The obesity epidemic has become a major public health concern. The phenomenon is typically attributed to changes in diet and lifestyle, and socioeconomic factors like poverty and poor education.

Genetic factors have been known play a role as well, but a recent study by UK-based scientists suggests they play much more prominent role, at least in a subset of people who become morbidly obese at a young age.

In the study, Sadaf Farooqi of the University of Cambridge and colleagues showed that many such kids are missing a large chunk of DNA, known as SH2B1, from chromosome 16.

The missing genetic code had been known to play a role in regulating weight and blood sugar levels. Kids with the chromosomal abnormality tended to overeat on a massive scale, and gain weight easily. 

To reach these conclusions, the scientists scanned the genomes of 300 morbidly obese kids in search of copy number variants (CNVs), which are lengthy strands of DNA that are either duplicated or missing.
The scientists compared their findings with information from healthy controls.

In their write-up, which appears in Nature, the scientists wrote, “we identified several rare copy number variants that were recurrent in patients but absent or at much lower prevalence in controls.”

“Part of chromosome 16 can be deleted in some families. People with this deletion have severe obesity from a young age,” Farooqi told Medical News Today: “One particular gene on chromosome 16 called SH2B1 plays a key role.”

The finding may have broad social implications, since it is common to blame parents or guardians for morbid obesity in kids. The scientists noted for example, that some kids in the study had been handed over to Social Services because their parents were assumed to have been deliberately overfeeding them.

A multinational group of scientists has concluded that about a third of the genetic underpinnings of schizophrenia are caused by the interactions of many thousand common genetic variants. While each variant may be harmless on its own, the combined impact vastly increases the risk of both schizophrenia and bipolar disorder.

The results imply that the genetic basis of the 2 common psychoses  are more complex than had been thought, and that the conditions can develop not just from a rare, devastating genetic variant, but from dozens or hundreds of common ones.

The write-up is in Nature.
 
“This is an enormous first for our field,” co-author Patrick Sullivan told BurrillReport. “We now have the outline of the puzzle, we just need to… see how (the pieces) fit together,” added the professor of psychiatry at the UNC School of Medicine.
 
Although scientists have long recognized that schizophrenia has a genetic basis, it’s only recently that they’ve started pinpointing offending genetic loci.
 
To reach their conclusions, Sullivan and colleagues isolated 30,000 genetic variants that occurred more frequently in 3,000 people having schizophrenia than in a control group without the condition. The team confirmed the differences in 2 other populations of schizophrenic patients and 2 groups with bipolar disorder.

The genetic link between schizophrenia and bipolar disorder had not previously been recognized.
 
“While our study finds a surprising number of genetic effects, we expect that future work will assemble them into meaningful pathways that will teach us about the biology of schizophrenia and bipolar disorder,” senior author Pamela Sklar told Burrill.
 
The scientists also found that a particular HLA haplotype increased the risk for both psychoses. Since HLA proteins are involved in the immune response to infections, they speculated that an infectious agent might be an etiologic factor.

Just 6 years after scientists decoded the human genome, a line of research derived from the breakthrough known as personal genomic medicine is increasingly perceived to be an expensive bear with an uncertain future, according to commentaries in the New England Journal of Medicine.

Since the heralded announcement in 2003, geneticists have undertaken hundreds of genomewide association studies designed to compare the DNA of healthy people with those of patients having specific diseases.

The hope was to pinpoint a handful of culprit genes and by association, biochemical processes that could become targets for disease-modifying drugs, immune therapy or what have you.

But the studies appear capable of explaining just a fraction of the genetic component underlying complex diseases like cancer, schizophrenia and diabetes.

The problem, it seems, has been the assumption that such conditions were promoted by variations in a small number of genes, say 10. Instead, thousands of genes appear to be involved, with multiple variations at each locus exerting myriad effects on other genes and their variants.  

The snafu represents a setback for personal genomics companies that hoped to inform customers about their risk for these diseases.

