For many women, finding out they’re pregnant is the kick in the pants they need to quit smoking.  But for some, a genetic variation may stand in their way.

The SNP rs1051730 is located in a cluster of genes on chromosome 15 that are involved in regulating the brain’s response to nicotine. Studies have already shown that the SNP is associated with nicotine addiction. Now a new report, published online last week in the journal Human Molecular Genetics, suggests that the effect of this variation is strong enough to overcome the maternal instinct and social pressure to protect one’s unborn child from the harmful effects of cigarette smoke.

British researchers studied 2,474 women who smoked regularly before becoming pregnant.  When questioned about smoking during their first trimester, 31% of the women with two Gs at rs1051730 had kicked the habit, compared to only 21% of the women with two As.  During the third trimester, 47% of women with two Gs were smoke-free, while only 34% of women with two As were.

Overall, after adjusting for pre-pregnancy smoking quantity, the researchers calculated that each A at rs1051730 increases a woman’s odds of continuing to smoke throughout her pregnancy by about 1.2 times.

The authors say their results show how genes can influence what is perceived by many to be a matter of self-control, but that “it’s in my genes” shouldn’t used as an excuse to avoid giving up smoking during pregnancy.

23andMe customers can check their data for rs1051730 using the Browse Raw Data feature.  This SNP is also featured in the Nicotine Dependence Research Report.  For more information, check out the following Spittoon posts related to this SNP:

• SNPwatch: Genetic Variation Linked to Smoking and Lung Cancer Might Also Raise Risk for COPD
• How A Person Smokes Might Affect Lung Cancer Risk
• SNPwatch: Two Vices, One SNP — Drinking and Smoking Behavior Both Linked to Nicotine Receptor Genes
• SNPwatch: Focusing on a Gene Variant that Might Help Counter Cigarette Cravings
• SNPwatch: “Environment” also genetic?

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A new discovery could someday help identify smokers at risk for chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the United States.

More than 12 million people in the U.S. have been diagnosed with COPD, and another 12 million may have the condition and not know it.  These people have difficulty breathing due to excessive inflammation in their lungs that has narrowed their airways.  The cause of the inflammation is usually prolonged exposure to an inhaled irritant, most often cigarette smoke. Nine out of ten COPD deaths can be attributed to smoking.

But even though most people with COPD are current or former smokers, not every smoker gets COPD.  Only about 20% will develop the disease, suggesting that there might be genetic factors that make some smokers more susceptible than others. New research, published yesterday in the journal PLoS Genetics, suggests that variation in a genetic region on chromosome 15 previously linked to nicotine addiction, lung cancer and peripheral artery disease might also increase the risk for COPD.  In light of the mounting evidence for the importance of this stretch of DNA, the authors of the new report suggest that genetic screening of smokers in order to find those at the highest risk may be an attractive interventional strategy.

Sreekumar Pillai, a scientist at GlaxoSmithKline, and colleagues from several research institutions studied a total of more than 5,000 people with European ancestry and found that each A at the SNP rs1051730 on chromosome 15 increased odds of COPD by about 1.3 times.  They also found that each C at SNP rs8034191 increased the odds of COPD by about 1.4 times. The two SNPs are very close to each other and probably both mark the same variation affecting COPD risk, although the authors did not test this.

[23andMe customers can check their data for rs1051730 and rs8034191 using the Browse Raw Data feature.  Keep in mind that because the SNPs are closely linked, having the same version of both (either non-risk or risk) is expected.  A riskier version at both does not indicate doubled risk.]

Research has shown that in smokers, each A at rs1051730 is associated with smoking one more cigarette per day.  Whether rs1051730 is linked to lung cancer and peripheral artery disease because of or in addition to its effects on smoking has been controversial.  The authors of the current study say that while their data does not allow them to solve this dilemma with regard to the effects of the chromosome 15 SNPs on COPD, several aspects of their study indicate that the genetic variation has a direct effect on the disease, independent of smoking behavior.

The authors do note, however, that in some subsets of their study population the effect of the riskier versions of the genetic variations was greater in current smokers compared to former smokers.  This could mean that people who have a harder time quitting are more likely to develop COPD.  Alternatively, it could be the case that some people are at higher risk for COPD if they continue to smoke.

