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Introduction: It is unknown how much of the increased all-cause mortality risk in Black individuals who ever-smoked is due to race as a social construct versus biological factors such as genetic ancestry. We examined the association of genetic ancestry with all-cause mortality, controlling for risk factors and self-reported race/ethnicity, in the PLCO cohort. Methods: We used PLCO data from 52,708 White individuals who ever-smoked (18281 deaths) and 2,585 Black individuals who ever-smoked (1108 deaths). Genetic ancestry was determined by GRAF (https://github.com/ncbi/graf) on a set of 10,000 pre-selected fingerprinting variants. Percent ancestry for each of Europe, Africa, and East-Asia was determined for each person. We fit Cox models for time to death, controlling for smoking history and other risk factors. Results: Self-reported Black individuals who ever-smoked had increased all-cause mortality versus self-reported White individuals who ever-smoked (HR=1.14, 95%CI: 1.07-1.22, p=0.00007). For White individuals, increases in European ancestry were associated with increased death risk, (HR=1.009 per 1% increase in European ancestry, 95%CI:1.003-1.015, p=0.002). HRs for European ancestry, by quartile, were 1.040, 1.061 and 1.063, with the last two HRs demonstrating statistical significance (95%CI:1.0018-1.106, p = 0.005, and 95%CI:1.020-1.108, p=0.004), respectively. For Black individuals, increases in African ancestry were associated with increased death risk, (HR=1.003 per 1% increase in African ancestry, 95%CI: 0.998-1.008, p=0.214), although not statistically significant. HRs for African ancestry, by quartile, were 1, 1.16, 1.14, and 1.21, with the last HR demonstrating statistical significance (95%CI:1.010-1.450, p = 0.03). Conclusions: For self-reported White individuals who ever-smoked, increasing European ancestry was associated with an increased all-cause mortality risk. For self-reported Black individuals who ever-smoked, there was suggestive evidence that increasing African ancestry may increase all-cause mortality risk. However, associations with ancestry were small and may be vulnerable to residual confounding. Impact/Significance: A mechanistic explanation for this finding is unclear, but it could be related to population genetic “fitness” with reduced genetic admixture leading to decreased fitness for survival. Citation Format: Courtney D. Dill, Dontray Crump, Rebecca Landy, Li C. Cheung, Wen-Yi Huang, Sonja Berndt, Neal Freedman, Hormuzd Katki. Association between genetic ancestry and all-cause mortality among Black and White ever-smokers in the PLCO cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1953. |