Australian researchers have demonstrated a strong association between the FTO (fat and obesity) gene and hip fracture in women. While the gene is already well known to affect diabetes and body fat, this is the first study to show that its high-risk variant can increase the risk of hip fracture by as much as 82%.
The study, undertaken by Dr Bich Tran and Professor Tuan Nguyen from Sydney’s Garvan Institute of Medical Research, examined six gene variants (single nucleotide polymorphisms, or SNPs) of the FTO gene, taken from the DNA of 943 women in the Dubbo Osteoporosis Epidemiology Study (DOES). The women were all over 60, and their bone health was followed between 1989 and 2007. During that period, 102 women had hip fractures.
On average, the risk of fracture is about 11%. The study showed that if a woman has a low-risk genotype, or gene variant, the risk of fracture is 10%. If she has a high-risk genotype, it is 16%.
The authors believe that the findings have the potential to improve prediction of hip fracture. Known risk factors, also to be taken into account, include advancing age, falls, history of fracture, low bone mineral density, low body mass index (BMI) and genetic make-up.
‘We found that for a woman of the same age and same clinical risk factors, those with the high-risk genotype have an increased risk of fracture of 82% – a very high effect in genetic terms,’ said Professor Tuan Nguyen.
‘A genome-wide association study published in 2007 suggested that genetic variants in the FTO gene were associated with variation in BMI. This led us to hypothesise that they might also be associated with variation in hip fracture risk.’
‘The present study tested our hypothesis by examining the association between common variants in the FTO gene and hip fracture.’
‘Our results showed a strong association with hip fracture, with some gene variants doubling the risk of fracture. Interestingly, this was independent of both the bone density and BMI of the women we studied.’
‘We also found that the FTO gene expresses in bone cells, and may have something to do with bone turnover, or remodelling, although its exact mechanisms are unclear.’
‘It’s important to emphasise that, while promising, our finding is a first step. It will need to be replicated in other studies, and its mechanisms clearly understood before it is useful in drug development.’ Garvan Institute of Medical Research

The human papillomavirus (HPV) may be to blame for the alarming increase of young adults with oropharyngeal cancer, according to researchers from Henry Ford Hospital in Detroit.

The study reveals an overall 60 percent increase from 1973 and 2009 in cancers of the base of tongue, tonsils, soft palate and pharynx in people younger than age 45.

Among Caucasians, there was a 113 percent increase, while among African-Americans the rate of these cancers declined by 52 percent during that period of time.

But compared to Caucasians and other races, the five-year survival rate remains worse for African Americans.

‘The growing incidence in oropharyngeal cancer has been largely attributed to the sexual revolution of the 1960s and 1970s, which led to an increased transmission of high-risk HPV,’ says study lead author Farzan Siddiqui, M.D., Ph.D., director of the Head & Neck Radiation Therapy Program in the Department of Radiation Oncology at Henry Ford Hospital.

‘We were interested in looking at people born during that time period and incidence of oropharyngeal cancer. Not only were we surprised to find a substantial increase in young adults with cancer of the tonsils and base of tongue, but also a wide deviation among Caucasians and African Americans with this cancer.’

The study – which examined the trends in cancers of the base of tongue, tonsils, soft palate and pharynx among people 45 years-old and younger – will be presented Sept. 23 at the 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO) in Atlanta.

The American Cancer Society estimates about 36,000 people in the U.S. will get oral cavity and oropharyngeal cancers in 2013; an estimated 6,850 people will die of these cancers. Oropharyngeal cancers are more than twice as common in men as in women, and about equally common in African Americans and Caucasians.

Recent medical research has shown that HPV exposure and infection increases the risk of oropharyngeal squamous cell cancer independently of tobacco and alcohol use, two other important risk factors for the disease, according to the National Cancer Institute.

The incidence of oropharyngeal cancer has been growing in recent years due to increasing rates of HPV infection. This has been largely attributed to changes in sexual practices. Studies have shown, however, patients with HPV related head and neck cancer do have a better prognosis and survival. Henry Ford Hospital in Detroit

