Cigarettes and Genetic Risk

Evidence From a 4-Decade Study.

Pediatricians have often remarked upon it: Give one adolescent his first cigarette, and he will cough and choke and swear never to try another one. Give a cigarette to a different young person, and she is off to the races, becoming a heavily dependent smoker, often for the rest of her life. We have strong evidence that this difference in reaction to nicotine is, at least in part, a genetic phenomenon.

But so what? Is there any practical use to which such knowledge can be put? As it turns out, the answer may be yes. People with the appropriate gene variations on chromosomes 15 and 19 move very quickly from the first cigarette to heavy use of 20 or more cigarettes per day, and have more difficulty quitting, according to a report  published last year in JAMA Psychiatry. From a public health point of view, these findings add a strong genetic rationale to early smoking prevention efforts— especially programs that attempt to “disrupt the developmental progression of smoking behavior” by means of higher prices and aggressive enforcement of age restrictions on smoking.

What the researchers found were small but identifiable differences that separated people with these genetic variations from other smokers. The gene clusters in question “provide information about smoking risks that cannot be ascertained from a family history, including information about risk for cessation failure,” according to authors Daniel W. Belsky, Avshalom Caspi, and colleagues at the University of North Carolina and Duke University.

The group looked at three prominent genome-wide association studies of adult smoking to see if the results could be applied to “the developmental progression of smoking behavior.” They used the data from the genome work to analyze the results of a 38-year prospective study of 1,037 New Zealanders, known as the Dunedin Study. A total of 405 cohort members in this study ended up as daily smokers, and only 20% of the daily smokers ever achieved cessation, defined as a year or more of continual abstinence.

The researchers came up with a multilocus genetic risk score (GRS) based on single-nucleotide polymorphisms associated with smoking behaviors. Previous meta-analyses had identified several suspects, specifically a region of chromosome 15 containing the CHRNA5-CHRNA3-CHRNB4 gene cluster, and a region of chromosome 19 containing the gene CYP2A6. These two clusters were already strong candidate genes for the development of smoking behaviors. For purpose of the study, the GRS was calculated by adding up the alleles associated with higher smoking quantity. The genetic risk score did not pertain to smoking initiation, but rather to the number of cigarette smoked per day.

When the researchers applied these genetic findings to the Dunedin population cohort, representing ages 11 to 38, they found that an unfortunate combination of gene types seemed to be pushing some smokers toward heavy smoking at an early age. Individuals with a high GRS score “progressed more rapidly to heavy smoking and nicotine dependence, were more likely to become persistent heavy smokers and persistently nicotine dependent, and had more difficulty quitting,” according to the study. However, these effects took hold only when young smokers “progressed rapidly from smoking initiation to heavy smoking during adolescence.” The variations found on chromosomes 15 and 19 influence adult smoking “through a pathway mediated by adolescent progression from smoking initiation to heavy smoking.”

Curiously, the group of people who had the lowest Genetic Risk Scores were not people who had never smoked, but rather people who smoked casually and occasionally—the legendary “chippers,” who can take or leave cigarettes, sometimes have one late at night, or a couple at parties, without ever falling victim to nicotine addiction. These “light but persistent smokers” were accounted for “with the theory that the genetic risks captured in our score influence response to nicotine, not the propensity to initiate smoking.”

Naturally, the study has limitations. Everyone in the Dunedin Study was of European descent, and the life histories ended at age 38. Nor did the study take smoking bans or different ages into account. The study cries out for replication, and hopefully that won’t be long in coming.

Could information of this sort be used to identify high-risk young people for targeted prevention programs? That is the implied promise of such research, but no, probably not. The gene associations are not so dramatic as to cause youngsters with the “bad” alleles to inevitably become chain smokers, nor do the right set of genes confer protection against smoking. It’s not that simple. However, the study is definitely one more reason to push aggressive smoking prevention efforts aimed at adolescents.

