High-Risk Haplotypes in Smokers

It’s getting harder to interpret genetics studies, and that’s a good thing.

Reporting the results of published studies concerned with genetic risk factors has always been a tricky proposition. Beyond the inevitable, and too often ideological nature/nurture split, there has been an unfortunate history of false positives in the rush to make news with a “gene for” alcoholism or schizophrenia or belief in God.

But single gene theories are mostly a thing of the past, and results tend to be broader and more tentative, as befits the state of our knowledge about genes and risk in a post-epigenetic landscape. Nonetheless, there’s no denying that genes play a strong role in all kinds of behaviors and processes. A large group of U.S. tobacco researchers went looking for associations between genetic risk factors and the ability to stop smoking successfully, and published their results in the American Journal of Psychiatry. The group came down strongly in favor of the proposition that genetic variations in the chromosome 15q25 region help dictate who manages to quit smoking and who does not.

The genetic variants in question are for nicotine receptors, and are called CHRNA5-CHRNA3-CHRNB4. They compose a “high-risk haplotype” that Li-Shiun Chen and coworkers believe to be involved in the ability to quit. (A haplotype is a combination of DNA sequences on a chromosome that are transmitted as a unit). People with these genetic variants “quit later than those at low genetic risk; this difference was manifested as a 2-year delay in median quit age.” However, this association tended to wash out at very high levels of smoking. Nonetheless, “pharmacological cessation treatment significantly increased the likelihood of abstinence in individuals with the high-risk haplotype,” compared to the low-risk group.

The suspicious haplotypes did not reliably predict tobacco abstinence across all groups that were studied. And any pharmacological treatment at all vastly increases abstinence rates, compared to placebo, while those who smoke the fewest cigarettes per day have the best shot at abstinence no matter what. In one sense, all the study is saying is that anti-craving drugs are more likely to be effective in smokers “who are biologically predisposed to have difficulty quitting.” Other smokers may not need them at all as a quitting aid—which is very much as common sense would have it. But further research in this area may allow medical workers to genetically identify smokers who will definitely require a pharmacological booster shot to overcome their crippling addiction.

In brief, the study says that success in quitting may be directly modulated by certain types of genetic variation among smokers. And genetic variations influencing quitting success may be different from gene variants controlling for “severity of nicotine dependence” (how many cigarettes you smoke), and whether you get addicted in the first place. It is all very complicated. But it’s the sort of thing that gives researchers hope when they contemplate deploying forms of personalized medicine in addiction treatment.

Study limitations abound. The work looked at only one genetic locus, while the success of smoking cessation might depend on multiple gene sites. The placebo arm was relatively small, and the smoking reports were obtained through a combination of biochemical confirmation and self-reporting.

Baker, T. (2012). Interplay of Genetic Risk Factors (CHRNA5-CHRNA3-CHRNB4) and Cessation Treatments in Smoking Cessation Success American Journal of Psychiatry DOI: 10.1176/appi.ajp.2012.11101545

Graphics Credit: (Li-Shiun Chen)

Alcohol: The Genetic Puzzle (3 of 3)

What about other drugs?

Do the same genetic relationships demonstrated in the alcohol adoption studies prove true for other drugs? Was it conceivable that heroin addiction or cigarette smoking could be traits (disorders, really) that men and women inherited?

“There have been a number of animal studies showing genetic differences in sensitivity to nicotine,” said Dr. Neal Benowitz of the Clinical Pharmacology Unit at San Francisco General Hospital, one of the nation’s premier nicotine research centers. And Professor Ovide Pomerleau, the Director of Behavioral Medicine at the University of Michigan Medical School, who collaborated with Cloninger’s group on genetic studies of nicotine and alcohol, told me: “Some people are drawn to smoking, and some people are not. Everybody pretty much goes through the same kind of peer pressures, the same kind of socialization pressures, and then you have some people who emerge as smokers, and some people who don’t. Some people who start smoking give it up easily, and there are others who can’t. Well, why? My answer is that I think there are innate differences in susceptibility.” 

The Cadoret group looked into the question and reported in the Archives of General Psychiatry that alcohol problems in biological relatives appeared to correlate highly with drug abuse in siblings. “Some theorists have suggested that multiple addictions to a wide variety of substances constitute evidence against a genetic interpretation of addiction,” wrote Cadoret. “The present data appear to refute that position, suggesting instead some underlying biochemical foundation involved in all of the substances abused….” 

Dr. Janice Keller Phelps, the drug treatment specialist from Seattle, maintained that “a large number of addicted people I have treated over the years had strong family histories of addiction. Time and again I encountered heroin addicts, cocaine addicts, or speed addicts with one or both parents addicted to alcohol, for example, or with one or more brothers or sisters also addicted—though not necessarily to the same drug. It is known and acknowledged that many alcoholics have one or more alcoholic parents; the large number of children of alcoholics who are not alcoholic but instead are addicted to other substances, however, is not so well recognized.”

In many ways, the genetic findings by Goodwin, Cloninger, and others were as far from the old problems-in-living approach, the Freudian approach, as it was possible to get. As Dr. Edward Sellers, who directed the psychopharmacological research program at the University of Toronto’s Addiction Research Foundation during the 1990s, explained to me: “One simplified way of looking at it is that every cell, every hormone, every membrane in the body has got genetic underpinnings, and while many of the genetic underpinnings are similar in people, in fact there are also huge differences. So on one level, the fact that there is a genetic component to addiction is not very surprising. What is surprising is that you could ever have it show up in a dominant enough way to be something that might be useful in anticipating risk.”