“With few exceptions, what the genomics companies are doing right now is recreational genomics,” Duke University geneticist David Goldstein told the New York Times. “The information has little or…no clinical relevance.”

In his NEJM piece, Goldstein therefore recommends a strategic shift in genomics research towards decoding the entire DNA of patients with certain diseases.

But Peter Kraft and David Hunter of the Harvard School of Public Health, publishing in the same issue, remain optimistic about genomewide association studies.

“There will be more common variants to find,” Hunter told the Times. “It would be unfortunate if we gave up now.”

Plavix-popping patients in posession of a particular gene that prevents its proper metabolism were at twice the risk of sustaining cardiovascular events, and the risk could not be mitigated by high doses of the stuff, according to 2 studies presented at last week’s meetings of the American College of Cardiology.

In the first study, Paul Gurbel and colleagues showed that 21% of patients with the cytochrome P450 2C19*2 polymorphism had a cardiovascular event within a year following coronary artery stenting, even though they received Plavix to prevent such occurrences.

The University of Maryland-based scientists found that only 10% of noncarriers experienced that outcome.

“This common variant encodes a defective enzyme that likely fails to convert Plavix to its active metabolite, leading to lesser inhibition of platelet function and diminished cardiovascular protection,” Gurbel told MedPageToday.

In the second study of 33 patients that had a poor response to the standard 75 mg dose of Plavix, Jean-Philippe Collet and colleagues at INSERM in Paris found that doubling the standard dose improved results in all but 7 patients.

Six of these 7 patients were CYP2C19*2 positive.

The scientists prescribed Effient, an alternative antiplatelet drug to eligible patients in this group, and all responded nicely.

“The day is rapidly approaching” when physicians can determine in advance how patients will respond to antiplatelet therapy and select agents likely to be effective “rather than blindly administering Plavix as we do now,” Gurbel concluded.

Plavix is co-marketed by Sanofi-Aventis and Bristol-Meyers Squibb. It is the world’s second largest selling drug, with $4 plus billion in revenues last year. It enjoys patent protection until November, 2011.

Eli Lilly and Daiichi Sankyo co-developed Effient, which was recently approved in the EU and is edging toward FDA approval.

Scouting video on the Big O confirms he doesn’t just lean left politically.

Interestingly though, 5 of the last 7 presidents have been left-handed including Ford, Reagan, Bush the semi-reasonable, Clinton and Obama. Only Carter and Bush II went right.

That seems odd given that only 10% of humans are lefties, but it’s probably just a statistical fluke.

Even if it wasn’t, no one knows whether or how left-handedness impacts factors that drive electoral success like political skill, smarts, charisma, appearance, insider connections, and wealth. 

And before lefties start popping their collars, they’d be well to remember they’re at increased risk of accidental death not to mention a possibly increased risk for some psychiatric diseases. 

It’s not clear why some people become left-handed, although genes are clearly involved. About one-quarter of the sons of left-handed parents are left-handed, whereas only 10% of boys who have right-handed parents end up as southpaws.

But genes aren’t the whole story since 20% of identical twins have different handedness.

Non genetic effects on handedness can be demonstrated in chickens, in whom brain lateralization is driven by light penetrating the shell during incubation.

In most chick embryos, the right eye is exposed to light. These chickens end up being more adept at identifying food and prey with their right eye, and are better able to detect predators and potential mates with their left eye.

If the eggs are incubated in darkness however, the resulting adults don’t lateralize this way.

A consortium of US scientists has reported that an easy-to-perform analysis of 50 genes can reliably sort breast cancer tissue samples by type and predict which therapies are most likely to work. 
  
Philip Bernard, Joel Parker, Matthew Ellis and many others published the heartening findings in the Journal of Clinical Oncology.

“Unlike a widely used genomic test that applies only to lymph-node negative, estrogen-receptor positive breast cancer, this new genomic test is broadly applicable for all women diagnosed with breast cancer,” Ellis, a breast cancer expert from Washington University told BurrillReport.
 
