American College of Physicians: Internal Medicine — Doctors for Adults ®

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Genes have influence over whether you smoke, quit or die

From the October ACP Internist, copyright © 2008 by the American College of Physicians

W. Gregory Feero, MD, PhDBy W. Gregory Feero, MD, PhD

The burden of smoking on our society is remarkable. Estimates are that as many as 1 in 10 of all deaths are smoking related. Billions of dollars are spent yearly in the U.S. on treating upper respiratory tract infections, myocardial infarction and age-related macular degeneration. Smoking clearly ranks among America’s most pressing health care issues and is an increasingly important health care issue worldwide. Even a small decrease in the U.S. smoking rate would confer major benefits not only on the suffering of individual smokers but on the entire economy.

Genomics can bring quite a lot to bear on this issue, including insights into the genetic underpinnings of addiction behavior, disease risk associated with smoking, and novel approaches to smoking cessation.

Twin studies have long shown that inheritance plays an important role in smoking behavior, with heritability estimates of over 50% for both smoking and the ability to quit smoking. Anecdotally, each of us has probably experienced the hale and hearty 90-year-old who has smoked two packs a day since “before you were born,” as well as the 50-year-old smoker with oxygen and steroid-dependent chronic obstructive pulmonary disease (COPD). Is there a genetic basis for this variable response to a toxic environmental insult?

Genes have influence over whether you smoke, quit or dieIn rare cases, the genetic contribution to the effects of smoking is clear. Single-gene Mendelian disorders like alpha-one antitrypsin deficiency show a very strong gene-environment interaction. Until recently, sorting out the more subtle interactions between common gene variants and smoking was fraught with difficulties, mainly because the environmental factor frequently so strongly outweighs the genetic contributions to the development of disease. Multiple studies demonstrated a correlation between various genes, health conditions and smoking, but few were widely replicated. More recently the genome-wide association studies have begun to unravel this Gordian knot.

This unraveling began with the discovery of the gene variations associated with macular degeneration in 2005-2006, for which both genetics and smoking are clear risk factors. Recently, three simultaneously published studies examined variable genetic markers known as single nucleotide polymorphisms (SNPs) and their relationship to smoking and several health conditions.

The three studies identified a region on chromosome 15 as an important contributor to the genetic component of smoking-related disease risk. The markers fall in a gene cluster consisting of nicotinic acetylcholine receptor genes, with several other genes interspersed, and were associated with nicotine dependence, smoking quantity, peripheral arterial disease and lung cancer. As is the case with many variants identified through genome-wide association studies, these variants each confer only a small increase in an individual’s risk, albeit with a high degree of statistical certainty.

Unsurprisingly, one of the research groups concluded that the effect on lung cancer risk was mediated indirectly through changes in smoking behavior. Intriguingly, the authors of the other two studies concluded that the risk of lung cancer conferred by these markers might be mediated directly. In some way, changes in DNA present in lung tissue and associated with these SNPs make it more likely for a tumor to occur. Further studies are needed to sort out which of these mechanisms is correct, but these early studies give a tantalizing look at the underpinnings of some of the variability noted among smokers, and a window on potential new therapeutic approaches.

Much also is being learned about the influence of genetic variation on smoking cessation. Studies suggest that variations in genes associated with nicotine metabolism alter the effectiveness of nicotine replacement therapies. Similarly, studies have shown that individuals with variants in genes in pathways associated with dopamine metabolism seem to respond to pharmacologic interventions differentially. These emerging insights will very likely lead to novel therapeutic compounds. At some point, health care providers will probably be able to use genetic information to tailor approaches to smoking cessation.

We are just scratching the surface of the intersection of smoking, health and genomics. This research will help blaze the trail for a better understanding of other important environmental influences on disease, such as a high-fat diet, air pollution or alcohol use. The intersection of genes and the environment is a major focus of study for the National Human Genome Research Institute and the National Institutes of Health, as in the Genes and Environment Initiative.

As we become increasingly sophisticated in conducting large genome-wide association studies, novel interactions will be found between genetic variants, smoking and other smoking-related disorders like stroke, myocardial infarction and COPD. Though genomic discoveries will never provide a complete solution to the monumental and complex problem smoking presents to society, small victories will come with time, and make a difference in the lives of many.

W. Gregory Feero, MD, PhD, a family physician with a doctorate in human genetics, is senior adviser for genomic medicine in the Office of the Director at the NIH’s National Human Genome Research Institute.

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