Using two independent adult cohorts, we demonstrated that smoking has a greater impact on reduced lung function among African Americans with high African ancestry than those with low African ancestry. Importantly, we found smokers with high African ancestry had lower baseline lung function than individuals with lower African ancestry. Inclusion of the 1,332 AIMs separately in models examining the association between tobacco smoke exposure and baseline FEV1
did not abrogate the response, even after correcting for multiple testing using false discovery rate 
, suggesting none of the ancestry informative markers were responsible for the observed associations. Moreover, baseline examination of FEV1
among European Americans indicated that their smoking-associated reduction in lung function was less (−3.9ml FEV1
/ smoking pack-year) than in African Americans. It is well recognized that smoking leads to reduced lung function and increases the rate of lung function decline with increasing age 
. Despite this knowledge and established racial/ethnic differences for pulmonary function, few studies have examined the complex relationship between race, smoking, and rate of lung function decline among healthy adults. Using genetic ancestry, we can elucidate racial/ethnic differences in smoking-related lung function decline. Genetic ancestry itself is unlikely the cause of these differences, but may be a proxy for population-specific rare genetic variants contributing to racial/ethnic differences in lung function and susceptibility to tobacco smoke 
. Novel approaches, such as admixture mapping, may enable us to identify population-specific variants that contribute to lung function decline 
Prior to our study, other groups have found inconsistent associations between race and smoking associated lung function decline. Vollmer et
. examined racial differences in smoking-related effects on cross-sectional FEV1
in European American and African American individuals and found no statistically significant difference in smoking associated decline 
. This is distinct from the findings of others who identified a greater susceptibility to FEV1
decline per pack-year smoked and a greater susceptibility to COPD among African American individuals 
. Some of the inconsistencies in prior investigations of racial differences in smoking-related pulmonary function may be due to their cross-sectional design 
or designs which matched on smoking 
, thereby precluding the ability to examine its impact on racial differences in pulmonary measures. With statistical approaches only recently developed for estimating admixture, prior studies were unable to quantify the degree of African ancestry. Our study compliments and extends prior investigations comparing African American and European American individuals by examining smoking-related changes in lung function in relation to a continuous measure of African ancestry.
Our findings suggest that tobacco-related lung damage and African ancestry together have a substantially greater impact on lung function and perhaps its decline than either factor alone. In other words, the relationship between smoking and pulmonary function depends on the level of African ancestry. Individuals with high African ancestry are particularly susceptible to the impact of cigarette smoking on the decline of FEV1
. In contrast to current smokers, former smokers with high African ancestry have lung function that becomes more similar to individuals with low African ancestry, suggesting lung function improves with smoking cessation irrespective of African ancestry. In fact, former smokers with high African ancestry may have an even greater benefit from smoking cessation, such that their lung function approaches that of former smokers with low African ancestry. These findings reveal greater complexity in the relationship between race and tobacco smoking associated lung function decline than was seen in an earlier study 
. Our findings suggest lung function depends on smoking status and the proportion of individual African ancestry and highlight the importance of smoking cessation. Future studies with greater statistical power are needed to confirm this relationship.
To assess potential survival bias, we compared baseline characteristics between those lost to follow-up and individuals remaining in the Health ABC study. Individuals remaining in the study were more likely to be male, higher BMI, higher education, fewer smoking pack-years, and lower African ancestry (Table S4
) compared to those lost to follow up during the study period suggesting survival bias may impact our findings. However, we found similar associations in the younger CARDIA cohort with a 20-year follow-up and 65% retention for African American participants, thus supporting the robustness of our findings. CARDIA participants included in analyses were slightly more educated and included more females than participants not included in analyses, but were similar for other key demographic characteristics (Table S5
). The consistency of the associations showing greater effect sizes in individuals of higher African ancestry for various measures of smoking suggests that smoking and African ancestry together may have an important impact on pulmonary function decline over time. We recognize that this observation may be due to social, environmental and genetic factors that co-vary with genetic ancestry. For example, environmental factors which could co-vary with ancestry include discrimination and proximity to roadways. The reduction in lung function in those with greatest African ancestry may have occurred in the distant past due to childhood or adolescent exposure to tobacco smoke leading to suboptimal lung growth or may be due to rapid decline in lung function in the early years of smoking.
Health ABC provides a robust approach for observing baseline spirometry measures, but also allows for assessment of longitudinal changes in lung function associated with smoking in this unique population of older African American adults. Replication of our findings in the CARDIA African American participants provides additional support. Few studies have ascertained repeated pulmonary function measures in either older populations or African American individuals. Thus the collection of repeated pulmonary function measures over a ten year time period in Health ABC and over 20 years in CARDIA is a notable strength of this study. Additionally, stringent protocols were implemented to ensure that quality spirometry measures were obtained. The prospective design of CARDIA and Health ABC minimizes possible participant response bias in reporting of smoking exposures.
In summary, we have demonstrated that African ancestry and tobacco use act synergistically to accelerate rate of lung function decline. Specifically, our results suggest that individuals with high African ancestry have increased risk of smoking-related changes in lung function and may be an important group for smoking intervention. In addition, the observation that former smokers with high African ancestry may have a less rapid rate of decline in lung function suggests that this group may preferentially benefit from cessation. Our findings have important public health implications. We have demonstrated that genetic ancestry may serve as a biomarker for identifying smokers who would benefit from targeted counseling regarding smoking cessation 
. One important implication of our findings is that there may be rare genetic variants relevant to smoking associated lung function decline that are population-specific and which co-vary with genetic ancestry 
. While we cannot rule out that some of these associations may be in part due to environmental factors which co-vary with ancestry, these results highlight the scientific advantages of studying racially mixed populations. Future analyses should include admixture mapping to identify genomic regions associated with rate of lung function decline. These regions are likely to harbor rare population-specific variants that could illuminate pathogenetic pathways involved in the regulation of tobacco metabolism and lung function 
. Reduced lung function is a predictor of overall morbidity and mortality 
; therefore, it is imperative to recognize and intervene in the populations at greatest risk.