Sickle Cell Trait and Risk for Common Diseases: Evidence from the UK Biobank



      Sickle cell trait is typically considered benign. Although evidence remains inconsistent, recent studies suggest that it is associated with several common diseases. We systematically assessed associations of sickle cell trait with reported diseases in a large population-based cohort.


      Study subjects were self-reported Blacks from the UK Biobank (UKB), a United Kingdom population-based cohort of subjects aged 40-69 years at recruitment in the United Kingdom. Sickle cell status was based on the International Classification of Diseases, Tenth Revision (ICD-10) or mutations in the HBB gene. Diagnoses of diseases were obtained from ICD-10 and self-reports. Associations of sickle cell trait and diseases were tested using logistic regression, adjusting for age at recruitment, sex, and genetic background (top 10 principal components).


      Among the 8019 Blacks in the UKB, 699 (8.72%) were sickle cell trait carriers; the rate was significantly higher in females (9.74%) than males (7.48%), P = .0005. Sickle cell trait was under-diagnosed; most heterozygous hemoglobin subunit beta (HBB) gene Glu6Val carriers did not have a sickle cell trait ICD-10 record. Compared with non-sickle cell trait, sickle cell trait carriers had significantly increased risk for type 2 diabetes; odds ratio 1.38; 95% confidence interval, 1.12-1.68; P = .002. Sickle cell trait was also significantly associated with increased risk for renal diseases (rhabdomyolysis, end-stage renal disease, chronic kidney disease, renal papillary necrosis) and vascular diseases (hypertension, retinopathy, non-ischemic stroke), P < .05. While most of these diseases are complications/comorbidities of diabetes, their associations with sickle cell trait remained significant after adjusting for diabetes. Association with end-stage renal disease was stronger in subjects without diabetes, odds ratio 6.45; 95% confidence interval, 1.93-19.61; P = .001.


      Sickle cell trait is significantly associated with increased risk for diabetes and diabetes-related complications/comorbidities.


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        • Sundd P
        • Gladwin MT
        • Novelli EM
        Pathophysiology of sickle cell disease.
        Annu Rev Pathol. 2019; 14: 263-292
        • Platt OS
        • Brambilla DJ
        • Rosse WF
        • et al.
        Mortality in sickle cell disease. Life expectancy and risk factors for early death.
        N Engl J Med. 1994; 330: 1639-1644
        • Ogu UO
        • Badamosi NU
        • Camacho PE
        • Freire AX
        • Adams-Graves P
        Management of sickle cell disease complications beyond acute chest syndrome.
        J Blood Med. 2021; 12: 101-114
        • Shah N
        • Bhor M
        • Xie L
        • Paulose J
        • Yuce H
        Sickle cell disease complications: prevalence and resource utilization.
        PLoS One. 2019; 14e0214355
        • Thein MS
        • Igbineweka NE
        • Thein SL
        Sickle cell disease in the older adult.
        Pathology. 2017; 49: 1-9
      1. Centers for Disease Control and Prevention (CDC). Data & statistics on sickle cell disease. Available at: Accessed August 30, 2021.

        • Tsaras G
        • Owusu-Ansah A
        • Boateng FO
        • Amoateng-Adjepong Y
        Complications associated with sickle cell trait: a brief narrative review.
        Am J Med. 2009; 122: 507-512
        • Piel FB
        • Patil AP
        • Howes RE
        • et al.
        Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates.
        Lancet. 2013; 381: 142-151
      2. American Society of Hematology Clinical Practice Guidelines on Sickle Cell Disease. Published 2016. Available at: Accessed May 6, 2022.

        • Xu JZ
        • Thein SL
        The carrier state for sickle cell disease is not completely harmless.
        Haematologica. 2019; 104: 1106-1111
        • Naik RP
        • Smith-Whitley K
        • Hassell KL
        • et al.
        Clinical outcomes associated with sickle cell trait: a systematic review.
        Ann Intern Med. 2018; 169: 619-627
        • Bycroft C
        • Freeman C
        • Petkova D
        • et al.
        The UK Biobank resource with deep phenotyping and genomic data.
        Nature. 2018; 562: 203-209
        • Rees DC
        • Williams TN
        • Gladwin MT
        Sickle-cell disease.
        Lancet. 2010; 376: 2018-2031
        • Liem RI
        • Chan C
        • Vu TT
        • et al.
        Association among sickle cell trait, fitness, and cardiovascular risk factors in CARDIA.
        Blood. 2017; 129: 723-728
        • Zhou J
        • Han J
        • Nutescu EA
        • et al.
        Similar burden of type 2 diabetes among adult patients with sickle cell disease relative to African Americans in the U.S. population: a six-year population-based cohort analysis.
        Br J Haematol. 2019; 185: 116-127
        • Al Harbi M
        • Khandekar R
        • Kozak I
        • Schatz P
        Association between sickle cell trait and the prevalence and severity of diabetic retinopathy.
        PLoS One. 2016; 11e0159215
        • Oli JM
        • Watkins PJ
        • Wild B
        • Adegoke OJ
        Albuminuria in Afro-Caribbeans with Type 2 diabetes mellitus: is the sickle cell trait a risk factor?.
        Diabet Med. 2004; 21: 483-486
        • Page MM
        • MacKay JM
        • Paterson G
        Sickle cell trait and diabetic retinopathy.
        Br J Ophthalmol. 1979; 63: 837-838
        • Bleyer AJ
        • Reddy SV
        • Sujata L
        • et al.
        Sickle cell trait and development of microvascular complications in diabetes mellitus.
        Clin J Am Soc Nephrol. 2010; 5: 1015-1020
        • Naik RP
        • Irvin MR
        • Judd S
        • et al.
        Sickle cell trait and the risk of ESRD in blacks.
        J Am Soc Nephrol. 2017; 28: 2180-2187
        • Diaw M
        • Pialoux V
        • Martin C
        • et al.
        Sickle cell trait worsens oxidative stress, abnormal blood rheology, and vascular dysfunction in type 2 diabetes.
        Diabetes Care. 2015; 38: 2120-2127
        • Oli JM
        • Reid HL
        Do Nigerian diabetics with haemoglobin genotype Hb AS have greater risks of developing renal complications and hypertension? A preliminary report.
        Trop Geogr Med. 1985; 37: 309-313
        • Ajayi AA
        • Kolawole BA
        Sickle cell trait and gender influence type 2 diabetic complications in African patients.
        Eur J Intern Med. 2004; 15: 312-315
        • Skinner SC
        • Diaw M
        • Pialoux V
        • et al.
        Increased prevalence of type 2 diabetes-related complications in combined type 2 diabetes and sickle cell trait.
        Diabetes Care. 2018; 41: 2595-2602
        • Taylor C
        • Kavanagh P
        • Zuckerman B
        Sickle cell trait–neglected opportunities in the era of genomic medicine.
        JAMA. 2014; 311: 1495-1496
        • Benson JM
        • Therrell BL
        History and current status of newborn screening for hemoglobinopathies.
        Semin Perinatol. 2010; 34: 134-144
        • Streetly A
        • Clarke M
        • Downing M
        • et al.
        Implementation of the newborn screening programme for sickle cell disease in England: results for 2003-2005.
        J Med Screen. 2008; 15: 9-13