(First published March 28, 2013)

Belsky D.W.  Polygenic Risk and the Developmental Progression to Heavy, Persistent Smoking and Nicotine DependenceEvidence From a 4-Decade Longitudinal StudyDevelopmental Progression of Smoking Behavior, JAMA Psychiatry,   1. DOI: 10.1001/jamapsychiatry.2013.736

Graphics credit: http://www.sciencemediacentre.co.nz/

Nature, Nurture, and Me

Which came first, the addiction or the trauma?

About a year ago, Jonathan Taylor, a professor at California State University in Fullerton, assigned his students some reading from my book, The Chemical Carousel, for his “Drugs, Politics, and Cultural Change” course. At the same time, the class watched an interview with Dr. Gabor Maté, author of In the Realm of Hungry Ghosts: Close Encounters with Addiction. In a letter written for his readers, Dr. Mate´ insists that addiction “is very close to the core of the human experience. That is why almost anything can become addictive, from seemingly healthy activities such as eating or exercising to abusing drugs intended for healing. The issue is not the external target but our internal relationship to it. Addictions, for the most part, develop in a compulsive attempt to ease one’s pain or distress in the world…. The more we suffer, and the earlier in life we suffer, the more we are prone to become addicted."

I find this perspective interesting, because I agree with so little of it. I do not believe that almost anybody can become involved in an addictive relationship with almost anything—not unless they have the genes for it. I do not believe that the genuine heart of addiction, its true root cause, is childhood abuse—although that is frequently and tragically a component of addiction, for many reasons. Overall, I see addiction as a biochemical disorder with strong behavioral attributes, mostly genetic in origin, influenced by—but not hostage to—environmental impacts, making it not so different from, say, diabetes or depression.

No doubt about it, there is a fair amount of distance between the doctor and your humble science journalist, from the nature/nurture point of view. And, students being students, they picked up on this, and wanted an explanation that would make some sense of these two seemingly opposite positions. Professor Taylor threw the question back to me:

My class was wondering how one would reconcile your and Mate’s views.  Both of you discuss the addicted brain and clearly view addiction as a brain disorder.  The fundamental difference is that Mate disputes the genetic component of addiction, or at least he says there is some genetic component but that the majority of the brain dysfunction and low levels of neurotransmitters found in addicted individuals relates to environmental influences during early childhood (or in the womb), rather than a genetic component…. In the book he discusses studies that indicate that insufficient maternal care, exposure to conflict etc. all lead to improper brain development which leads to increase susceptibility to addiction.  So while you write about “inherited susceptibility,” he seems to favor an “environmental induced susceptibility…. Any elucidation I can share with my students would be helpful.

So. I was well and truly on the hook. I kept my response short, for the obvious reasons, but there is no getting around the fact that it’s a damn good question. Here’s what I ended up telling the class:

-------------------------------------------------------------------------------------------------------------------------
Jon:

"Your students ask, quite rightly, how to reconcile the views expressed in The Chemical Carousel and In the Realm of Hungry Ghosts. Or, nature vs. nurture. Dr. Maté looks to environmental impacts during early childhood as the addiction trigger, while I advocate a view of addiction as a genetic disorder, expressed because of changes in DNA, not bad mothering. (It wasn’t very long ago that schizophrenia was firmly believed to be a result of bad mothering, too!) More to the point, Maté believes, for example, that ALL female heroin addicts were sexually abused as children. That is certainly not an assertion widely agreed upon or well supported by the scientific literature. In the most recent population study of addicts and non-addicted siblings, published in Science (Feb. 3 2012), when the researchers looked at the early lives of sibling pairs, they found all the same risk factors: both the addicts and their siblings had seen roughly equal amounts of trauma in childhood. 'We really looked at their childhoods,' says Karen Ersche, lead author of the study and group leader for human addiction research at the University of Cambridge in England, quoted at Time Healthland. 'There was a lot of domestic violence, there was sexual abuse — but both [groups] had that.'

