January 16, 2003 — University of Utah scientists are mounting a five-year, $10.7 million effort to identify genes that make some people susceptible to nicotine addiction and cigarette smoking, and to developing emphysema, bronchitis and other chronic lung diseases.

The genetics of addiction program is funded by $10,666,767 in grants from the National Heart, Lung and Blood Institute and the National Institute on Drug Abuse (NIDA). The project was announced today at the university’s Eccles Institute of Human Genetics. NIDA also awarded the university’s Genetic Science Learning Center another $750,000 to develop materials to educate high school students and teachers in Utah and nationwide about genetic factors contributing to addiction. That brings the total to more than $11.4 million.

The addiction program “is a chance to take advantage of the great resources we have in Utah to look at an important and complicated public health issue: the devastating problem of addiction,” said Ray Gesteland, Ph.D., the university’s vice president for research and a distinguished professor of human genetics. “It is another tribute to our expertise in genetics.”

About 15 faculty members and another 15 to 20 staff members and students are working on the program, which involves three major studies to seek genes that predispose people and mice to nicotine addiction and make some smokers more likely than others to develop chronic obstructive pulmonary diseases (COPDs) like emphysema.

“We are hoping to get clues to the genetic and molecular bases for addiction in general, for nicotine addiction in particular, and for the health consequences of cigarette smoking,” said lung specialist John Hoidal, M.D., principal investigator of the genetics of addiction program, interim chair of internal medicine and chief of respiratory, critical care and occupational medicine at the University of Utah School of Medicine.

The research effort is motivated by some frightening statistics, including World Health Organization estimates that 1.1 billion people in the world smoke.

“Every eight seconds, somebody in the world dies from cigarette smoking,” Hoidal said. “Cigarette smoking is the leading preventable cause of death in the United States.”

The university’s grant application stated that cigarette smoking “costs an estimated $97 billion annually in the U.S. for medical care and lost productivity. … It is our contention that an in-depth knowledge of the genetic factors [involved in nicotine addiction] and an understanding of how these factors are linked to the consequences of cigarette smoking are essential to impact upon survival, treatment and prevention of the disorder.”

“The more we know about the genetic basis for the disorder, the better position we are in to identify susceptible individuals, identify crucial biochemical pathways of addiction and thus modify them,” Hoidal said. “We hope to learn things that lead to ways of preventing nicotine addiction and some health consequences of cigarette smoking.”

“Quitting smoking is far and away the most effective way to decrease cancer incidence in this country,” Gesteland said. “So if understanding the genes involved in predisposition to smoking can lead to less overall smoking, it has a major impact on cancer and other smoking-related diseases.”

Previous studies involving twins suggest that genes account for as much as 50 percent to 70 percent of the risk of becoming a smoker.

“There is strong evidence that both the addiction to nicotine and its consequences – which include emphysema, coronary artery disease and lung cancer – have genetic predispositions,” Hoidal said. “This grant really focuses on trying to determine the genetic predispositions for both the addiction and for the consequences of that addiction.”

The research will not address artery disease or lung cancer, but will deal with emphysema and other forms of COPD, “which is the fourth leading cause of death in the United States,” he added.

The addiction project is focusing on nicotine because “it is the most prevalent addiction in our society,” Hoidal said. “It is the leading cause of death of all addictions. It is a legal substance, so opportunities to study it are probably greater than with something that is illicit. And what we learn about the addiction to nicotine may have implications for other addictive substances such as cocaine and alcohol.”

The researchers will study approximately 6,100 people during the course of the program, including 3,400 in Utah and 2,700 at the Center for Tobacco Research and Intervention at University of Wisconsin campuses in Madison and Milwaukee.

The scientists will look for nicotine addiction and lung disease genes among smokers and nonsmokers drawn from large Utah families, Veterans Affairs clinics in Utah, the Wisconsin center, pairs of Utah siblings, patients in a long-running University of Utah lung disease study, and a group of 100 Hispanics who are strongly addicted to nicotine.

The genetics of addiction program includes three main studies:

(1) Mark Leppert, Ph.D., co-chair of the university’s Department of Human Genetics, leads a study to look for genes involved in nicotine addiction.

“There could be as many as 20 genes or 50 genes. We just don’t know,” said Leppert, adding the long-term goal is to develop medicines to prevent or halt nicotine addiction.

“Almost certainly there will be many genes involved, each contributing some small part of the problem, and these have to be distinguished from environmental factors that contribute to smoking,” said Gesteland.

Leppert said nicotine addiction genes are more likely to be found in sibling pairs when both siblings smoke, and in smokers who are highly addicted. In families, nicotine-addiction genes occur more often among smokers than nonsmokers.

(2) Scott Rogers, Ph.D., an associate professor of neurobiology and anatomy, is looking for nicotine addiction genes in mice. Some mice, like some people, can become extremely addicted to nicotine, while others show only moderate or no dependence. By studying strains of mice with different genetic predispositions to nicotine addiction, Rogers hopes “the same genes can be found in humans to give us an idea what predisposes some individuals to chronic nicotine abuse and others to a life free of this problem.”

Once such genes are identified, researchers will analyze what happens at a biochemical level in the brain to cause the addiction. A key focus will be on genes that order the formation of nicotine receptors, which are places on cells to which nicotine can attach, triggering changes in how the cell functions. Such receptors are found throughout the body, including the brain, white blood cells, skin and the lungs.

What Rogers and colleagues learn about such receptors eventually “might give you tools to block nicotine’s effects,” Hoidal said.

(3) Hoidal runs a study looking for genes that make some people more susceptible than others to emphysema and other chronic obstructive pulmonary diseases. He said 20 percent to 25 percent of smokers develop COPDs, “and it is not just dependent on the amount they smoke,” suggesting some people are more susceptible.

The study also will try to relate the role of nicotine and nicotine receptor genes to the development of chronic lung diseases. It is possible some of the same genes involved in nicotine addiction also are involved in disease development, Hoidal said.

He said that in the past, nicotine was seen as less of a factor in the health consequences of smoking than other chemicals in cigarettes. But nicotine is important not only because it addicts people to cigarettes, but because recent evidence suggests it plays a role in the inflammation found in chronic lung diseases, clogged arteries and perhaps cancer, he added. Nicotine also may impair the body’s ability to repair damage to lung cells.

In addition to the gene studies, Jennifer Logan, Ph.D., co-director of the university’s Genetic Science Learning Center will lead a $750,000 effort to train teachers and develop curriculum supplements to educate high school students about genetic factors in addiction.

“We seek to dispel the social stigma associated with addiction by exploring it as a biological disorder, driven by a complex combination of environmental and hereditary factors,” Logan said. “By placing the topic in the context of basic genetics, molecular biology and modern laboratory research, we aim to help improve the overall scientific literacy of teachers and students nationwide.”