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• Gene study explains why smokers are burning the fat as well as cigarettes 

But the real reason why people pile on the pounds after quitting smoking could lie in our DNA.

Scientists have identified a fat-burning gene that becomes more active when exposed to cigarette smoke.

The finding could help explain why slim smokers find their weight starts to balloon after the final cigarette is stubbed out.

But anti-smoking groups warned against smokers using the research to justify a habit that kills more than 120,000 Britons a year.

The scientists, from Cornell University in New York, focused on a gene called AZGP1 (alphazincglycoprotein1) which makes a protein that speeds up the breakdown of fat.

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• NCI, Canary Seek Non-smoking Lung Cancer Causes 

The National Cancer Institute and the Canary Foundation are partnering to fund a number of studies aimed at understanding the genetic causes of lung cancer in non-smokers and developing early-stage diagnostics.

NCI's Early Detection Research Network and the Canary Foundation will give $1 million each to a number of studies that will involve genomic and RNA analysis, protein and tumor biomarker discovery, transcriptomics, cellular alterations, and other research areas. The partners did not say how much in total funding they intend to disburse under the collaboration.

There is a need for such research because as many as 25 percent of lung cancers cases are not attributable to smoking, but the disease in non-smokers can be missed in its early stages, according to the National Institutes of Health. The disease in non-smokers also differs in many ways than it does in cases involving smoking.

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• In Utero Smoke Exposure, Glutathione S-Transferase P1 Haplotypes, and Respiratory Illness-Related Absence Among Schoolchildren  

BACKGROUND. The GSTP1 Ile105Val variant and secondhand tobacco smoke exposure have been independently associated with acute respiratory illness; however, susceptibility to in utero and secondhand tobacco smoke has yet to be examined in relation to variation across the GSTP1 locus. . . .

CONCLUSIONS. A common GSTP1 haplotype, which includes the functional Ile105Val polymorphism, was associated with respiratory-related school absences. The protection afforded by this haplotype was lost in children exposed to involuntary tobacco smoke. The paradigm of loss of genetic protection among those exposed to tobacco smoke has clinical and public health implications that warrant broader consideration in research and practice.

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• Throwing the micro switch: MicroRNA may link smoking risk gene to neurobiology of addiction 

In the traditional genetic dogma, DNA codes for RNA and RNA codes for protein. But what about the leftover bits of RNA that do not seem to code for proteins? One type of RNA 'leftovers' is the microRNAs. These small pieces of RNA do not code for proteins. Instead, they influence the extent to which other genes are expressed, i.e., the rate or extent of conversion of DNA to RNA. To date, there have been relatively few examples of the direct involvement of microRNAs in psychiatric disorders.

However, a study scheduled for publication in the April 15th issue of Biological Psychiatry (http://www.elsevier.com/locate/biopsychiat), published by Elsevier, has now provided new insights into how variation in the dopamine D1 receptor gene (DRD1) may be linked to the risk for nicotine dependence through microRNA action.

Huang and Li, researchers at the University of Virginia, previously showed that the DRD1 gene, one of the major receptors in the brain that mediate the actions of the neurotransmitter dopamine, is associated with tobacco dependence, and that two alleles of a variant within this gene are differentially expressed. "In the current study, we demonstrated that such differential expression of DRD1 is regulated by microRNA miR-504," explains Dr. Li.

In other words, this microRNA seems to directly influence how these genetic variations are expressed within the DRD1 gene, thereby influencing ones risk to developing nicotine dependence. John Krystal, M.D., Editor of Biological Psychiatry, comments: "This study provides an interesting example of how variation in a gene that contributes to the risk of smoking may do so by throwing a 'micro switch' and thereby increasing the expression of the dopamine 1 receptor gene."

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• Experts Highlight Inroads to Preventing Cancer  

Scientists looking at everyday factors that influence cancer risk are finding important new clues that could affect cancer prevention strategies.

"Many of us believe that prevention is better than trying to identify drugs for people after they get cancer," said Dr. Peter Shields, deputy director of the Lombardi Comprehensive Cancer Center and interim chairman of the Department of Medicine at Georgetown University Medical Center in Washington, D.C. "As we understand risk factors better, it may be possible to personalize cancer prevention."

Shields moderated a Monday teleconference highlighting cancer prevention-related findings that are being presented at the annual meeting of the American Association for Cancer Research, in Denver.

One study found that two common gene variants do not protect individuals from the ill effects of smoking.

In the study, smoking boosted the odds for the two most common types of colorectal polyps: adenomas and hyperplastic polyps, although the association was stronger in the latter.

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• 'Cancer risk of nicotine gum and lozenges higher than thought' 

Nicotine chewing gum, lozenges and inhalers designed to help people to give up smoking may have the potential to cause cancer, research has suggested.