"So, which came first, the trauma, or the trauma-prone personality? Where Dr. Maté sees childhood trauma, I tend to see behavioral dysregulation. Children born with an addictive propensity also carry with them the potential for various kinds of behavioral problems, impulsivity being a common one. And it is entirely likely that most addicts have had rocky childhoods, since, quite often, they have had alcoholics in the nuclear family, with all the attendant problems, including sexual violence. Or, their own behavioral template leads to problems—angst, worry, fights, trauma. In a sense, we can say that sooner or later, something, or someone, or a series of environmental impacts, will traumatize a child with addictive propensities, in the same way that latent schizophrenia is “switched on” by a traumatic or highly emotional event. Addicts feel like outsiders from an early age, and many of them sense that something is not quite right with them, long before they ever take a drink or a drug.

"Sorting out this chicken-egg problem is a major headache. And we haven’t even discussed the possibility of trauma in the womb. But I am willing to say that none of this is as settled or as straightforward as Dr. Maté would have it. On the matter of nature/nurture, I’m willing to put the odds of that mix at 60/40, which is a good deal less genetically loaded than my estimates used to be. The growing research field of epigenetics has brought the two views closer together by demonstrating that a person’s DNA can in some cases be modified, and genes turned off and on, by environmental impacts.

"Overall, it’s safe to say that Dr. Maté and I do agree on this: One of the best defenses against the scourge of addictive disease is a stable, loving, empathetic family."

Best,
Dirk

Photo Credit: http://lofalexandria.blogspot.com/

The Genetics of Cigarettes

Mutations on chromosome 15 linked to lung cancer.

A variation among the genes that code for nicotine receptors in the brain has been linked with increased cigarette smoking and a heightened risk for lung cancer, according to three new studies released this week.

Two studies in Nature, and one in Nature Genetics, demonstrated that people who inherited the genetic variation, or allele, from one parent—roughly 50 percent of the population--had a 30 percent higher risk of developing lung cancer. “What’s more,” according to Michael Hopkin at Nature News, “another 10 percent of the population is likely to carry two copies of this set of mutations, raising cancer risk by as much as 80 percent relative to people with equivalent lifestyles without the cancer-linked gene variant.”

More than 35,000 Caucasian smokers in Europe and North America took part in the government-funded research. It was the strongest evidence to date of a firm link between genetics and lung cancer. It was also added evidence for the existence of biological proclivities in addicted cigarette smokers.

Earlier studies had demonstrated that having a parent or sibling with lung cancer could triple the odds of developing the disease. But teasing out the precise genes responsible has been, as always, a frustrating hunt.

Christopher Amos of the University of Texas, author of one of the studies, characterized the variant as “kind of a double whammy gene” in an Associated Press article by Seth Borenstein. Amos said of the nicotinic acetylcholine receptor gene alleles on chromosome 15: “It also makes you more likely to be dependent on smoking and less likely to quit smoking.” In the same article, psychiatry professor Dr. Laura Bierut of Washington University in St. Louis said that the three studies are “really telling us that the vulnerability to smoking and how much you smoke is clearly biologically based.”

Study author Kari Stefansson of Iceland’s deCode Genetics believes strongly that the genetic variation in question makes people more susceptible to nicotine addiction, and increases the difficulties of quitting: “In our study, we found if you have one allele you smoke about one more cigarette per day; if you have 2 alleles you average two more cigarettes per day.”

However, according to Denise Gellene of the Los Angeles Times: “The studies were divided on whether the genetic variant directly increased the risk of lung cancer or did so indirectly by predisposing people to smoking.” In a third study, Paul Brennan of the International Agency for Research on Cancer in Lyon, France noted no evidence of a link between the rogue gene and nicotine addiction itself.

It is not clear whether non-smokers with the mutation suffer an increased risk of lung cancer as well. (However, even smokers who lack the gene variant are still ten times as likely to develop lung cancer than nonsmokers).

About one million people die annually from lung cancer. According to the World Health Organization, smoking is the leading cause of preventable death worldwide.

Graphics Credit: Technology Review

smoking nicotine