Using powerful genetic sequencing technology, a team of investigators, led by researchers at the Icahn School of Medicine at Mount Sinai, scanned the genome of hundreds of individuals, and discovered those diagnosed with autism spectrum disorder (ASD) were more likely to have gene deletions than were people without the disorder. That means those individuals — seven percent of the study group — had one copy of one or more genes when they should have had two.
‘This is the first finding that small deletions impacting one or two genes appear to be common in autism, and that these deletions contribute to risk of development of the disorder,’ says the study’s lead investigator, Joseph D. Buxbaum, PhD, Professor of Psychiatry, Genetics and Genomic Sciences and Neuroscience at the Icahn School of Medicine at Mount Sinai.’This conclusion needs to be expanded in other independent samples of ASD so that we can truly understand how the risk manifests,’ he says.
Autism, which affects about one percent of the population, is a developmental disorder thought to be caused by a complex interplay between genetic and environmental factors. Although the disorder is highly heritable, the majority of autism cases cannot be attributed to known inherited causes, Dr. Buxbaum says.
While research has indicated that there might be as many as 1,000 genes or genomic regions that contribute to ASD, most studies have looked for either single point mutations—a change in a single letter of DNA on a gene—or for large areas of the genome, encompassing many genes, that is altered.
In this study, the researchers looked for small copy number variation—deletion or duplication of genes—between ASD individuals and a ‘control’ population without the disorder.
To conduct the study, they used exome sequencing to look at all 22,000 human genes in the sample set, and analysed that data using the eXome Hidden Markov Model (XHMM) program. Together, the tools are the first that can find single gene-sized deletions or additions in the genome.
‘This gives us the power, for the first time, to run one test from a blood sample and compare it to a reference genome to search for mutations and small copy number variation in patients,’ Dr. Buxbaum says.
They applied this method to analyse a database consisting of 431 ASD cases and 379 matched controls, totalling 811 individuals. They found 803 gene deletions in the ASD group and 583 deletions in the control group, and the ASD population had a greater likelihood of having multiple small deletions.
‘It is now known that imperfect gene copy number is one of the major sources of variability between people. One of the reasons we are different from each other is because of gene additions or deletions which are often inherited,’ he says. ‘But of the extra deletions we see in ASD not all are due to genetic inheritance. Some occur during the development of the egg or sperm, and deletions that develop in this way tend to be associated with the disorder.’
The researchers then examined the deletions they found in the autistic group and found that a significant proportion of them related to autophagy, a key process that keeps cells healthy by replacing membranes and organelles.
‘There is a good reason to believe that autophagy is really important for brain development because the brain produces many more synapses than it needs, and the excess needs to be pruned back,’ Dr. Buxbaum says. ‘Too many, or too few, synapses have the same effect of not making communication work very well. It could mean that some synaptic connections come in too late and may not solidify properly.’
The researchers believe the findings will have clinical significance. ‘Key copy number variations—those that consistently appear in an autistic population—can impact genetic testing,’ Dr. Buxbaum says. Mount Sinai Health System

Using mice, lab-grown cells and clues from a related disorder, Johns Hopkins researchers have greatly increased understanding of the causes of systemic sclerosis, showing that a critical culprit is a defect in the way certain cells communicate with their structural scaffolding. They say the new insights point the way toward potentially developing drugs for the disease, which affects approximately 100,000 people in the United States.
‘Until now we’ve had little insight and no effective treatment strategies for systemic sclerosis, and many patients die within a year of diagnosis,’ says Hal Dietz, M.D., the Victor A. McKusick Professor of Genetics and Medicine in the Institute of Genetic Medicine, director of the Smilow Center for Marfan Syndrome Research at Johns Hopkins and Howard Hughes Medical Investigator. ‘Our group created mouse models that allowed us to learn about the sequence of events that leads to the disease’s symptoms, and we hope drugs can be developed that target one or more of these events.’
Patients with systemic sclerosis, also known as systemic scleroderma, experience a sudden hardening, or fibrosis, of the skin. For some patients, this hardening occurs only in limited areas, but for others, it quickly spreads across the body and to organs such as the heart, intestines and kidneys. It is this fibrosis of the internal organs that is often fatal.
Systemic sclerosis rarely runs in families, Dietz says, making the gene for the disease, if it exists, very difficult to find. Without a known genetic mutation, researchers had not been able to create a genetically altered mouse with which to study the condition. But Dietz’s group was struck by the similarities between systemic sclerosis and a less severe, much rarer condition called stiff skin syndrome (SSS), which does run in families, and they suspected that learning more about SSS would also shed light on systemic sclerosis.
In a previous experiment, they pinpointed the genetic mutation responsible for SSS in a gene for a protein called fibrillin-1, which plays a role in other connective tissue disorders. In certain types of tissues, including skin, fibrillin-1 helps make up the scaffolding for cells. The specific changes in fibrillin-1 seen in SSS patients were predicted to impair the ability of cells to make contact with fibrillin-1 through bridging molecules called integrins.
In the current study, M.D./Ph.D. student Elizabeth Gerber created a line of mice with a genetic variant similar to that found in SSS patients. To test the group’s hypothesis, Gerber also created a line of mice with a variant the team knew would prevent fibrillin-1 from interacting with integrin. As the team expected, both groups of mice developed patches of stiff skin, along with elevated levels of proteins and cells involved in the immune response—much like humans with SSS or systemic sclerosis. ‘It seemed we were right that the SSS mutation causes the condition by blocking fibrillin’s interaction with integrin,’ Dietz says. ‘Something else we found was that both types of mice had high levels of integrin in their skin, which made us think their cells were trying to compensate for the lack of fibrillin-integrin interaction by making more and more integrin.’
This still left open the question of what was ultimately causing fibrosis, however: Was it the integrin levels or the immune response? Dietz’s group delved deeper into the question by creating mice that had both the SSS mutation and artificially low levels of integrin, and found that the mice never developed fibrosis or an abnormal immune response. ‘They looked normal,’ Dietz says.
The team next tried waiting until mice with the SSS mutation had developed fibrosis, then treating them with a compound known to block a key molecule with known connections to both fibrosis and the immune response. This reversed the mice’s skin fibrosis and immunologic abnormalities. The team also tested the compounds on lab-grown human skin cells with systemic sclerosis, with the same results. This raises the possibility that systemic sclerosis patients could eventually be treated with similar compounds in humans, Dietz says. A number of the compounds that proved effective in SSS mice and systemic sclerosis cells are currently being explored by drug companies for the treatment of other conditions, prominently including cancer.
The results raised another big question for the team: Which of the several types of skin cells were responsible for the runaway immune response and fibrosis? They traced the activity to so-called plasmacytoid dendritic cells, or pDCs, a cell type known to either tamp down or ramp up immune response, depending on the circumstances.
‘Dietz’s work gives scleroderma patients hope that we have gained fundamental insights into the process of fibrosis in scleroderma. In particular, I am confident that within a relatively short time, novel therapies can be tested in patients, and I am optimistic that such treatments will have a profound effect,’ says Luke Evnin, Ph.D., chairman of the board of directors of the Scleroderma Research Foundation and a scleroderma patient. John Hopkins Medicine