Scientists have discovered a link between mouth cancer and exposure to nicotine, which may indicate that using oral nicotine replacement therapies for long periods could contribute to a raised risk of the disease. A study led by Muy-Teck Teh, of Queen Mary, University of London, has found that the effects of a genetic mutation that is common in mouth cancer can be worsened by nicotine in the levels that are typically found in smoking cessation products.

The results raise the prospect that nicotine, the addictive chemical in tobacco, may be more carcinogenic than had previously been appreciated.

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• Ohio researchers ID gene related to lung cancer 

A gene identified by University of Cincinnati researchers could be used to identify people at high risk for developing lung cancer.

Smokers with the gene could be directed toward earlier, more aggressive lung cancer checks, said Marshall Anderson, the cancer biologist who led the study, while younger people with the gene could be discouraged from smoking in the first place.

Discovering the gene, dubbed RGS17, "could change clinical diagnosis and treatment as radically as the discovery of the breast cancer genes did," Anderson said. "A proven genetic test could help us identify people at risk before the disease progresses."

Anderson has led the multi-institutional Genetic Epidemiology of Lung Cancer Consortium since 1997.

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• Gene Variants May Determine Lung Function and Susceptibility to Maternal Smoking 

A tiny variation within a single gene can determine not only how quickly and well lungs grow and function in children and adolescents, but how susceptible those children will be to exposure to second-hand tobacco smoke, even in utero, according to researchers from the University of Southern California.

“Many factors can affect lung function and growth, including genetic variation and environmental exposures such as tobacco smoke and air pollutants,” said Carrie Breton, Sc.D., lead author of the study conducted at the University of Southern California. “We wanted to determine whether specific gene variations would have measurable and predictable effects on lung function growth and susceptibility to environmental insults. We looked at a class of genes known to be involved in antioxidant defense, the glutathione-s transferase (GST) genes. Overall, we found that variation in several of the GST genes was important. This was particularly true for children of mothers who had smoked during pregnancy.”

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• Genetically Stratifying Smoking-Cessation Trials Could Save Up to $15M, Researchers Find  

With genotyping costs declining and the cost of conducting conventional trials increasing, researchers from the National Institutes of Health and Duke University have modeled data suggesting it may save money to genetically stratify patients in clinical trials for smoking cessation.

In mid-sized Phase II trials enrolling around 200 patients, "there was the clearest benefit for genotyping under a wide range of assumptions, [such as] cost per subject for the trial and genotyping cost per subject," lead study author George Uhl of the National Institute on Drug Abuse, told Pharmacogenomics Reporter this week.

The findings of the study, published in The Pharmacogenomics Journal, shed light onto the circumstances in which genotyping may be cost-effective in smoking-cessation studies, and could help inform the design of studies for other addictions and disease indications, the study authors noted.

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• Caltech Researchers Find Tiny Genetic Change Keeps Nicotine from Binding to Muscle Cells 

A tiny genetic mutation is the key to understanding why nicotine--which binds to brain receptors with such addictive potency--is virtually powerless in muscle cells that are studded with the same type of receptor. That's according to California Institute of Technology (Caltech) researchers, who report their findings in the March 26 issue of the journal Nature.

By all rights, nicotine ought to paralyze or even kill us, explains Dennis Dougherty, the George Grant Hoag Professor of Chemistry at Caltech and one of the leaders of the research team. After all, the receptor it binds to in the brain's neurons--a type of acetylcholine receptor, which also binds the neurotransmitter acetylcholine--is found in large numbers in muscle cells. Were nicotine to bind with those cells, it would cause muscles to contract with such force that the response would likely prove lethal.

Obviously, considering the data on smoking, that is not what happens. The question has long been: Why not?

"It's a chemical mystery," Dougherty admits. "We knew something subtle had to be going on here, but we didn't know exactly what."

That subtlety, it turns out, lies in the slight tweaking of the structure of the acetylcholine receptor in muscle cells versus its structure in brain cells.

The shape of the acetylcholine receptor, and the way the chemicals that bind with it contort themselves to fit into that receptor, is determined by a number of different weak chemical interactions. Perhaps most important is an interaction that Dougherty calls "underappreciated"--the cation-pi interaction, in which a positively charged ion and an electron-rich pi system come together.

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• Smoking ups brain-bleed risk with family history  

Smokers whose family members have had a type of bleeding stroke are six times more likely to suffer the same fate than people without these risk factors, according to a new study.

The stroke type known as an "aneurysmal subarachnoid hemorrhage" -- essentially a burst blood vessel in the brain -- runs in families, note Dr. Daniel Woo and others in the medical journal Neurology, and they wanted to see if smoking added to the hereditary risk.

Their study, funded by the National Institute of Neurological Disorders and Stroke, compared 339 patients with aneurysmal subarachnoid hemorrhage with 1016 "controls" without the condition, matched by age, race and gender.

