Nicotine and Genetics and Dependence – Is There a Connection?

It’s no surprise to anyone who smokes cigarettes today that the additives in the tobacco are stronger than they were a decade or so ago. That some people can smoke a cigarette now and then without becoming a pack or more smokers a day is actually a rarity. The reality is that it’s far more likely that even casual smoker will become addicted to nicotine – and faster than they think. For some, it’s a built-in vulnerability or predisposition, a genetic component that researchers are only now beginning to unravel. Although much more research still needs to be done, scientists say there is a strong link between genetics, nicotine and dependence.

What do we know now about nicotine, genetics and dependence? The issue is complicated, of course, but the body of knowledge is expanding in this field of study.

Facts about Nicotine

Cigarette smoking is the leading cause of preventable death worldwide, according to data from various sources, including the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC) and the American Cancer Society. Smoking causes about 5.4 million deaths worldwide each year. By 2030, according to a report from WHO, tobacco use will kill more than 8 million people worldwide each year if current trends continue. According to the National Institute on Drug Abuse (NIDA), in the U.S. alone, one of every 5 deaths can be linked to smoking, making tobacco more lethal than all other addictive drugs – combined.

Nicotine is an addictive substance, and is the primary component in tobacco. In addition to nicotine, however, there are numerous other dangerous chemicals in cigarette smoke. These include tar, acetaldehyde, carbon monoxide, nitrosamines, and more. When a smoker inhales the tar in cigarette smoke, he or she increases the risk of bronchial disorders, emphysema, and lung cancers. Carbon monoxide also increases the risk of cardiovascular disease. It is also well known that second-hand smoke increases the risk of lung cancer in adults. But the great risk from second-hand smoke is to our children, who are at greater risk of developing respiratory diseases. Data from WHO shows that more than 600,000 people worldwide die from second-hand tobacco smoke each year.

Smoking Risk Factors

Smoking harms almost every organ in the human body.

• Cigarette smoking has been linked to almost 90 percent of all lung cancer cases, and is the leading cause of cancer death in men and women, accounting for about one-third of all cancer deaths, according to some reports. Overall, the death rate from cancer is twice as high among smokers as non-smokers. Among heavy smokers, the rate is 4 times greater.

• Other diseases associated with smoking include cancer of the mouth, pharynx, larynx, esophagus, cervix, kidney, urethra, bladder, stomach, and pancreas.

• Lung diseases, such as chronic bronchitis and emphysema, are linked to smoking. Smoking exacerbates asthma symptoms in adults and children. A frightening statistic is that more than 90 percent of all deaths due chronic obstructive pulmonary diseases are attributable to smoking.

• Smoking substantially increases the risk of heart disease – including aneurysms, heart attack, stroke, and vascular disease. Smoking is said to account for an estimated 21 percent of deaths from coronary heart disease each year.

• Second-hand smoke increases the risk for many diseases. It is estimated that second-hand smoke causes approximately 3,000 lung cancer deaths per year among non-smokers and contributes to more than 35,000 cardiovascular-related deaths.

• Smoking in the home contributes to the initiation of smoking among other family members. It also increases severity of childhood asthma and has also been associated with sudden infant death syndrome (SIDS).

Nicotine Addiction

In the classic sense, addiction to nicotine is like addiction to any other drug. It is characterized by compulsive behavior – the seeking and continued use of a particular stimulus – despite negative health consequences. Anyone who smokes knows that it is harmful to their health. Many smokers say they want to or have tried to quit – repeatedly. The statistics on smoking cessation among those who say they want to quit isn’t good. Only about 6 percent of those who try to quit last for more than a month before resuming smoking.

Why such a dismal record? Why can’t people just toss their cigarettes and be rid of them? Scientists have discovered there’s more to it than just the pleasant feeling that smokers experience – and don’t want to give up. Besides, whenever they do try to quit, they have to go through withdrawal symptoms: headaches, irritability, anxiety, cravings, insomnia, fatigue, cough, dry mouth, sore throat, constipation, inability to concentrate, and tightness in the chest. Some can quit with the help of smoking cessation aids, such as nicotine replacement therapies (nicotine gum and transdermal nicotine patch), non-nicotine medications (such as bupropion and varenicline), or counseling (cognitive behavioral therapy). Some who want to quit, however, find it almost impossible to do so. Why? It may be genetic.

