A NEW LINK: Research shows smoking as a teenager is associated with greater consumption of cigarettes as an adult and a stronger addiction to smoking in adulthood. A recent breakthrough study revealed a link between a genetic variant and early-onset nicotine addiction. The research, conducted at University of Utah, shows those who begin smoking at or before age 16 are likely to suffer a severe dependence on nicotine as adults. Although much research points to an association between early-onset smoking and severe addiction in adulthood, this study is the first to link gene variances, adult addiction and the age at which smoking begins. A related finding in the same study suggests another genetic variant actually protects against nicotine addiction in adulthood. Although the study only involved European Americans, researchers say the findings will likely apply to other populations.
WHAT NOW? During the teenage years, the human body is highly sensitive to nicotine reward and not very sensitive to nicotine's negative effects. This knowledge, coupled with the recent discovery of a genetic link to addiction in adulthood, leads experts to speculate on a possible plan to put a dent in the smoking epidemic. Study authors say one of the next steps is to identify those who have the risky genetic factor and create targeted prevention and treatment plans for them. This could combat a portion of the smoking epidemic and perhaps lower the national burden of smoking-related illness.
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Robert Weiss, Ph.D., a professor of human genetics at the University of Utah in Salt Lake City, talks about the role genetics play in nicotine addiction.
What's the most important finding of this study? Dr. Weiss: The basic finding was that we demonstrated that amongst a set of genes that encode key components of the nervous system that respond to the presence of nicotine, these molecules called nicotinic receptors, that we've measured in our study variation in the normal population within those genes and within the receptors they encode; and then we ask, "Could we associate any of those variants with the measurement of nicotine dependence in long-term smokers?" This had been an approach that others had tried. At our stage in our study, we were able to do it fairly comprehensively with large numbers of smokers -- about 3,000 subjects -- and covering fairly exhaustively a large portion of the known variation in these genes. When we did that, there was one particular signal that we found that was associated with the dependence phenotype, a surrogate of the addiction to nicotine; and we found that that genetic signal was strongest in people who began smoking in their teen years. A known correlate [is] age of onset of smoking, that [is], if you began smoking when you were a teenager, you often have higher levels of lifetime dependence. We found that there's a genetic variant that will differentiate amongst long-term smokers and associate with people at higher levels as well as lower levels of dependence because of variation in one of these particular genes So basically, you can now prove genetically that people who start smoking at a younger age have a stronger dependence?
Dr. Weiss: It existed before we found the genetic effect. The question is, when you have these types of phenomena, they're going to be consisted both of perhaps an underlying biological susceptibility that's interacting with the environmental exposure -- in this case, the long-term exposure to nicotine and cigarette smoke. What we found is one part of that puzzle; but the overall puzzle is the behavior of daily smoking and what causes the nervous system to adapt to that exposure and manifest itself as a lifetime addiction to nicotine.
What percentage of smokers has this genetic variant?
Dr. Weiss: There are different ways you can do genetics in [a] human population. You can look for very rare phenotypes, and you can look for changes in a gene that would underlie that rare phenotype, say muscular dystrophy, where the most common form of muscular dystrophy affects perhaps one out of 3,000 people; so you have to find that rare person that has that genetic disorder, and then you can find the underlying genetic cause. The other approach to genetics these days is to try to find the influence of people's genotype on much more common diseases. Smoking affects a large portion of the current U.S. adult population. Twenty percent of the adult population are regular smokers, so we could ask amongst people in general where the genetics effects are, and rather than looking for rare phenotypes -- one out of a thousand smokers that perhaps has particular unusual smoking phenotype -- we look more in general amongst all smokers, and then asked, well, if we look at the spectrum of phenotypes, people who smoke only a few cigarettes per day versus people who smoke more than 25, can we find any genetic signal that would differentiate those people? That was one of our findings, that variation in this particular set of genes for nicotinic receptors segregated along that continuum, where people who smoked or were more heavily dependent tended to have one flavor of this gene, and people who were less dependent had another. That observation tells us at a more basic, biological level how the effect of nicotine is being elaborated into the complex phenotype of lifetime smoking behavior.
Is the takeaway for the general population that if they have this genetic variant, they'll have a harder time quitting smoking as adults?
Dr. Weiss: Smoking develops actually over a period of long-term exposure, so to go from experimentation through the transition to beginning to smoke regularly to eventually a pattern of behavior that becomes a daily habit is quite a lengthy process. What we measured is at the end stage of that and people who had been smoking for most of their lifetime, 25 years or more, and had begun to develop some phenotypes associated with long-term smoking; so a large portion of our population came from a study in which they were recruited for beginning symptoms of chronic obstructive pulmonary disease or emphysema and bronchitis that was related to their smoking behavior. We asked in those, was there an indication of whether or not their degree of smoking heaviness had an underlying genetic component? We found that in this case, this genetic measurement that we made, that they did, but only if they had begun smoking in their teen years. Somehow, we had the manifestation of a much earlier behavior or exposure of these people -- an exposure in their youth -- had manifested late in life as now an increased level of dependence, so it's sort of indicated that this window of vulnerability that exists for teenagers, part of that vulnerability, has an underlying genetic component that we could map precisely in the genome; and these genetic components, when you examine them, we're talking about just very subtle differences in people's genetic makeup, single nucleotide changes that can correlate now with a very complex outcome. In that sense, it gives an insight into the underlying biological mechanism, and a sense of entry points that we didn't have before in trying to understand why that period seems to be so critical and the eventual outcome of the exposure.
Is there a way to measure the percentage of smokers that would have this genetic variant?