The researchers also found evidence for variations contributing to COPD on chromosome 4, although the results were not statistically significant. However, this same region of DNA was correlated with lung function in a different report in same issue of PLoS Genetics.  Both research groups pointed out that the nearest gene to the chromosome 4 variations they identified is involved in lung development, suggesting that future research targeting these variations might reveal more insight into COPD and other lung diseases.

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For many common diseases, environment is far more important than genetics in determining whether a person will be affected. One of the best examples of this is lung cancer. Nearly 90% of the cases of this disease can be attributed to smoking.

Today at the American Association for the Advancement of  Science meeting in Chicago, however, Thorgeir Thorgeirsson of deCODE Genetics suggested that genetics may help foster a better understanding of the environmental risk factors for lung cancer.

Several studies published in April 2008, including one authored by Thorgeirsson, showed that a variation on chromosome 15 is associated with increased odds of lung cancer.  Thorgeirsson’s group also showed that this same variation is associated with increased smoking – about one cigarette per day per copy of the riskier version (Read more here.)

Together these findings raise an important question:  does this variation increase the odds of cancer because it increases the amount a person smokes?

According to Thorgeirsson, there should be only a 5% increase in the odds of developing lung cancer based on the increase in smoking associated with the genetic variation. But the data indicate that each copy of the riskier version actually increases odds of the disease by about 30%.

This, Thorgeirsson suggested, could mean that the variation is associated not just with smoking quantity, but also with another behavior, such as how deeply a smoker inhales or how far down he usually smokes his cigarettes.  He noted a recent study published in Cancer Research that found that, compared to smokers without the genetic variation, those with it take in more nicotine and carcinogens with every cigarette.

Another possibility is that the variation has a dual effect.  It could increase not just smoking quantity, but also the vulnerability of a person’s cells to the harmful effects of the smoke.

Although there’s still much work to be done in order to fully understand the effects of this particular genetic variation, the results so far hint at the fact that genes and environment may for more interconnected than previously appreciated.

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Our SNPwatch posts here at The Spittoon are one of our most exciting features. They give our customers the opportunity to connect their genetic data to the newest discoveries, often within just hours of a study’s publication.

Looking ahead to 2009, we can only begin to imagine the exciting discoveries that will be made in genetics. In the meantime, here are a few of our favorite SNPwatches from 2008:

SNPs That Affect Drug Response
We reported on several studies this year that showed the importance of genetic variations in determining how different people react to certain medications.

• A report in Nature Genetics showed that some women with a particular version of a SNP in the NQO1 are less likely to survive breast cancer after treatment with the commonly used chemotherapeutic epirubicin.
• A study by the SEARCH Collaborative Group found that a version of one SNP is associated with an increased risk for myopathy (muscle pain and/or weakness) in people taking cholesterol-lowering drugs called statins.
• Mayo clinic researchers found that the weight loss drug sibutramine (Meridia) is effective only in people with specific versions of three different genes.
• And just this month we brought you news of three studies that showed that a genetic variant known to affect the metabolism of the anti-clotting drug clopidogrel (Plavix) also affects heart attack patients’ risk of a second major cardiovascular event.

Shared SNPs
Sometimes multiple conditions strike the same person or run in families. Several studies published this year showed that shared genetic risk factors may be part of the reason why.

• Obesity is a known risk factor for many cancers. Researchers found that a variant of adiponectin, a hormone released by fat cells, can increase the risk of developing colorectal cancer.
• Other researchers found variants that affect the risk of developing both type 1 diabetes and celiac disease, two autoimmune diseases that tend to cluster together. One of these shared variants is also associated with HIV resistance.
• Finally, a report published this month in the Proceedings of the National Academy of Sciences showed that a single genetic variant can make a person prone to greater indulgence in both smoking and drinking.

SNPs Associated with Risk Factors for Disease
Several studies this year looked beyond disease itself and instead found associations between SNPs and traits known to be risk factors for disease.