The Genetic Connection

Much research has been devoted to identifying genes that are associated with initiation of smoking, addiction, and smoking cessation. Simply put, one or more genetic variants have been found that, among smokers, are associated with more smoking and higher rates of nicotine dependence – which makes it harder for them to quit.

It is important to note that the addictive properties of nicotine affect all smokers, whether or not they have a genetic variant that makes addiction more likely. In addition, there are individual differences in smoking behavior, dependence on nicotine, and the success of smoking cessation methods.

The National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov/researchreports/nicotine/newFrontiers.html) reports that studies of twins indicates that approximately 40 to 70 percent of an individual’s risk of becoming addicted to nicotine depends on his or her genes. Genetic variants associated with nicotine metabolism have been shown to influence how people smoke. One recent NIDA-funded study identified a variant in the gene for a nicotinic receptor subunit that doubled the risk of nicotine addiction among smokers. Later, another study found the same gene variant also increased susceptibility to severe health consequences of smoking, including peripheral arterial disease and lung cancer.

Interesting research centers on three genetic regions associated with the number of cigarettes smoked each day. In one study, which analyzed the phenotypes of more than 74,000 people, one region was associated with smoking initiation, while one was associated with smoking cessation. Genetic variants located on chromosome 15 that were associated with heavy smoking lie within a region that contains nicotine receptor genes, which other scientists have previously associated with lung cancer and nicotine dependence. Helena Furburg, study co-author and a research assistant professor at the University of North Carolina, cautioned that getting yourself tested for these variants won’t tell you anything meaningful about your smoking risk or ability to quit smoking. In the future, however, it might be possible for researchers to use these genetic variants to predict how different smoking cessation techniques may work.

In a second recently-reported study, a research team led by Clyde Francks from Oxford University tested the human genome for genes associated with cigarette smoking. Based on their analysis of more than 40,000 people, the team found that a group of genes located on chromosome 15q25 is associated with the number of cigarettes that people smoke each day. These three genes (CHRNA5, CHRNA3, and CHRNB4) encode neuronal nicotinic acetylcholine receptor subunits. The study was reported in the April 25 online issue of Nature Genetics and is available through PubMed (http://www.ncbi.nlm.nih.gov/pubmed/20418889).
In a third study, researchers in Iceland, using data from more than 70,000 smokers, confirmed that genes on chromosome 15 were linked to tobacco use. The researchers found two other genes involved in nicotine metabolism (CYP2A6 and CYP2B6), and two more (CHRNB3 and CHRNA6) that play a role in how the body processes nicotine. Researchers also pointed out that some of these gene regions are also associated with a predisposition to lung cancer. The abstract is available at PubMed (http://www.ncbi.nlm.nih.gov/pubmed/20418888).

A fourth study using mice finds that altering one letter (or nucleotide) in a genetic code significantly impacts how an individual responds to nicotine. In the study, mice engineered to differ at a single nucleotide in a gene called CHRNA4 don’t find nicotine to be rewarding and are less inclined to self-administer it orally. The researchers report that the change of this single nucleotide also alters how an area of the brain that is critical for nicotine dependence responds to nicotine. This is the first study to demonstrate that a single nucleotide change is enough to alter behaviors and change brain function relative to nicotine dependence. The study abstract, “CHRNA4 A529 knock-in mice exhibit altered nicotine sensitivity” is available through PubMed (http://www.ncbi.nlm.nih.gov/sites/entrez).

Outlook for the Future

Efforts to help curb smoking such as “Quit Smoking Day” and other media campaigns, bans on cigarette smoking in public places, and educational efforts aimed at youth are important elements in an overall coordinated plan to reduce smoking in this country, as they are worldwide. Some developing countries, where smoking initiation continues to rise, especially among women, are going even further by issuing a ban on tobacco advertising and sponsorships. While that’s not likely to happen in the U.S. anytime in the near future, keeping media and educational efforts going may begin to show results.
As with other addictive substances, the earlier an individual begins smoking tobacco, the quicker they are likely to become addicted. The more often they smoke, the greater their risk for developing serious illness and disease. Add in genetic and familial components – family history of tobacco use, genetic disposition to becoming addicted to nicotine – and the issue of tobacco use among young people becomes even more significant.