If there existed a set of genes that predisposed people to alcoholism, and possibly other addictions, then these genes had to control the expression of something specific. That’s what genes did. 

However, addiction researchers could not even agree on the matter of where they should be looking for such physical evidence of genetic difference. In the brain? Among the digestive enzymes? Blood platelets? A gene, or a set of genes, coding for…what? Substance H? Production of certain neurotransmitters? What was it they were supposed to be looking for?

What set of genes coded for happiness?

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008.

Graphics Credit: http://www.drugabuse.gov

Alcoholism: The Genetic Puzzle

Fathers and Sons.

The hunt for genetic influences on alcoholism derives largely from the work of Dr. Donald W. Goodwin, chair of the Department of Psychiatry at the University of Kansas Medical Center. Starting in the early 1970s, Dr. Goodwin and co-workers, using computer technology and a detailed database of Scandinavian health records, scrutinized the results of 5,000 adoption cases in Copenhagen. The results of the initial study stunned alcoholism experts around the world. The sons of alcoholics were more likely to become alcoholics themselves, as many had expected. But the relationship held true even when the children of alcoholics were separated from their natural parents shortly after birth, and subsequently raised by foster parents.

In Phase 2 of the Danish studies, Goodwin selected only alcoholic families in which one son had been raised by his biological parents, while the other son had been adopted away early in life. Raised in separate environments, twins of this sort are highly prized for genetic research. Goodwin compared the sons who had been raised by their alcoholic birth parents to their adopted-away brothers. It didn’t seem to make any difference: Rates of alcoholism were roughly the same. Environmental factors alone did not seem to account for it.

“By their late twenties or earlier,” Goodwin wrote, “the offspring of alcoholics had nearly twice the number of alcohol problems and four times the rate of alcoholism as the children whose parents had no record of hospitalization for alcoholism.” It did not look like family environment was the primary determinant.

Perhaps some of the children simply ended up with less effective foster parents, detractors pointed out. Alternatively, some unknown trauma might have been inflicted in the womb. Maybe the pregnant mother drank. Environmental factors can never be ruled out. Nonetheless, the basic implications of Goodwin’s work could not be shaken off. The Danish adoption studies were the first major scientific papers to establish a firm link between heredity and alcoholism.

Beginning in the 1980s, Dr. C. Robert Cloninger, professor of psychiatry and genetics at Washington University in St. Louis, and Michael Bohman, a Swedish pediatrician, began a broader series of adoption studies. The Stockholm Adoption Study scrutinized the records of more than 3,000 adopted individuals, and confirmed the Danish studies: The children of alcoholics, when compared with the children of non-alcoholic parents, were far more likely to become alcoholics themselves—even if they were adopted away. 

Moreover, “Alcohol abuse in the adoptive parents was not associated with an increased risk of abuse in the children they reared,” Cloninger later reported in the journal Science, “so there was no evidence that alcoholism is familial because children imitate their [non-biological] parents.”  

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008.

Graphics Credit: http://www.3dscience.com/

Epigenetics and Addiction

Turning off the genes for substance abuse.

If psychiatric disorders, including depression and addiction, are rooted in nature, but modified by nurture, some better way of viewing the interaction between genes and the environment is desperately needed.

Enter "epigenetics," defined as the study of how gene expression can be modified without making direct changes to the DNA. Writing in Science News, Tina Hesman Saey explains that "epigenetic mechanisms alter how cells use genes but don't change the DNA code in the genes themselves.... The ultimate effect is to finely tune to what degree a gene is turned on or off. Often the fine tuning is long-lasting, setting the level of a gene's activity for the lifetime of the cell."

A common form of epigenetic modification involves adding molecules to the DNA structure. Adding molecules from a methyl group or an acetyl group can change the manner in which genes interact with a cell's transcribing system. Cells can "mark" specific genes by attaching a methyl group consisting of three hydrogen atoms and one carbon atom to cytosine in the DNA base, effectively turning genes on or off without making major alterations to genetic structure. (Gene mutations or insertions, on the other hand, are capable of fundamentally altering the DNA protein structure.)

Scientists have learned that epigenetic changes can be caused by environmental impacts, but the details are not well understood. We have not yet reached the point of being able to link a specific experience of stress or infection or chemical exposure to specific epigenetic alterations.

What does any of this have to do with drug addiction or depression? One of the environmental impacts researchers have linked to epigenetic changes is drug addiction. The DNA double helix is packaged in proteins collectively called chromatin. One set of proteins, the histones, is a frequent site of epigenetic modification. In a study published in Neuron, Eric Nestler and co-workers in the Southwestern Medical Center at the University of Texas found that alterations in chromatin packaging were tied up with the dopamine release caused by cocaine addiction. The researchers concluded that chronic cocaine use was influenced by "chromatin remodeling." Specifically, modulating histone activity "alters locomotor and rewarding responses to cocaine."

How does this work? As Saey writes in Science News: "Another gene, known as delta-FosB, also switches on when a wave of dopamine washes over the nucleus accumbens.... Delta-FosB teams up with other transcription factors and recruits enzymes that acetylate histones and remodel control regions of some genes..... Such findings suggest that medicines that interrupt or reverse epigenetic changes caused by drugs of abuse could one day prevent or cure addiction."


Image Credit: Science in School

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