Although environment plays a major part in addiction — you can’t get hooked on something you’ve never tried — genetics plays a substantial role in determining whether a person who does use a drug will become addicted to it.

A few DNA variations have been identified that seem to increase the odds a person will become addicted to a specific drug. But twin studies suggest that there might be genes influencing addiction in general.

Xiang Chen and colleagues at Yale and Princeton set out to find some of these genes by analyzing the genetic data from several cohorts of people previously studied for addictions.  The researchers’ approach was to look for variations found more frequently in people addicted to at least two out of six categories of substances: nicotine, alcohol, marijuana, cocaine, opiates and other drugs.  Their results, published online this week in the Proceedings of the National Academy of Sciences, reveal a significant association between addiction and variations in a gene, PKNOX2, previously associated with alcohol dependence in mice.

The strongest signal was seen with rs12284594.  In white women, each copy of a G at this SNP corresponded to 1.77 times increased odds of being addicted to two or more substances.  The association with addiction of this and other SNPs in the PKNOX2 gene was also seen in the white men and black men and women in the study, but the findings were not statistically significant.

(23andMe customers can check their data for rs12284594 using the Browse Raw Data feature.)

The association of rs12284594 with addiction did not hold when the researchers looked at individual substances separately.

“This suggests that substance dependence or addiction as a whole has different risk genes compared to any single addiction outcome,” the authors write.

The authors admit that there are weaknesses in their study.  For example, people addicted to two or more substances might just have more access to drugs — not a biological predisposition to addiction.  Moe research in this area will definitely be needed.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

More Spittoon Posts About Addiction and Substance Dependence:
SNPwatch: Genetic Variation May Make It Harder For Expectant Moms To Quit Smoking
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?
SNPwatch: Genetic Variant Linked to Drinking Intensity in Alcoholics
SNPwatch: Next Year It’s Martinelli’s…
SNPwatch: Unlikely Gene May Contribute To Cocaine Dependence and Paranoia

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No matter what you call it – “flush”, “blush” or “glow” – the red face, nausea and rapid heart beat that many people with Asian ancestry experience when they drink alcohol is more than just a quirk of nature.  Research shows it’s a significant risk factor for esophageal cancer, one of the deadliest malignancies in the world.

In a paper published online yesterday in PLoS Medicine, researchers from the National Institute on Alcohol Abuse and Alcoholism and Japan’s Kurihama Alcohol Center advise physicians that they need to ask their Asian patients about their experiences with alcohol in order to identify and counsel those who are at the highest risk.

In the body, alcohol is first converted into acetaldehyde, a potentially cancer-causing toxin, and then into a harmless substance called acetate.  An enzyme called ALDH2 is responsible for the crucial detoxifying step.  But a genetic variation known as ALDH2*2, most commonly found in people with Asian ancestry, can render the enzyme unable to convert acetaldehyde into acetate.

Having two copies of the ALDH2*2 variation means a person can’t break acetaldehyde down at all.  Even a tiny amount of alcohol leads to a build up of the toxin and extremely unpleasant side effects, causing most of these people to avoid drinking altogether.

People with just one copy of ALDH2*2 flush when they drink alcohol too, but their bodies are able to process some acetaldehyde and their reactions are less severe.  Some of these people build up a tolerance to acetaldehyde, allowing them to drink in substantial quantities. But while these people may think they’ve learned to deal with the annoyance of alcohol flushing, what they’ve really done is train themselves to ignore their bodies’ warning signals.

According to the authors, evidence from several studies has consistently linked alcohol consumption with the risk of esophageal cancer in people with one copy of ALDH2*2.  Depending on the study, the odds of esophageal cancer are raised 3.7 to 18.1 times after taking into account the level of alcohol consumption.  For heavy drinkers with one copy of ALDH2*2 the news is even worse: most studies show their odds of esophageal cancer are increased at least 10-fold.

(23andMe customers can see their data for ALDH2 and learn more about alcohol flushing in the trait report found here.  Customers can also check their data at rs671 using the Browse Raw Data feature.  Each A is a copy of ALDH2*2.)

The authors say that doctors should routinely question Asian patients about their reactions to alcohol and advise those who do flush to keep their drinking to a minimum.  This simple step could have a real impact on esophageal cancer rates.

For example, the authors calculate that if Japanese males with one copy of ALDH2*2 who are moderate to heavy drinkers could be convinced to scale back to only light drinking, 53% of esophageal cancers in this population could be prevented.

“In view of the approximately 540 million ALDH2-deficient individuals in the world, many of whom now live in Western societies, even a small percent reduction in alcohol drinking would translate into a substantial number of lives saved,” the authors write.

Photo: doi:10.1371/journal.pmed.1000050.g001. From: Brooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A PLoS Medicine Vol. 6, No. 3, e50 doi:10.1371/journal.pmed.1000050

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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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A new study in Nature Genetics shows that the increased risk of developing cancer in the mouth, throat, voice box and esophagus due to drinking is partially offset by the rarer versions of two SNPs associated with alcohol metabolism.

Cancers of the oral cavity, throat (also called the pharynx), voice box (or larynx) and esophagus are collectively known as upper aerodigestive (UAD) cancers. Alcohol consumption is known to be a significant risk factor for these cancers. Studies have shown that the areas of the body that come into closest contact with ingested alcohol are at highest risk of being affected by cancer.

The two SNPs associated with UAD cancers are both located in genes that are part of the alcohol dehydrogenase (ADH) enzyme pathway, a group of proteins that aids the body in metabolizing alcohol. The authors of the study hypothesize that the protective versions of the SNPs they found exert their effect on UAD cancers by changing the carcinogenic effects of alcoholic beverages. These SNPs had no effect among non-drinkers.

Hasibe et al studied six SNPs in ADH pathway genes in a total of 3,876 people with UAD cancers and 5,278 healthy controls, in hopes of finding DNA variants associated with these diseases. This large study group was comprised of three smaller study groups: one group from eastern Europe with 809 patients and 2,586 controls; one group from western Europe with 1,356 patients and 1,407 controls; and a final group from Latin America with 1,711 patients and 1,285 controls.

Both rs1229984 and rs1573496 were significantly associated with UAD cancers in the large study group and each of the smaller study groups individually.

When the researchers broke the patients into groups based on specific cancer type – oral/throat, voice box, and esophagus – they found that both SNPs impacted the risk of developing the subtypes of cancer to different extents (see the chart at the end of this post for details).

About 19 out of every 100,000 people is diagnosed with UAD cancer per year in the United States. Individually, the lifetime risks of developing these cancers are: oral/throat, 1 in 99; voice box, 1 in 274; and esophagus, 1 in 198.

Those who have one or two copies of the T version of rs1229984 were found to have 0.56 times the odds of developing UAD cancer compared to those with two C versions. For those who carry one or two copies of the G version of rs1573496, their odds of developing UAD cancer were 0.68 times those with two C versions. People who carry at least one T at rs1229984 and one G at rs1573496 were found to have 0.45 times the odds of developing UAD cancer compared to people who had no protective versions of either SNP.

The authors say that the exact mechanism by which the protective versions of these two SNPs are working is not clear. It is known that people with one or two copies of the T version of rs1229984 metabolize ethanol up to 100 times faster than people with two copies of the C version. The authors of this study speculate that this faster metabolism may protect tissues by reducing their exposure to the effects of alcohol.

23andMe customers can check their data for rs1573496 (rs1229984 is currently not available). The tables below sum up the results of this study. The “effect” of each SNP is the change in odds for carrying either one or two copies of the protective version.

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