To develop and validate the 50 gene test, the scientists reviewed more than 1,000 breast cancer tissue specimens. They were able to establish a genetic signature for each major form of breast cancer: luminal A, luminal B, basal-like and HER2-enriched.
 
Then, having accurately classified 133 consecutive tissue specimens using their tool, the scientists assessed how the different breast cancer phenotypes responded to chemotherapy.

The test turned out to be highly predictive of chemotherapy response, and superior to currently used tests like estrogen and progesterone receptor status and HER2 gene expression status.
 
For example, patients with luminal A cancers did not respond to chemotherapy, suggesting that they ought to forgo chemotherapy in lieu of hormone-based treatment.

Conversely, basal-like breast cancer, which carries an ominous prognosis, turned out to be “the most sensitive to chemotherapy. By identifying (the cancer types correctly) we can ensure they are treated adequately,” Ellis said.
 
The scientists are now studying how each breast cancer type responds to the 20 or so chemotherapeutic drugs on the market.

When it’s ready, the new genomic test will be marketed by University Genomics, which is owned by Washington University, the University of Utah and the University of North Carolina.

For decades, scientists theorized that aging was caused by oxidative stress, a phenomenon in which cellular damage is caused by free radicals and nasty oxygen-based molecules that build up over time as byproducts of normal biological processes.

According to the theory, the cellular defense against the culprits-which are enzymes known as superoxide dismutases-gets overwhelmed by the accumulating bad guys and the next thing you know, cells are looking like Methuselah.

From the theory sprung an entire industry hawking antioxidant therapies from Vitamin A to Coenzyme Q which supposedly boosted the body’s ability to water-cannon the free radicals.

Alas clinical trials have never shown them to work and now McGill University scientists are raising doubts about the validity of the oxidative stress theory itself.

Siegfried Hekimi and colleagues disabled one-by-one, 5 genes coding for superoxide dismutases in a worm that goes by the unassuming name C. elegans.

The successive gene deletions did not shorten the worms’ lifespan; in fact in one instance, the altered critters outlived the wild-types.

The report is in PloS Genetics.

Come to think of it, the evidence supporting the oxidative stress theory is circumstantial, Hekimi told BurrillReport.

And oxidative stress could be the result of aging rather than its cause.

“It is true that the more an organism appears aged, whether in terms of disease, or appearance or anything you care to measure, the more it seems to be suffering from oxidative stress. (But) people think correlation is causation,” he told BurrillReport.
 
Hekimi’s not saying oxidative stress is actually a good thing. It clearly interferes with normal cellular functioning. But it’s a stretch, he says, to say that oxidative stress causes aging.

Scientists at Dana-Farber Cancer Institute and the CDC have produced monoclonal antibodies that can destroy most strains of flu virus, a new line of attack that promises to overcome the virus’ maddening ability to mutate and thus fool today’s vaccines.

Such antibodies “could provide broad protection against all seasonal and pandemic influenza A viruses,” according to Wayne Marasco of Harvard Medical School and colleagues.

The potion targets the flu virus near its base, a region that turns out to be genetically stable.

The base mediates viral entry into cells, Marasco’s team wrote in Nature Structural & Molecular Biology.

Today’s vaccines stimulate antibody production against the viral head, a region that demonstrates extraordinary genetic polymorphism. That’s why flu vaccines are useless after one year at best and queueing-up for a jab has become an annual ritual for millions.

Coauthor Ruben Donis of the CDC is confident his group has flu by the short hairs, pointing out to MedpageToday that “By mutating (at the base, the flu virus) commits suicide.” 

The monoclonal antibodies appear to work against multiple strains of flu, including H5N1 avian flu and the H1N1 Spanish flu strain that killed 50 million people in 1918.

They also were shown to prevent flu symptoms in animals even when given 24 hours after exposure to flu virus, so long as they’re given in higher but “achievable” doses, according to the scientists.

The next step is to see whether the antibodies work in ferrets, which strangely enough have immunologic responses to flu virus more like humans than any other species.

Clinical trials could begin in 2 years.
 
