Introduction Sickle cell trait (SCT) is among the most prevalent carrier states on earth. While traditionally considered benign, uncertainty remains about whether SCT shortens life or predisposes to specific diseases. Several studies have reported associations between SCT and various adverse outcomes, including exertion-related death and pulmonary embolisms. In January 2025, an expert panel reviewed all current literature and found no evidence to support physical exertion (without rhabdomyolysis or heat-injury) as a cause of sudden death in individuals with SCT but emphasized the lack of high-quality evidence on risk of disease and death in SCT carriers. Therefore, we examined whether individuals with SCT had increased risk of death, cardiovascular disease, or other diseases previously linked to SCT.

Methods We prospectively studied 467,957 general population individuals from the UK Biobank, including 1,253 with SCT and 11 with sickle cell disease, identified by consecutive whole-exome sequencing of the entire study population. Inclusion criteria for this study were age 40-70 years and available HBB sequencing data. Individuals carrying any of the following variants were excluded: β-thalassemia, HbC, HbD-Punjab, HbE, and/or HbO.For all main analyses, we chose two different approaches: one including all individuals, and one only including individuals self-reporting to be ethnic Black.

For all analyses, follow-up began at study enrollment.

Cox regression models were multivariable adjusted for age, sex, smoking status, cumulative smoking in pack-years, alcohol consumption, body mass index, non-HDL cholesterol, triglycerides, income, household ownership, and Townsend Deprivation index. Analyses including all individuals were furthermore adjusted for self-reported ethnicity. This research has been conducted using the UK Biobank Resource under Application Number 99692.

Results During a median follow-up of 15 years (range 0-18), 50,387 individuals died. Individuals with SCT were not at increased risk of death from any cause in the full cohort (hazard ratio[HR] 1.04;95%CI 0.84-1.29 when compared to non-carriers) nor when restricting to ethnic Black individuals (HR 1.00;95%CI 0.78-1.29). Likewise, individuals with SCT were not at increased risk of death from cardiovascular disease (1.29;0.86-1.95) or for being diagnosed with myocardial infarction (0.76;0.44-1.31), ischemic stroke (1.28;0.85-1.94), pulmonary embolism (1.20;0.76-1.89), or heart failure (0.74;0.51-1.08).

Notably, we found increased risk of diabetes (HR 1.23;95%CI 1.06-1.43;p=0.005), chronic kidney disease (HR 1.42;95%CI 1.14-1.77;p=0.002), and hypertension (OR 1.20;95%CI 1.05-1.36;p=0.008) in individuals with SCT. Surprisingly, risk of death from cardiovascular disease was increased in individuals with SCT and diabetes when compared to non-carriers with diabetes (HR 2.24;95%CI 1.17-4.26;p=0.01), but risk of death from any cause was not increased in SCT carriers with diabetes (1.38;0.88-2.16). All the above-mentioned analyses gave similar results when restricting to Black individuals.

To examine whether selection bias may explain why some previous studies based on hospital diagnosed SCT have found increased risk of cardiovascular disease and other adverse outcomes, we repeated our main analyses where instead of defining SCT carriers based on consecutive genotyping, we used hospital diagnoses of SCT from national registries (ICD-10 code D57.3). Individuals diagnosed as being SCT carriers in a hospital registry before study enrolment had markedly increased risk of death from any cause (HR 2.26;95%CI 1.43-3.57;p=0.0004 when compared to non-carriers), death from cardiovascular disease (3.68;1.73-7.85;p=0.0007), and being diagnosed with ischemic stroke (3.10;1.37-7.00;p=0.007). These findings highlight the risk of spurious associations due to selection bias when relying on hospital diagnoses rather than consecutive genotyping to define SCT status in population-based studies and likely reflect a systematic bias in prognosis between individuals who have been admitted to hospital and those who have not.

Conclusion Individuals with SCT were not at increased risk of death from any cause or for being diagnosed with cardiovascular disease in this large, prospective, consecutively genotyped general population cohort. These findings offer important reassurance regarding long-term survival, while also identifying specific areas of increased morbidity that merit attention.

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2025
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