The good news is that smokers can improve their health by stopping. The U.S. Surgeon General has said that, “Smoking cessation represents the single most important step that smokers can take to enhance the length and quality of their lives.” Based on data from the 1990s, the CDC estimates that adult male smokers lost an average of 13.2 years of life and female smokers lost 14.5 years because of smoking. The American Cancer Society says, “No matter how old you are or how long you smoked, quitting can help you live longer and healthier.” People who quit smoking before the age of 50 cut their risk of dying within the next 15 years in half, compared to people who continue to smoke.

Here’s what happens in the human body after you quit smoking (data from the American Cancer Society):

• 20 minutes after quitting: Heart rate and blood pressure drops.
• 12 hours after quitting: Carbon monoxide level in blood drops to normal.
• 2 weeks to 3 months after quitting: Circulation improves and lung function increases.
• 1 to 9 months after quitting: coughing and shortness of breath decrease; cilia (tiny hair-like structures that move mucus out of the lungs) regain normal function in the lungs, increasing the ability to handle mucus, clean the lungs, and reduce the risk of infection.
• 1 year after quitting: Excess risk of coronary heart disease is half that of a smoker’s.
• 5 years after quitting: Stroke risk is reduced to that of a non-smoker 5 to 15 years after quitting.
• 10 years after quitting: Lung cancer death rate is about half that of a person who continues to smoke. Risk of other cancers decrease as well, including cancers of the mouth, throat, esophagus, bladder cervix, and pancreas.
• 15 years after quitting: Risk of coronary heart disease is the same as a non-smoker’s.

How to Quit Smoking

Experts recommend a coordinated and comprehensive approach to smoking cessation. For those who do not have a genetic predisposition that increases their risk of addiction to nicotine, nicotine replacement therapy, or NRT, (gums, patches, and lozenges) can make it easier to quit. But NRT only handles the physical symptoms of nicotine withdrawal. Pairing NRT with a program that helps to change the smoker’s behavior will likely yield greater success. Such a combined approach doubles the smoker’s chance of successfully quitting.

Hard-core, chronic smokers who also have a genetic and familial component to their smoking habit can also benefit from the combined approach to quitting, although it may necessitate additional measures. There is some evidence that high-dose NRT may help heavy smokers. Research suggests that patients’ withdrawal symptoms go away and their cravings improve without harmful effects on the heart and circulation. Still, the patient must not attempt this on his or her own. They must be carefully monitored and supervised by their physician.

Medications may also be prescribed for certain smokers trying to quit. Bupropion (Zyban), a prescription anti-depressant in an extended-release form, reduces symptoms of nicotine withdrawal. Doctors may recommend combination therapy (bupropion and nicotine patch, for example) for heavily-addicted smokers – along with counseling or behavior therapy.

Varenicline (Chantix), another prescription medication, is a newer drug developed to help people quit smoking. It interferes with the nicotine receptors in the brain to lessen the pleasurable effects of smoking and to reduce nicotine withdrawal symptoms.
Other older drugs used for smoking cessation include clonidine and nortriptyline.

A smoking vaccine, NicVax, may soon be available. As of April 2010, studies are already being conducted. NicVax stimulates the immune system to create antibodies that bind nicotine molecules so they can’t pass into the brain. In essence, the smoking vaccine reduces the rate of nicotine delivery to the brain.

Other aids to help an individual quit smoking include hypnosis, acupuncture, and low-level cold laser therapy. Some communities have Nicotine Anonymous groups, which operate according to 12-step programs such as Alcoholics Anonymous. Support from family and friends are also critical in any attempt to stop smoking. Quit smoking classes are also available through the American Cancer Society, the American Lung Association, or local health departments.

For more information on how to quit smoking, see the American Cancer Society’s “Guide to Quitting Smoking” (http://www.cancer.org/docroot/PED/content/PED_10_13X_Guide_for_Quitting_Smoking.asp). The American Cancer Society can help smokers find other resources that may be available for quitting. Call them at 1-800-227-2345.

Bottom line: You’re not losing your mind if you find that it seems almost impossible to quit smoking. If you’ve determined that you want to quit, utilize every resource available to you to put together a comprehensive program that will provide you the support and encouragement you need to follow through with your decision. Keep at it. If you relapse, get back into the program and keep going. Look at it this way. Your life – and the lives of those you love – may depend on it.