The Dana-Farber holds patents on the discovery of the static region and the monoclonal antibodies against it.

It’s been 40 years since Louise Brown, the world’s first test tube baby was born. Since then millions of babies conceived via in vitro fertilization have entered the world and gone on to live normal, healthy lives.

In fact Brown’s recently born baby boy was conceived the old fashioned way.

But IVF involves growing embryos in a petri dish for days before implantation. Can that really be risk free?

No it turns out, but the risks-while still not completely understood-are small.

Last fall the CDC reported that IVF babies have a slightly higher risk of birth defects including atrial septal defect, cleft palate and digestive system abnormalities. About 1.1% of the mothers of normal babies had used IVF, whereas 2.4% of mothers that had babies with birth defects had used IVF.

And a few hereditary syndromes are more common among IVF babies. Beckwith-Wiedemann syndrome, which is characterized by tissue hyperplasia and multiple childhood cancers, occurs in less than 1 in 13,000 normal births, but it’s 10 times more frequent in IVF babies.

Angelman syndrome, which is characterized by mental retardation and motor defects, is also linked to IVF.

 “There is a growing consensus…that there are risks,” said Richard Schultz, the associate dean for the natural sciences at the University of Pennsylvania told the New York Times. “It is now incumbent on us to figure out what…we can do…to minimize (them).”

Scientists believe the culture medium used during incubation affects gene expression but as of now there is no standard medium and little data linking specific media to outcomes.

In fact, according to Elizabeth Ginsburg, director of IVF at Brigham and Women’s hospital, “programs use multiple media, and (frequently) switch from one media to another.”

Reykjavik-based Decode Genetics, which is a lot better at personal genomics than selecting investment advisors, is back in the news now that its scientists have determined that 57% of all thyroid cancer is attributable to 2 genetic variations.

Julius Gudmundsson and colleagues report in Nature Genetics that the variants are simple base-pair substitutions occurring in genes residing near those controlling thyroid gland development, one on Chromosome 9 and the other on Chromosome 14.

Compared with those having neither variant, “the risk associated with these variants was almost six-fold, which is quite extraordinary,” Erich Sturgis, a head and neck surgeon at Houston’s MD Anderson Cancer told the New York Times.

Each year in the US, about 35,000 cases of thyroid cancer are diagnosed. Treatment generally includes surgical resection of the gland followed by lifelong thyroid replacement. It’s quite effective and only 1,500 people die from thyroid cancer each year.

The Decode breakthroughs are thus not going to trigger interest in population-wide screening programs, but the information would be useful in the assessment of people at high risk, such as those with a positive family history of the disease. 

Gudmundsson’s group reached its conclusions by performing a genome-wide association study involving 192 positive cases and a large control group.

They showed that people having both genetic variants had low levels of thyroid-stimulating hormone, which is produced normally by the pituitary gland.

TSH helps thyroid cells mature, so the authors postulate that chronically low TSH levels might impede their differentiation and thus increase the risk of malignant transformation.

If this theory proves correct, TSH supplementation might reduce the risk of developing thyroid cancer in affected individuals.

Christakis and Fowler are at it again!

Two months ago they caused a stir by publishing research in BMJ which seemed to show that happiness is contagious, a conclusion that some chalked up to an inexcusably naïve failure to recognize the effects of epiphenomena in social networks.

Now these crowd pleasers have put a piece in PNAS which concludes that a person’s popularity is genetically determined. 

Or as Christakis, a medical sociologist at Harvard told Medical News Today, “We were able to show that our particular location in vast social networks has a genetic basis.”

“In fact, the beautiful and complicated pattern of human connection depends on our genes to a significant measure,” he waxed.

Does this guy think he’s Ram Dass or what?

To reach this data-mining epiphany, Christakis and Fowler characterized the social networks of 1,110 identical and non-identical teen-aged twins from the National Longitudinal Study of Adolescent Health.

They measured popularity by the number of times an individual was named as a friend and the likelihood those friends knew each other.