• One study found an association between several SNPs and fasting plasma glucose, a measure of how well a person’s body can control blood sugar levels – a process that goes awry in diabetes.
• Another research group reported SNPs associated with glycated hemoglobin levels, a measure of long-term blood sugar control and another factor associated with the risk of developing diabetes.
• The findings of three papers published in Nature Genetics roughly doubled the number of SNPs associated with blood levels of cholesterol and triglycerides, important risk factors for cardiovascular disease.
• And finally, in a study that looked at behavior instead of metabolic markers, researchers found that a variant in the FTO gene known to increase the risk for obesity affects food choices in children, pushing them towards foods denser in calories.

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When the toxins in cigarette smoke are inhaled, lung cells don’t just sit there and take it. A complex network of proteins is activated with every puff. The proteins break down, modify, or pump out as many of the hundreds of cancer-causing chemicals in tobacco smoke as possible.

But when this system fails or falls behind, toxins have a chance to damage cells. New results published online this week in Cancer show that variants in the genes for ABCB1 and ABCC1, two important pump proteins that transport a variety of toxins out of lung cells, increase the risk of lung cancer.

Haijian Wang and colleagues studied 500 lung cancer patients and 517 healthy controls from Nanjing City and the surrounding area in southeast China. They found that, overall, having one or two Cs at rs3842 in the ABCB1 gene was associated with 1.36 times increased odds of lung cancer compared to having two Ts. For rs212090 in the ABCC1 gene, having one or two As increased the odds by 1.37 times.

(23andMe customers can use the links above to check their data using the Browse Raw Data feature.)

Further analysis showed that the C version (one or two copies) of rs3842 increased the odds of lung cancer in women of all ages by 2.57 times and by 1.5 times in those younger than 60. The A version of rs212090, on the other hand, was not significantly associated with lung cancer in those under 60, but did increase the odds by 1.6 times in those 60 and above. In those people with a history of cancer in a first-degree relative (parent, sibling or child), the C version of rs3842 increased the odds of lung cancer by 1.91 times.

A final correlation the authors found was between the riskier C version of rs3842 in the ABCB1 gene and a specific type of lung cancer called adenocarcinoma. The authors say that the rates of this type of cancer has been increasing in the last few decades, as has the amount of a specific carcinogen in cigarette smoke that is dealt with by the ABCB1 protein.

“Because tobacco smoking is the leading preventable cause of cancer and the cancer –prone genotypes of these genetic components are relatively prevalent in the human population, our findings have important implications for the prevention of tobacco smoking-related cancers,” the authors write.

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As anyone who indulges in both smoking and drinking can tell you, the two are a natural — if unhealthy — combination. Now research suggests that some people possess a single genetic variation that makes them prone to greater indulgence in both vices — and the attendant health risks.

Several research papers published in the last year or so show that a cluster of genes on chromosome 15 encoding nicotinic receptors, which regulate the brain’s response to nicotine, are related to smoking behavior. We cite one of those papers in the 23andMe Health and Traits entry for Nicotine Dependence — it shows that on average, smokers with an A at both copies of the SNP rs1051730 light up once more per day compared to those with the AG or GG genotype.

The authors of the new study, which appears in the latest issue of the Proceedings of the National Academy of Sciences, noted that connection between chromosome 15 and nicotine dependence. They also observed the fact that twin studies have established a genetic connection between smoking and alcohol abuse and that experiments show mice consume less alcohol when treated with a drug that blocks nicotinic receptors.

So the researchers, who were from the Ernest Gallo Clinic and Research Center in Emeryville, Calif., and the University of California, San Diego, reasoned that the very same genetic variations recently associated with smoking behavior could influence drinking as well. To test that hypothesis, they genotyped 367 participants aged 18 to 29 and tested them on various measures of alcohol response. Those with an A at both copies of rs1051730 were better able to maintain their coordination after drinking a given amount of alcohol and reported feeling less drunk compared to those with either the AG or GG genotypes. The researchers also found a second SNP nearby on chromosome 15 — rs8034191 — that was also linked to alcohol sensitivity. In that case, having a C at both copies of the SNP decreased a person’s response to alcohol. 23andMe customers can check their own genotypes at both SNPs using the Browse Raw Data feature.

Some people might consider it good news to learn that they have a genetically enhanced ability to hold their drink. But a reduced response to alcohol increases a person’s risk of alcohol abuse. So in addition to causing people who do smoke to light up more often, this particular genetic signature also appears to threaten health by increasing a drinker’s chances of developing problems with alcohol.