Huskies football defensive lineman Caleb Eidsvik takes up a lot of room as he sits on an examining table in the Huskies trainer’s room at Griffiths Field, patiently waiting for pharmacology student Hungbo Qudus to draw a small sample of his blood.

At six-foot three and 260 pounds, Eidsvik exudes strength and good health. And that’s the problem, according to researcher Changiz Taghibiglou, since Eidsvik is suspected of having a concussion.

‘There’s no easy way to conclusively diagnose concussion now. You need an MRI or a CT scan,’ he said. ‘Whether it’s car accidents, falls or sports injuries, we actually don’t have any simple tests.’

Taghibiglou is an assistant professor in the College of Medicine’s Department of Pharmacology. If he gets his way, testing for concussion will be so simple that a test kit will be a standard item in every medical bag, to be used by trainers and coaches at football fields and hockey arenas, and even by first responders and EMTs.

Diagnosis of concussion is critical. While short term symptoms such as vomiting, confusion and headache may be easy to spot, Taghibiglou explained that long-term effects can be more subtle and easier to brush off. This can be extremely dangerous: if the person suffers a second concussion before fully recovering from the first, they are at high risk of developing permanent brain damage, psychiatric problems or even dying. There are also risks of long term effects, including Parkinson’s and Alzheimer diseases, and post-traumatic stress disorder.

At the heart of Taghibiglou’s concussion test is a molecule that exists on the surface of brain cells. Through research carried out with scientists at the Canadian Department of National Defence, a link was found between the molecule and brain trauma. This research is ongoing and represents one of the agency’s many inquiries into the effects of battlefield blasts on soldiers.

‘Physical injuries are easy to spot but with a concussion a person can appear fine,’ Taghibiglou said. ‘In the worst case, there are no outward signs of injury so they are sent back out, re-injured, and suffer significant neurological issues later.’

Taghibiglou explains that head trauma – whether from an accidental blow to the head, a hard slam on the gridiron or a forceful check against the boards – can knock certain brain cell molecules loose. Once free, they circulate in the blood where they can be detected by a simple blood test (a patent for the test has been applied for through the U of S Industry Liaison Office).

Working with Huskie Athletics, Taghibiglou, Qudus and graduate student Nathan Pham are gathering blood samples from athletes pre- and post-injury. Taghibiglou praised Director of Huskie Athletics Basil Hughton and Huskies Head Therapist Rhonda Shishkin for arranging access, particularly during peak season.

‘We’re collecting from the football team and are also looking for concussion in other teams such as soccer and hockey,’ he said.

Since the test is so new, the research team also needs about 300 male and female volunteers to donate small blood samples to establish the normal level of the concussion-associated molecules in the blood.

‘There are no values in the reference books, simply because no one has gathered the data yet. Our ultimate goal is a simple diagnostic test, much like the blood sugar tests used by diabetics.’ The test would be particularly valuable for rural and remote communities that lack the medical equipment typically used for trauma diagnosis.

‘Small health clinics don’t have an MRI. It may help rural doctors refer their patients to larger centres and know what’s going on.’ University of Saskatchewan