Does this work for everybody?

Whatever, the scientists observed a higher concordance among the networks of identical twins than their non-identical counterparts.

They also concluded that whether a person was central to, or at the periphery of her social network was genetically determined, which inspired them to raise Charles Darwin from the dead, all in the same article.

Maybe it’s good to be on the periphery of a social group, they mused, like when there’s Ebola virus floating around. Then again, those hub-of-the-network types have access to more information like which Starbucks still has Christmas Blend in stock.
 
Please people.

Twenty-five years after tamoxifen was introduced for the treatment of breast cancer, David Flockhart and his team at Indiana University determined that the body coverts the drug into a different substance known as endoxifen, and the latter is actually the cancer-figher.

Flockhart’s group discovered that the body uses an enzyme known as 2D6 to engineer the conversion, and that there is considerable variation in 2D6 gene expression.

In fact 7% of the general population possess a wholly inactive enzyme and another 20-40% have a weakly active variation.

Flockhart told the New York Times that was “scary” because it meant tens of thousands of women had received a drug that did not protect them against recurrent breast cancer as they had thought.

It’s scary for Big Pharma too. Tamoxifen had fallen out of favor ever since clinical trials showed that aromatase inhibitor drugs performed better.

But the studies were done before we knew about 2D6 and as an aside, the aromatase inhibitors net up to 36 times more revenue per patient than the now-generic tamoxifen.

Suppose the trials had assessed only women with a fully active 2D6 enzyme. Could tamoxifen have performed as well or better than the aromatase inhibitors? 

Matthew Goetz and colleagues from the Mayo clinic went back and checked tumor samples from a previous trial for 2D6 gene status and reported that 32% of women with the inactive variant had relapsed or died in 2 years. Only 2% percent of women with a fully active enzyme relapsed or died.

But other studies reached contradictory conclusions and it turns out there are dozens of 2D6 variants which can confound results in clinical labs.

Two years ago, an FDA advisory panel recommended that the 2D6 test be discussed on the label for tamoxifen. Just recently, the agency got around to accepting the recommendation.

Influenza is a viral infection of the nose and throat that typically causes fever, headache, muscle aches and weakness. Sometimes pneumonia complicates the flu. The cause can be bacterial or the virus itself. In a typical season, flu mortality is well below 1%.

In 1918, an extraordinary number of flu victims developed pneumonia. Mortality ran 400% higher than usual.

In fact, “The 1918 influenza pandemic was the most devastating outbreak of infectious disease in human history, accounting for about 50 million deaths worldwide,” according Yoshihiro Kawaoka and colleagues from the University of Wisconsin and the Universities of Kobe and Tokyo.

Now these scientists think they’ve discovered what triggered the pandemic.

The team isolated genes one-by-one from the 1918 strain, substituted them into the modern flu virus and then infected ferrets, which develop flu a lot like humans do.

Time after time the ferrets developed normal flu until the scientists used a 3-gene combination called PA, PB1, and PB2 (along with a 1918 version of the nucleoprotein or NP gene).

This combination enabled the flu virus to invade the lungs, causing pneumonia and death. The team has published its findings in the Proceedings of the National Academy of Sciences.

Most experts believe there will be another flu pandemic someday. No one knows when or which strain will cause it, but the H5N1 avian influenza virus that currently circulates among birds and domestic poultry in Asia, Africa and Europe remains a likely suspect.

The current strain of Avian flu rarely infects humans but when it does, it kills. More than 60% of the 391 people infected so far have died. 

A few mutations that increase its attack rate in humans would transform H5N1 into a monster that could kill millions in months.

Genetic mutations can cause or prevent disease and scientists at the University of Maryland recently came across an interesting case of the latter.

The scientists asked folks from an Amish community near Lancaster, Pennsylvania to swill down a creamy milkshake and then tracked what happened to fat levels in their blood.

In nearly all participants, triglyceride levels rose for several hours then slowly declined to baseline as would be expected. But in about 5%, the levels started out low and jumped no more than a smidge.