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“I feel like a fish with no water.”

That’s how the child in the public service announcement featuring a flopping, gasping goldfish describes what it feels like to have an asthma attack. The spot encourages parents of the close to nine million kids who suffer from asthma to take steps to decrease the number of attacks their kids have because, as the announcer says, “even one attack is one too many.”

Both environmental factors – things like mold, pollen, cold air and cigarette smoke — and genetic factors are thought to contribute to childhood asthma, a disease that causes more than 10 million missed days of school and leads to about two million trips to the emergency room each year.

Researchers are beginning to realize that asthma that strikes early in life may be a distinct disease from cases that set in later. In 2007, a genomewide association study linked several related SNPs in a region of chromosome 17 specifically to childhood asthma. New research published online today in the New England Journal of Medicine confirms these genetic findings and adds a new twist: the SNPs have an effect only in kids exposed to tobacco smoke.

(23andMe customers can check their data for one of the chromosome 17 SNPs associated with childhood asthma in Research Reports.)

Bouzigon and colleagues studied several hundred French families and found a number of SNPs linked with asthma on chromosome 17, just as in earlier studies. The SNPs were associated only with asthma that began at age four or younger.

Like previous researchers, Bouzigon et al could not determine exactly how the SNPs are related to childhood asthma risk; but they could clearly show that the variants’ effects are triggered by exposure to tobacco smoke. The researchers found that the overall risk of early-onset asthma was increased at least 1.7-fold for people with two risky copies of any of the SNPs compared to those with none or only one. But when they took smoking into account, they saw that children with two risky copies of any of the SNPs who were also exposed to tobacco in utero, during infancy or both actually had risk at least 2.3-fold higher than those with the more favorable genotypes. The SNPs had no statistically significant effect among children who were not exposed to tobacco smoke early in life.

In an accompanying editorial in NEJM, two researchers not involved in the study — John Holloway and Gerard Koppelman — say that the influence of early life events in the development of asthma is well supported, and that the interaction of genes and tobacco smoke seen by Bouzigon and colleagues “further highlights the detrimental effect of such early life exposure on respiratory health.”

But, say Holloway and Koppelman, the importance of the exact timing of exposure to tobacco smoke is not clear, as Bouzigon et al could not differentiate between prenatal and postnatal exposure.

Although more research will be needed to confirm the results in this new report, Holloway and Koppelman think that as more is learned about how chromosome 17 variants affect asthma risk, this knowledge may help physicians better treat the disease.

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Tobacco use is the leading cause of preventable deaths in the United States — every year it kills nearly 440,000 Americans.

While about 70 percent of the 45 million Americans who currently smoke have said they want to quit, the Centers for Disease Control and Prevention estimates that only about 10 percent of them will succeed, due in large part to the addictive qualities of the active ingredient in tobacco, nicotine.

Researchers have been looking at the genetic basis of nicotine dependence, characterized by tolerance to the drug and the presence of withdrawal symptoms in its absence, with the long-term goals of better assessing a person’s risk for addiction and potentially developing targeted treatments.

Last year, Laura Bierut and her colleagues at the Washington University School of Medicine identified a single variant in a nicotine receptor that increases a person’s risk of developing nicotine dependence. A later study indicated the same SNP can actually reduce the risk of developing cocaine dependence. And now a study published this month by Bierut and her colleagues shows that the variant also influences how much pleasure a first-time smoker will experience from the first puff of a cigarette.

“The type of variant you have at this particular receptor — the alpha-5 nicotinic receptor — may actually predict whether or not you will do well on nicotine replacement therapy,” Bierut said in a statement at the time.

The version of SNP rs16969968 that can increase the risk for nicotine addiction is found at appreciable levels only in European populations. People with two copies of the less common A version of the SNP are twice as likely to develop nicotine dependence when exposed to smoking than people with two copies of the more common G version.

(This SNP isn’t in 23andMe’s database, but we do have data on an equivalent SNP: rs1051730, which has also been linked to nicotine dependence in European populations, as The Spittoon previously mentioned here. As with rs16969968, the rarer A version of rs1051730 is associated with increased nicotine dependence compared to the more common G version. Though both SNPs have the same effect on nicotine dependence, the size of the effect caused by rs1051730 may be slightly larger or smaller compared to the SNP Bierut and her colleagues study.)

