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Genetic Studies Offer Clues about Addiction Risks, Treatments

NEW YORK (GenomeWeb News) – The social and health tolls of alcohol abuse, nicotine dependence, and drug addiction have been known for some time. But the genetic patterns that make some individuals more susceptible to abusing these substances — as well as those influencing their ability to quit — are less well understood.

Even so, a growing body of evidence is starting to unravel how genetics and epigenetics contribute not only to an individual's predisposition for becoming hooked on alcohol, nicotine, or other drugs, but also their ability to kick such habits. And experts say genetics is poised to impact clinical treatments for addiction in the not-too-distant future, with researchers already identifying genetic variants that may eventually help guide smoking-cessation therapy.

"[T]he rapid advances in the genetics of addiction hold great promise for developing treatments for addiction and reducing the enormous health burden of addiction," Jonathon Pollock, chief of the National Institute of Drug Abuse's genetics and molecular neurobiology research branch, and Trinity College geneticist Mani Ramaswami wrote in a preface to a special issue of the Journal of Neurogenetics earlier this year.

The issue contains numerous papers and reviews stemming from a NIDA short course on the genetics and epigenetics of addiction held in the spring of 2008.

Alcohol abuse, nicotine dependence, and other drug addictions belong to a group of psychiatric conditions that not only tend to overlap with one another but also frequently co-occur with conditions such as schizophrenia, bipolar disorder, depression, post-traumatic stress disorder, and some personality disorders.

Over the years, twin and sibling studies, genetic linkage scans, and genome-wide association studies have confirmed that genetics are a factor in addiction.

But while co-morbidity between various addictions suggests they might share some of the same risk genes, so far the candidate gene and genome-wide studies used to identify genes involved in these conditions have found specific variants and risk loci for each type of addiction, Joel Gelernter, a psychiatry, genetics and neurobiology researcher at Yale University, told GenomeWeb Daily News.

Nevertheless, unlike some other complex diseases, environmental factors are also very important to all types of addiction. "Substance abuse is one of the ultimate gene-environment exposures," Pollock told GWDN.

Studies aimed at getting to the bottom of addiction genetics focus on many different aspects of addiction behavior — from an individual's risk of moving from initial substance use to addiction, to his or her levels of use and ability to quit.

For instance, an online paper in the International Journal of Epidemiology in September suggested that a chromosome 15 region called 15q25 is associated with the number of cigarettes an individual smokes.

Smoking studies, including a 2007 genome-wide association study in Human Molecular Genetics by Washington University researcher Laura Jean Bierut and her colleagues, have also turned up genes coding for nicotinic acetylcholine receptor sub-units such as alpha3, alpha5, and beta4.

A meta-analysis of published linkage studies by Gelernter and his co-workers, published in the January 1, 2010 print issue of Biological Psychiatry and appearing online in October, further supported a link between smoking behavior and a region containing the CHRNA4 gene, which codes for the alpha4 nicotinic receptor subunit.

That study also identified new loci with weak linkage across multiple studies, though it did not find strong support for some of the regions reported in previous studies. Such findings don't necessarily mean these regions harbor risk loci, lead author Shizhong Han, a post-doctoral researcher in Gelernter's lab at Yale, told GenomeWeb Daily News.

Instead, Han said, the meta-analysis method helps find regions with weak but consistent evidence of linkage across multiple studies — a method that can help guide follow-up studies, including re-sequencing studies.

A number of studies may also have implications for helping smokers kick the habit. For instance, several studies on the genetic variation of nicotine metabolism suggest slow nicotine metabolism may be more common in non-smokers and light smokers — and these slow metabolizers also seem to have an easier time quitting.

That has made the nicotine-metabolizing enzyme cytochrome P450 2A6 (also known as CYP2A6) one the most promising pharmacogenetic and pharmacogenomic targets so far. The enzyme converts nicotine to cotinine and helps to further metabolize this inactive form of nicotine with the help of other enzymes such as CYP2B6, CYP2D6, and CYP2E1.