Compared with non-smokers, smokers had more than three times the risk of an aneurysmal subarachnoid hemorrhage. The risk in smokers without a family history of this condition was increased by 2.5-fold, but the combination of a family history and smoking raised the risk more than a six-fold

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• Genes May Decide Which Smokers Get Lung Disease  

Genes may be the reason why one-quarter of smokers develop chronic obstructive pulmonary disease (COPD), while the rest aren't afflicted with the serious breathing problem, U.S. researchers conclude.

They studied a gene called ADAM33 in 880 long-term heavy smokers with and without COPD. Previous research has linked ADAM33, which is located on chromosome 20, with asthma.

The researchers from the Wake Forest University School of Medicine and Saint Louis University identified five single nucleotide polymorphisms (SNPs) -- human DNA sequence variations -- in ADAM33 that were more common in smokers with COPD than in those without the disease.

There was a particularly strong link between an SNP called S1 and lung abnormalities.

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• Combination of Genes and Prenatal Exposure to Smoking Increases Teens' Risk of Disruptive Behavior 

A study funded by the National Institute on Drug Abuse, a component of the National Institutes of Health, shows that prenatal exposure to smoking combined with a specific genetic variant places children at greatest risk for behavioral problems. Many studies have established that there is an increased risk of aggressive behavior in children exposed to cigarette smoke before birth, a significant problem given that many women still smoke during pregnancies. According to the National Survey on Drug Use and Health, in 2006-2007 slightly more than 16 percent of pregnant women aged 15-44 (426,000) were current cigarette smokers.

A team of researchers led by the Institute for Juvenile Research, University of Illinois at Chicago, identified a long-lasting influence on behavior of the monoamine oxidase A (MAOA) gene variant following tobacco exposure before birth. MAOA is an enzyme which regulates key neurotransmitters[*], or chemical messengers in the brain. Strikingly, the genetic variant that confers this increased risk differs between boys and girls.

"These findings illuminate how the interaction between genes and the environment can mold behavioral patterns very early in development," said NIDA Director Dr. Nora Volkow. "This research provides a foundation for studies of the impact of these interactions on brain development during pregnancy."

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• Smokers Have Rapid Aging Defect 

Cigarette smoke causes the same cellular defect seen in people with Werner's syndrome -- a rare genetic disease that makes people age very fast.

Smoking speeds the aging process, causing smokers to die about 10 years before their time. Now researchers may have found a clue to this process, giving them unexpected new paths to treatment.

The clue comes from the observation that smokers aren't the only people who age too fast. In their 20s, people with a rare genetic disorder called Werner's syndrome get gray hair, thin skin, and hoarse voices.

They soon develop cataracts, diabetes, hardening of the arteries, and weak bones. In their 40s or 50s, they tend to die of heart disease and cancer.

Smokers also age prematurely and tend to die of heart disease and cancer. Might there be a link?

Yes, say University of Iowa researchers Toru Nyunoya, MD, and colleagues.

Werner's syndrome is caused by a mutation in a gene called WRN. The gene makes the WRN protein that protects and repairs DNA in every cell of the body. . . .

When the researchers cultured lung cells in the laboratory, they found that cigarette smoke extract decreased the cell's WRN production -- and made the cells age more quickly.

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• Effects Of Smoking Linked To Accelerated Aging Protein 

A University of Iowa study is apparently the first to make a connection between a rare, hereditary premature aging disease and cell damage that comes from smoking. The study results point to possible therapeutic targets for smoking-related diseases.

The investigation found that a key protein that is lost in Werner's syndrome is decreased in smokers with emphysema, and this decrease harms lung cells that normally heal wounds. The findings appear in the Feb. 6 issue of the American Journal of Respiratory and Critical Care Medicine.

While people know that smoking is bad for health, not all the mechanisms by which smoke damages the body are fully understood, said Toru Nyunoya, M.D., assistant professor of internal medicine at the University of Iowa Carver College of Medicine and a pulmonologist with University of Iowa Hospitals and Clinics.

"Smoking can accelerate the aging process and shorten the lifespan by an average of more than 10 years. We focused on what happens within the lungs because of the similar aging effects, including atherosclerotic diseases and cancer, seen in people with Werner's syndrome and people who smoke," said Nyunoya, whose study was based in the lab of senior author Gary Hunninghake, M.D., University of Iowa professor of internal medicine and a researcher with the Iowa City Veterans Affairs Medical Center. . . .

"Werner's syndrome involves a genetic mutation that causes a deficiency in what's known as Werner's syndrome protein. The protein normally helps repair DNA damage," Nyunoya said. "Smoking does not appear to cause the same mutation, but our study showed that it does decrease Werner's syndrome protein."

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