A new study from Bierut’s group published this month in the journal Addiction shows that the same version of rs16969968 previously associated with nicotine dependence is also linked to the pleasurable rush some first-time smokers get. Each A at rs16969968 increased a person’s odds of having found that first puff pleasurable by 1.6 times compared to people with no copies of an A. This “buzz” was in turn associated with an 8-fold increase in odds of being a current smoker.

“The finding of a genetic association with pleasurable early smoking experiences may help explain how people get addicted — and, of course, once addicted, many will keep smoking for the rest of their lives,” said the study’s senior author Ovide Pomerleau in a statement.

“It appears that for people who have a certain genetic makeup, the initial physical reaction to smoking can play a significant role in determining what happens next. If cigarette smoking is sustained, nicotine addiction can occur in a few days to a few months.”

Bierut’s research on SNP rs16969968 also extends to addictive substances other than nicotine. Back in June, her group released a study that examined cocaine addicts and non-drug abusing controls to show that having the nicotine dependence-predisposing A version of this SNP actually decreases the risk for cocaine dependence. Having one A decreases the odds of cocaine dependence risk by about 33 percent; two copies decrease the odds by about 45 percent.

The involvement of this SNP in both nicotine and cocaine addiction, and its opposing effects, may seem perplexing. But Bierut and her colleagues suggest that the answer lies in how each addictive substance affects dopamine in the brain’s reward pathway – a key player in the pleasurable feelings produced by drugs that can lead to addiction.

Nicotine triggers the release of dopamine, a neurotransmitter that activates pleasure pathways in the brain. In contrast, cocaine produces pleasurable feelings by preventing the dopamine that is naturally released in the brain from being reabsorbed when its job is done. Excess dopamine hangs around in the brain and produces the “high” associated with the drug.

The nicotine receptor that rs16969968 affects is involved in normal dopamine release, even in the absence of nicotine. So when the A version of this SNP dials down the receptor’s activity, natural dopamine release is reduced. This means there is less dopamine available for cocaine to keep around in the brain, and the amount of pleasure the drug can induce is diminished, possibly enough to keep a person from getting addicted.

Image from FreeDigitalPhotos.net

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Despite the success of genome-wide association studies, many experts rightly point out the need to remember that most common diseases have a significant environmental component. For example, cigarette smoking increases one’s risk of lung cancer 10- to 20-fold, according to the National Cancer Institute. But other studies have found that even after controlling for smoking, having first-degree relatives with lung cancer increases one’s own risk by a modest amount, suggesting at least a small genetic component.

A trio of papers published today in Nature and Nature Genetics has found a SNP on chromosome 15 that is linked to lung cancer risk. Two of the studies, by Hung et al. and Amos et al., matched lung cancer cases and healthy controls for smoking behavior and compared their genotypes across 300,000 SNPs. Both studies found that one copy of the A version of rs1051730 increased subjects’ odds of lung cancer by about 1.3 times compared to those with none; having two copies increased subjects’ odds by 1.8 times. (23andMe users can see their genotype at rs1051730 in the Genome Explorer (now called Browse Raw Data).)

A 1.8-fold increase may not seem like much compared to the 10- to 20-fold increase seen for smokers. But if this genetic effect is independent of the effect of smoking, smokers with the AA genotype might find themselves at 18- to 36-fold increased risk compared to nonsmokers with the GG genotype.

A third study questions whether the SNP’s effect on lung cancer risk is truly independent of smoking. Thorgeirsson et al. found evidence that the same SNP, rs1051730, is actually linked to nicotine dependence. On average, each copy of the A version increased the number of cigarettes subjects smoked by about one cigarette per day. The authors also reported that most of the increased risk of lung cancer conferred by the A version was due to its effect on smoking. Thus, an environmental component itself appears to have a genetic component.

However, the effect of rs1051730 on smoking quantity was seen only if a subject smoked at all. Genotype at rs1051730 wasn’t connected with whether subjects smoke, only with how much they smoke once they start.

So in the nature vs. nurture debate, perhaps there is room for free will after all.

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