Fast nicotine metabolizers, who have more active forms of CYP2A6, tend to have worse outcomes with many nicotine-replacement smoking cessation therapies such as the patch, gum, inhaler, or nasal spray, Caryn Lerman, director of the University of Pennsylvania's Tobacco Use Research Center, and her colleagues explained in a Journal of Neurogenetics review.

Instead, these individuals may respond better to alternative treatments such as the antidepressant bupropion (marketed under the trade names Wellbutrin or Zyban) or varenicline (marketed by Pfizer as Chantix), which partially activates the nicotinic receptor and interferes with nicotine binding to these receptors.

Curbing CYP2A6 activity might be beneficial in others ways too: Lerman and her co-authors noted that along with its role in turning nicotine into an inactive form, the enzyme also produces precursors to some of the carcinogenic compounds that may contribute to lung and other smoking-related cancers.

Together, these results suggest CYP2A6 inhibitors — such as the psoriasis treatment methoxsalen — could also prove effective for helping some individuals quit smoking and decrease the production of pre-carcinogenic compounds in the process. Still, Lerman and her co-authors emphasized, despite some promising preliminary studies, methoxsalen and other CYP2A6 inhibitors have not been tested in clinical trials.

The findings may also have implications for treating nicotine dependence in different populations, since polymorphisms linked to reduced CYP2A6 enzyme activity and slower nicotine metabolism seem to be more common in Japanese, Korean, and Chinese populations than in Caucasian and African American populations.

Meanwhile, genetic variants in another cytochrome P450 enzyme, CYP2B6, seem to influence an individual's success with some smoking cessation therapy through a different mechanism. Researchers from Tufts University reported in Pharmacogenetics in 2004 that certain CYP2B6 variants are linked to slower metabolism of the antidepressant and smoking cessation aid bupropion.

Still other studies suggest genetics could help predict which individual will fall back into the habit of smoking after they quit.

"The ultimate goal is to select the type, dose, and duration of therapy for smokers based on individual genetic and biological factors," Lerman told GWDN in an e-mail message. But, she emphasized, while many genetic markers have been associated with treatment success, these findings must be validated in multiple independent clinical trials before they can be translated to clinical practice.

Genetic factors affecting metabolism seems to play a role in alcohol dependence as well. For instance, polymorphisms in the genes coding for the alcohol dehydrogenase enzymes that converts ethanol to acetaldehyde and the aldehyde dehydrogenase enzymes that further metabolizes acetaldehyde can affect an individual's reaction to alcohol — and, subsequently, their propensity to continue using it.

But genes from other pathways are also turning up in alcohol addiction studies. Among them: GABRA2, which codes a subunit of a receptor for the inhibitory neurotransmitter gamma-aminobutyric acid, and CHRM2, a gene coding for a muscarinic cholinergic receptor that's also thought to contribute to processes such as memory and cognition.

More generally, twin, sibling, and linkage studies have implicated several chromosomal regions, including parts of chromosomes 4, 6, 12, 15, and 16, in alcohol use and withdrawal.

Along with his group's work on the genetics of smoking behavior, Yale's Gelernter was also lead author on a Biological Psychiatry study last January in which researchers used a linkage approach to identify a region on chromosome 10 that was associated with alcohol dependence in African American families tested.

"Regardless of whether such a risk locus would affect outcome exclusively in [African Americans] or generalizes to other populations," the researchers concluded, "it might be expected to point to mechanisms of action for risk that apply globally."

Finding such risk loci is just the first step, experts say. In order to fully understand various addictions and come up with ways to treat them most effectively, researchers not only need to identify risk variants, but also delve into the functional consequences of such changes as well as the epigenetic patterns contributing to addiction-related gene regulation.

While these epigenetic and imprinting studies are currently at an earlier stage, Pollock explained, they are expected to provide an even more refined view of how an individual's environment and genetic predispositions coalesce during the process of addiction.

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