies.

What if these physicians deny care because they are incentivized to enhance personal bonuses? More so, what if some are making decisions outside the realm of their medical expertise (e.g., a urologist deciding about a diabetic)? Who holds these physicians accountable for moral transgressions or lack of judgement?

In California, we have a Medical Board that oversees licensing for all state physicians. If you report a licensed physician for making substandard medical decisions, an investigation ensues. If, though, the doctor is employed by an insurance company, workers comp or HMO and makes denial decisions on their behalf, it is considered utilization review, and they are not held accountable.

I do not pretend to understand every law and rule governing the Medical Board. But these companies have created legal barriers protecting doctors who might make substandard medical decisions.

Many physicians continue to fight for patient care rights despite frustration and helplessness of ongoing phone calls and paperwork they face. Yet substandard medical care will hamper their efforts as laws are manipulated and oversight is negligible.

Making medical decisions has never been easy. Assuring accountability makes it even harder.

Gene Uzawa Dorio, M.D., is a housecall geriatric physician and member of thePhysicians Organizing Committee atHenry Mayo Newhall Hospital. The views expressed in this column as his alone.

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Non-Medical Medical Decisions | Commentary by Dr. Gene Dorio - SCVNEWS.com

Fifteen faculty members from the School of Medicine are among the 47 investigators announced today by the Chan Zuckerberg Biohub.

The CZ Biohub is an independent nonprofit medical research organization that has the goal of harnessing the power of science, technology and human capacity to cure, prevent or manage all disease. It is funded through a $600 million commitment by the Chan Zuckerberg Initiative, which was created by Facebook founder Mark Zuckerberg and his wife Priscilla Chan, MD.

The investigators were selected from the three institutions participating in the CZ Biohub: Stanford, UC-San Francisco and UC-Berkeley. Each of the investigators will be given a five-year appointment and up to $1.5 million for research in their respective areas of expertise. More than 700 researchers applied for the funding; the selections were made by an international panel of 60 scientists and engineers.

The investigators include both senior researchers and up-and-coming faculty.

The 47 CZ Biohub investigators were introducing today are quite literally inventing the future of life science research, said Stephen Quake, PhD, co-president of CZ Biohub and professor of bioengineering and applied physics at Stanford. The CZ Biohub is distinguished by our emphasis on technology and engineering, and our researchers are inventing tools to accelerate science for the good of humanity.

We are honored to have so many of our scientists selected to pursuetheirinnovative and ambitious projectsat the Chan Zuckerberg Biohub,said Lloyd Minor, MD, dean of the School of Medicine. If past is prologue, givingsuch inventivethinkersthe freedom to conduct fundamental research will result in trulyoutstanding discoveries, moving us toward a future wherewe can both cure and preventwhat today seems incurable and unpredictable.

The 15 medical school faculty members are:

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15 School of Medicine researchers named CZ Biohub investigators - Stanford Medical Center Report

How much, though, can these results and their interpretations be trusted? My feelings are mixed, says Stephen Jones, emeritus professor of human genetics at University College London. There are certain cases where genetic tests are tremendously beneficial. Take hypercholesterolaemia. It is an inherited, genetic condition in which your body cannot break down bad cholesterol. If one person has it, you can test their family to assess who has the genetic risk, and give them advice that may be live-saving.

Using genetic tests as a first line of health investigation will eventually be the norm, but we do not have sufficient knowledge to do it yet, Jones adds. Dr Sharon Moalem, a geneticist and bestselling author of Survival of the Sickest (about how some illnesses confer an evolutionary advantage), agrees. I have a lot of hesitation, he tells me over the phone from New York. There are too many claims being made, too soon.

We know that identical twins, with the same genomes, have different health patterns. The epigenetics, the environment in which your genes function, are tremendously important, Moalem adds. He also points out the hazards of testing: If you take a genetic test and find you are at higher risk of something serious, an insurance company can discriminate. A client of mine found a certain gene variant which meant his whole family lost their medical insurance. While that would be concerning in the UK, it could mean disaster in the States.

To this end, Moalems new book The Gene Restart suggests simple tests that can be done at home as an insight into losing weight. If you chew a water biscuit, for some people the taste turns sweet. Those people have the genetic ability to break down carbohydrates and burn up their energy. If it doesnt turn sweet, you may be wise to lay off potatoes. After speaking to Moalem, I was mindful of writing this article and sharing my data. However, I had been lucky with my results. I am, though, taking them with a pinch of scepticism.

I put the recommendation for me to eat low-fat dairy and vegetable oils to Karen Alexander, a nutritional therapist at Wild Nutrition. This is archaic advice: corn oil can be very inflammatory and bad for the heart. Also, rather than low-fat milk, it would be far better to have a small amount of full fat. When I talked about the test with one friend, he told me he sent off for one because there is a lot of cancer in his family. When he got an apparent genetic All clear, he went back to smoking.

That is lethal, comments Jones. If he responds like that, the worst thing he ever did was to take that test. Worse still if he went for a test like 23andMes, whose accuracy is around 65 per cent, and which in 2013 was banned from giving patients health reports by the US Food and Drug Administration as the reports were deemed unreliable. This year, it relaunched in the States with wellness data, but not the genetic risk factors of its original UK test.

Writing this article has made me promise myself I will learn how to check my breasts, and be sure to read up on osteoporosis. The real revelation was not about me, but about where genetic medicine is heading. I ask Wallerstorfer about the future of genetic medicine. He jokes that he knows his own future: if he has children with his girlfriend, because of his ginger gene every second child will be strawberry blond.

More seriously, he adds that by 2050, I think we will test children at birth, you will be able to alter their risk of genetic diseases at that time and then bring them up with the ultimate nutrition and exercise programmes for their genes. For the moment, though, unless you have plenty of money to throw around, you may be better off taking regular exercise, drinking less, eating well and maybe investing 80p in some water biscuits.

The Pure Genetic Lifestyle test costs 450 for a fullPharma, Nutrition and Weighttest, and 1,365 for the book;puregeneticlifestyle.com .

Excerpt from:
Would you take a new 1300 DNA test that could save your life? - Telegraph.co.uk