Dr. Weiss: Sure. We measure that very precisely, and the frequency in people who are of European descent is about 40 percent in the population, and since we're diploid organisms, it means that the people who have two copies of this variant, or about 10 percent of the people; one copy, about 60 percent; and then no copies, 30 percent; so most people carry these different variants, and the frequency of that variant we measured, which we call the A variant of this gene, is the most prevalent. We also measured other variants of the gene, a B variant and a C variant, that are also prevalent and seem to have different effects on the behavior, so it's as if there are different varieties of this gene that are common in the population, and depending on what variant of the gene you happen to carry, it will influence your response to long-term smoking behavior. I should also mention that as we were doing this study -- and our phenotypes were mainly nicotine dependents, which is psychological measure -- we measured levels of dependence with a questionnaire. It's a detailed questionnaire, but it's not a biochemical measurement. It's a psychological measurement, so the ability to measure the influence of a gene on a psychological questionnaire is quite challenging, and part of the reason that these types of studies are difficult is that measured, simple measurements like cigarettes per day can vary over lifetime, and it's hard. There's variance in that measurement that make for levels of imprecision that make these studies challenging; but as we were doing our study, other groups were making similar genetic measurements on the outcomes of lung cancer, so they were using very large populations and measuring, in long-term smokers, people who went on to develop lung cancer versus ones that hadn't. Contemporaneously with our study on nicotine dependence, they found their way to the same set of genetic variants that are predictive of development of lung cancer among smokers than we did for development of nicotine dependents, and it's a finding that's still being sorted out in the scientific community of what that means. Does this gene have a dual role both as susceptibility as the carcinogenic properties and cigarette smoke, or is it really just the outcome of lung cancer, a surrogate of having a heavier and longer lifetime dependence and therefore having a longer lifetime exposure caused by the behavioral effect that we measured on the level of nicotine dependence? So that was an interesting intersection of two different approaches.
What percentage of teens has two copies of the genetic variant?
Dr. Weiss: The effect seems to be additive, so given the frequency of these variants, about 10 percent of people have two copies. When we look at the level of dependence against how many copies of the genes you have, the most highly dependent people have two copies, but it's more complicated than that. As I mentioned before, there are at least three flavors of this gene. We call them A, B and C, and what we measured more precisely in our study was that the A variant is the most frequent in the population, the B variant second at about 30 percent, the C variant at about 20 percent; and it seems to be what combination of these that you have that is correlating with the phenotype as well, so if you have two copies of A, you're most highly dependent. If you have one A and one B, you have an intermediate phenotype. If you have two copies of B, we don't measure any genetic effect at this locus with dependence at this gene. With dependence, where if you have a copy of A and C, C actually seems to be predictive of less dependence, so people who have one copy of C or two copies of C are actually less dependent than if they have the neutral variant, B; so what that's telling us is that basically there are variants in the population that's perturbing the activity of this gene, and you can perturb it in both ways -- you could make people who have one variety of this gene be more susceptible to be more highly dependent where if you have the other, you are actually less dependent than if you have neutral copies of this, and that seems a bit counter-intuitive. How can a gene be doing both things? One has to realize that the gene is still active.
It's not a loss of function measurement we're making. It's a modulation of the gene's function, so it's as if one variant perhaps pushes the activity in one direction. The other pushes it in another direction, but that's only on the dependence phenotype. It's more complicated than that in the sense that if we look at other phenotypes that have to do with withdrawal symptoms or cessation symptoms, what looked like protective in one situation actually may be more susceptible to more acute withdrawal symptoms. We're seeing levels of complexity that need to be taken into account that it's not that if you have this gene it makes you more susceptible; it's more that a variation in this gene changes people's individual response to their ability to deal with nicotine exposure.
If you have two copies of A, is it true you would be five times more at risk of being a heavy smoker as an adult?
Dr. Weiss: Yes.
Can you do anything to counteract the gene or identify people who have it before they smoke?
Dr. Weiss: I think that perhaps could be examined first in the context of, can it be used in identifying people on cessation treatments who might be more susceptible to relapse, and therefore be factored in on the intensity of the treatment? I think that has to be measured now in settings in a controlled fashion to see if it's predictive at all, so the predictive use of this type of information really awaits further study. I think what it does currently is it reinforces that period of susceptibility during adolescence, where exposure to nicotine will have more severe long-term consequences. It reinforces the notion that not everybody is created equal, that some people are more susceptible, both for genetic reasons and environmental reasons, in having exposure and longer-term negative outcomes; and whether the most appropriate response to the way the world is whether you treat everybody equally and just remove negative influences uniformly or whether you try to perhaps identify the most high-risk population and intervene at that point, is probably an appropriate debate to have at this point. Whether genetics can help and identify that particularly high risk population and be used in a positive way to make a beneficial outcome, I think is a topic for future investigation.
I think it's important to know that these are studies now that are happening because of the advances that we've had in sequencing the human genome and understanding our own genetic inheritance, and there has to be cautious use of genetic information now, because nobody's responsible for their own genetics. It's a lottery, and you inherit from your parents your particular genetic makeup. That people that are more at risk for the effects of their genome I think has to be examined in the context of a societal issue. That people have to know that they're protected in the use of their genetic information, that they wouldn't be identified because they have a gene for this or that as not being included in the benefits that modern society gives us all. I think that in the sense that these studies are uncovering something about ourselves that may predict future outcomes, this is sort of the beginning of, I think, a new wave in how people will one, deal with their long-term health issues; and it's just one little piece of the equation now [of] what will become a much larger equation and puzzle for people to deal with as this type of information and these type of results become more routine in the practice of medicine.
