African-American smokers, on average, consume fewer cigarettes daily, inhale more deeply, and break down nicotine more slowly than European-American smokers. Such contrasts suggest that some of the biochemical processes underlying nicotine addiction differ between the two ethnic groups and may reflect genetic differences. Two NIDA-funded large-scale studies have linked some regions of the genome to the risk for nicotine dependence in African-Americans, other regions to risk in European-Americans, and still others to risk in both groups. The findings raise the possibility that specialized medications to treat smoking addiction in groups with different genetic backgrounds may eventually be developed.
"Environmental factors, such as whether family and friends smoke, strongly affect how and when a young person tries cigarettes. Studies suggest, however, that once that first cigarette is smoked, genetic makeup accounts for up to 50 percent of the likelihood that the individual will become nicotine dependent," says lead researcher Dr. Ming D. Li of the University of Virginia. "Identifying the genes that set addicted smokers apart, as well as those that increase the risk of the disorder in particular groups, ultimately will help determine the best brain proteins to target with medications. Future treatments may vary depending on a person's genes."
Smoke and Markers
Dr. Li and colleagues at the University of Virginia and five other universities conducted the studies, which together included 402 African-American families and 200 European-American families. Most of the 1,890 participants were from Tennessee, Mississippi, and Arkansas. One or more members of each family had smoked for at least 5 years and had smoked a pack or more a day for the past year. Most families had two or more smokers; 80 percent of all the study participants smoked. The researchers assessed each individual's smoking dependence by three different measures: the number of cigarettes smoked daily, the Heavy Smoking Index (HSI), and the Fagerstrom Test for Nicotine Dependence (FTND).The last two measures rate addiction severity based on the number of cigarettes smoked plus other behavioral indicators such as how soon after waking the first cigarette is smoked and how much difficulty the person has in refraining from smoking.
Each participant submitted a blood sample for DNA scanning. The research team genotyped hundreds of genetic markers—segments of DNA at known locations on a chromosome. If the marker showed up in most participants with high scores on one or more of the three smoking measures but not in most of the nonsmokers, researchers concluded that genes linked with the risk of nicotine addiction were likely to be situated nearby.
Ethnicity and Risk
The strongest correlation observed in the two studies, and the only one meeting the statistical standard for being "highly significant," linked a region on chromosome 10 to the number of cigarettes smoked by African-Americans (see table). Among African-Americans, statistically "suggestive" relationships tied this same region to HSI and FTND scores. "Because the same area on chromosome 10 linked with all three measures of smoking, we have confidence that the area is truly connected with nicotine addiction in African-Americans," says Dr. Li. The researchers did not see an association between this area and smoking behavior among European-Americans. Similarly, regions on chromosome 13 were associated with the number of cigarettes African-Americans smoked daily, but not with any dependence measure among European-Americans. "Further study of sites unique to African-Americans may elucidate the particular genes that increase vulnerability to nicotine addiction in this population," says Dr. Li.
|Chromosome Number||African-Americans||European-Americans||Combined Sample||Convergence Analysis|
|9 (region 1)*||Suggestive||Suggestive||AA and EA|
|9 (region 2)*||Suggestive||Suggestive||AA and EA|
|10 (region 1)*||
|10 (region 2)*||Suggestive||EA|
|11||Suggestive||Suggestive||Suggestive||AA and EA|
|18||Suggestive||Suggestive||AA and EA|
* The region was linked with more than one measure of smoking.
In their study with European-American families, the researchers found suggestive relationships between eight chromosomal regions and risk for nicotine dependence. Regions on chromosomes 4 and 9 produced the strongest links. The region on chromosome 4 was associated with all three nicotine dependence measures, and the region on chromosome 9 was linked to two of them. All the other linked regions—on chromosomes 2, 10, 11, 12, 17, and 18—appeared to affect only one of the three measures.
Except for one region on chromosome 12, all of the regions linked with smoking among European-Americans in Dr. Li's study had been detected in prior research. "Replication of the results in different populations gives one additional confidence of a connection with nicotine dependence. The converging evidence suggests that these chromosomal regions should receive top priority in the search for genes that increase susceptibility to nicotine dependence," says Dr. Li.
Comparison of the data from the separate studies showed that four regions on three chromosomes—9, 11, and 18—influenced risk in both the African-American and European-American families.
Refining the Analyses
Analyses of the combined data from the two studies affirm the importance of focusing on risk genes within ethnic groups rather than solely on ethnically mixed populations. Although many of the linkages seen in the two separate analyses were also observed in the analysis of data from the combined group of African-Americans and European-Americans, the regions on chromosomes 2, 4, 10, and 17 that affected vulnerability to nicotine addiction in the study of just European-Americans did not appear in the analysis of the mixed group. Dr. Li notes that if the research team had conducted a study only with the combined group, they would not have detected the risks associated with these regions.
Finally, the researchers conducted a further examination, called a convergence analysis, on their combined samples. In this study, the chromosomal regions linked with all three of the nicotine dependence measures among only African-Americans or only European-Americans showed an association with smoking in both groups. The convergence analysis implicated four regions in risks for both ethnic groups and seven regions in risks for one group or the other.
The chromosomal regions associated with vulnerability to nicotine dependence by Dr. Li and colleagues typically harbor hundreds of genes. Fortunately, geneticists already know the identity of many of those genes. They can point to several whose proteins have biochemical properties that make them likely to play a role in smoking addiction. The next step in this line of research is to choose the most promising of these genes and examine their effects on nicotine biochemistry. Animal studies are usually best for this type of investigation. Once genetic researchers pinpoint culpable genes and trace their effects, developers of medications can begin to create and test compounds to alter the genes' effects.
"Scientists have much work to do before they determine how gene variations affect the neurobiology underlying addiction, but these next steps will lead ultimately to improved smoking cessation treatment," says Dr. Joni Rutter of NIDA's Division of Basic Neuroscience and Behavioral Research. "Dr. Li's work suggests that future treatment options may differ according to the genome of the affected individual."
Li, M.D., et al. A genome-wide search finds major susceptibility loci for nicotine dependence on chromosome 10 in African Americans. The American Journal of Human Genetics 79(4):745-751, 2006. [Full Text (PDF, 590KB)]
Li, M.D., et al. Genome-wide linkage scan for nicotine dependence in European Americans and its converging results with African Americans in the Mid-South Tobacco Family sample. Molecular Psychiatry 13(4):407-416, 2008. [Abstract]
Li, M.D. Identifying susceptibility loci for nicotine dependence: 2008 update based on recent genome-wide linkage analyses. Human Genetics 123(2):119-131, 2008. [Abstract]