No overall increased risk of death in individuals with sickle cell trait: a study of 467 779 general population adults

Uncertainty remains about whether sickle cell trait (SCT) shortens life or predispose to disease. Therefore, we examined whether SCT-carriers had increased risk of death or diseases linked to SCT. We studied 467,779 general population individuals from the UK Biobank. All had whole-exome sequencing performed and were followed prospectively for a median of 15 years. Individuals with SCT (n=1,253) were not at increased risk of all-cause death (hazard ratio[HR]:1.04;95%CI:0.84-1.29), cardiovascular death (1.34;0.90-2.00), or for having myocardial infarction (0.72;0.42-1.24), ischemic stroke (1.30;0.88-1.94), pulmonary embolism (1.29;0.84-1.99), or heart failure (0.79;0.55-1.14) compared to non-carriers. However, SCT-carriers had increased risk of diabetes (HR:1.30;95%CI:1.12-1.50), chronic kidney disease (HR:1.46;95%CI:1.18-1.80), and hypertension (odds ratio:1.24;95%CI:1.08-1.42). Surprisingly, risk of cardiovascular death was increased in SCT-carriers with diabetes when compared to non-carriers with diabetes (HR:2.17;95%CI:1.14-4.12). To examine whether selection bias may explain why previous studies based on hospital-diagnosed SCT found increased risk of cardiovascular disease, we repeated our analyses using hospital diagnoses of SCT from national registries, instead of defining SCT from genotyping. Individuals registered as SCT-carriers in hospital registries had markedly increased risk of all-cause death (HR:2.24;95%CI:1.42-3.52) and ischemic stroke (2.92;1.30-6.60), likely due to selection bias. In conclusion, SCT-carriers were not at increased risk of all-cause death or cardiovascular disease.