Norway Funding by the Norwegian

Norway: Funding by the Norwegian Cancer Society and the Norwegian Research Council. The Resource for Lung Cancer in North Trent (ReSoLUCENT)/Sheffield: This study has been supported by Sheffield ECMC (Experimental Cancer Medicine Centre) and Weston Park Hospital Cancer Charity. Tampa, FL: This study was supported by Public Health Service grants P01-CA68384 and R01-DE13158 from the National Institutes of Health. UCLA: This study is supported by the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center and the National Institute of Health (CA90833, DA11386, CA77954, CA09142, CA96134, and ES 011667).
Conflict of interest All other authors have no conflict of interest to disclose. Contribution to Literature Search Contribution to Figures Contribution to Study Design Contribution to Data Collection: Contribution to data analysis: Contribution to data interpretation: Contribution to writing: Contribution to manuscript scientific review and comments: All authors reviewed the manuscript for scientific content and approved the final version.
Acknowledgements
International Lung Cancer Consortium (ILCCO): We thank Xuchen Zong for the data management of ILCCO Data Repository. German Lung Cancer Study (Germany): We thank the subjects who participated in any contributing study, the LUCY-consortium (detail in Sauter et al. 2008), Wiebke Sauter, Martina Mittelstrass, Vera Zietemann and Prof. H.-E. Wichmann, the KORA study group, P. Drings and the staff at the Thoraxklinik Heidelberg. Greater Toronto Area Study: We thank Dr. Geoffrey Liu\'s laboratory for the genotyping work related to this manuscript. Mayo Clinic: We thank the study participants for their dedication and commitment to Epidemiology and Genetics of Lung Cancer (REGLC) and Mayo Foundation for their support. Tampa, FL: We thank Kathy Eyring and Lindsay Mericle for sample and data collection at the H. Lee Moffitt Cancer Center. UCLA: We thank the study participants for their dedication and commitment and the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center for their support. UCSF: We appreciate the subjects and their ap1 for participating in this study.
Introduction Sickle cell trait is the carrier status of sickle cell disease (SCD), a severe hemolytic disease that is caused by a point mutation in the gene encoding beta-hemoglobin (β6Glu→Val) that increases the hydrophobicity of this protein when deoxygenated. In SCD RBCs, this mutation causes Hb polymerization under small reductions in physiologic oxygen saturation leading to cell dehydration, increased membrane rigidity and hemolysis (Rees et al., 2010; Brittenham et al., 1985). These altered red cell properties promote vaso-occlusive events in microcirculation, causing severe pain and end-organ ischemia, infarction and progressive dysfunction. Red blood cells (RBCs) from individuals with sickle cell trait (SCT) contain 25–50% HbS that polymerizes only at low fractional oxygen saturations <50% (Brittenham et al., 1985). Thus, under normal physiologic conditions, individuals with sickle cell trait are asymptomatic. However, under extreme conditions of hypoxia and dehydration, vaso-occlusive events can occur (Statius van Eps and De Jong, 1997). Historically, donor RBC genetic background is considered benign if the donor lacks clinically relevant symptoms but prolonged storage exposes RBCs to non-physiologic stress conditions and may amplify the effects of occult mutations (Dern et al., 1967; Latham et al., 1982). Sickle cell trait has a high prevalence in malaria endemic regions, which increases the probability that patients requiring RBC transfusions in these regions will receive stored HbAS RBCs. Current transfusion practices supporting the use of sickle cell trait RBCs are based on limited studies performed decades ago, which reported no differences in post-transfusion survival or recovery of sickle trait RBCs compared with normal RBCs. However, storage duration was relatively short (<21days compared with present 42-day storage limits) and utilized less sensitive methods to evaluate RBC post-transfusion survival (Callender et al., 1949; Ray et al., 1959; Levin and Truax, 1960). Here, we show that sickle cell trait increases storage hemolysis and reduces red cell post-transfusion survival in mice, an effect that increases with increasing time in storage. Interestingly, transfused HbAS RBCs do not exhibit higher intravascular hemolysis compared to HbAA RBCs, but rather become entrapped in the systemic microcirculation. These findings raise concerns about the viability of stored sickle cell trait red blood cells after prolonged storage and suggest a need for further clinical evaluation of post-transfusion recovery of stored human HbAS containing RBCs.