Tori Pollin and colleagues traced the favorable phenotype back to a gene mutation that had already received the inauspicious name apoC-III. The gene codes for APOC3, a protein that normally slows down triglyceride metabolism.

According to Pollin’s report in Science, the cohort with the gene mutation also had higher levels of HDL (good)-cholesterol and lower levels of LDL (bad) –cholesterol. And they had fewer coronary artery calcifications on CT scanning. In short, the mutation was cardio-protective.

The isolated nature of the Amish population enabled the scientists to trace the apoC-III mutation to a man born more than 200 years ago.

In commenting on the study, Daniel Rader told the New York Times, “this is among the strongest human evidence we have that APOC3 is quote, unquote, bad.”

We love it when University of Pennsylvania cardiac researchers talk like that. He added, “if you had a drug to turn off the gene to prevent as much APOC3 being made, this study suggests that that would be beneficial to do.”

We’re on it.

Scientists from Columbia University are reporting that osteoporosis, a chronic bone-wasting condition that affects 10 million elderly Americans, may be mediated by serotonin, a compound previously known for its role in brain functioning.

The astonishing conclusion appears in the journal Cell.

Scientists had known for years that a rare, inherited brittle bone disease was caused by a mutation of a gene known as LRP5. More recently, a second mutation of LRP5 was reported to cause just the opposite—bones so dense that tooth extractions became nearly impossible.

So something was up with LRP5, and the tempting assumption was that the gene directly impacted bone formation.

Not so, according to Gerard Karsenty and colleagues. They proved that LRP5 blocks production of serotonin in the gut.

Then they proved that while gut serotonin has no impact on brain functioning, it does impair bone formation after travelling there through the blood stream.

“We made mice with the inactivated gene,” Dr. Karsenty told the New York Times. These mice had 4 times the normal levels of circulating gut serotonin, and in their bodies “the bone-forming cells are on strike,” he added.

The mice developed marked osteoporosis.

Karsenty’s team then harvested bone cells from the brittle boned mice and proved in the laboratory that the cells were perfectly capable of normal development and functioning, so long as they were not bathed in serotonin.

Karsenty’s team hopes its work might prompt development of a drug that suppresses gut serotonin synthesis and thus stimulate bone growth in osteoporosis patients.

Atlas Sports Genetics claims to have a test that predicts which kinds of sports match your child’s innate abilities. You can buy it right now for $149.

The test determines ACTN3 gene expression. ACTN3 is one of 20,000 human genes.

The so-called R variant of ACTN3 instructs the body to produce alpha-actinin-3. This protein component of fast-twitch muscles provides forceful, quick contractions required to excel in power and speed sports like football and sprinting. The X variant suppresses the production of alpha-actinin-3.

Children inherit one copy of the ACTN3 gene from each parent, so they can be “RR,” “RX,” or “XX.”

Atlas Sports claims that power and speed sports are best suited to RR offspring, whereas endurance sports like marathons and distance swimming are best suited for XX offspring. Apparently RX offspring can do anything.

If this sounds dicey to you, you’re not alone.

Dr. Theodore Friedmann, the director of the gene therapy program at UCSD for example, told the New York Times the test amounted to “an opportunity to sell new versions of snake oil.” He elaborated, “I don’t deny that these genes have a role in athletic success, but it’s not that black and white.”

There is no doubt the science being commercialized here is compelling, if not ready for prime time.

In 2003, Australian scientists studied 429 world class athletes including 50 Olympians. They found that 50% of the 107 sprint athletes were RR. That’s twice the frequency of RR in the general population. And not one female sprinter was XX. What is more, every male Olympian involved in power sports had inherited an R variant from at least one parent.

So where does the XX Spanish long jumper fit in?

It’s hard to know but Carl Foster, a co-author of the study and director of the human performance laboratory at the University of Wisconsin-La Crosse has devised another way to see whether your 6th grader will excel at power and sprint sports:

“Just line them up with their classmates for a race and see which ones are the fastest,” he said.