Risk of death and comorbidities in β-thalassemia carriers identified by consecutive genotyping: A prospective cohort study of 467,242 general population individuals

Abstract Introduction:Approximately 1.5% of the global population are heterozygous carriers of β-thalassemia. While the condition is typically characterized by microcytic anemia and often considered clinically benign, evidence on risk of death and comorbidities remains limited. Some previous studies have reported increased risks of comorbidities, including chronic kidney disease, cholelithiasis, liver cirrhosis, and diabetes. Based on mechanistic studies, it has also been hypothesized that β-thalassemia carriers could potentially be at increased or decreased risk of cardiovascular disease. Objective: To examine the risk of death and comorbidities in β-thalassemia carriers based on consecutive genotyping of general population individuals.Methods:We prospectively studied 467,242 general population individuals from the UK Biobank age 40-70 years. All individuals had whole-exome sequencing performed, and we identified 549 heterozygous β-thalassemia carriers by cross-referencing all HBB variants with the ITHANET database. Individuals with β-thalassemia homozygosity, compound heterozygosity, or structural hemoglobin variants (HbS, HbE, HbC, HbD, HbO) were excluded. This project was conducted using the UK Biobank Resource under Application Number #99692.Cox proportional hazards regression was used to study risk of death and risk of comorbidities previously linked to the β-thalassemia carrier state. All models were multivariable adjusted for age, sex, income, self-reported ethnicity, smoking status, cumulative smoking in pack-years, alcohol consumption, body mass index, non-HDL cholesterol, and triglycerides. Results:Individuals were followed for a median of 15 years when studying risk of death, and a median of 26 years for risk of disease. During follow-up, 50,326 individuals died from any cause. When compared to non-carrier individuals, β-thalassemia carriers were not at increased risk of death from any cause (hazard ratio[HR] 0.75;95%CI 0.54-1.04) or cause-specific death from cancer, cardiovascular disease, respiratory disease, or neurodegenerative disease. When studying risk of being diagnosed with comorbidities, β-thalassemia carriers were not at increased risk of cholelithiasis (HR 1.17;95%CI 0.82-1.65), liver cirrhosis (1.48;0.55-3.98), diabetes (0.91;0.74-1.13), myocardial infarction (0.66;0.39-1.09), ischemic stroke (0.66;0.31-1.38), pulmonary embolism (1.38;0.76-2.50), or heart failure (0.65;0.39-1.08). However, β-thalassemia carriers had a decreased risk of chronic kidney disease (HR 0.49;95%CI 0.30-0.80; p=0.004) when compared to non-carriers. Our above mentioned results based on studying consecutively genotyped individuals were substantially different from previous studies based on individuals diagnosed as β-thalassemia carriers in hospital registries. Therefore, we examined whether selection bias in such hospital registry studies could explain the previous reports of increased risk of comorbidities in β-thalassemia carriers. Indeed, when repeating our analyses but defining β-thalassemia carriers not based on consecutive genotyping but instead based on having received a hospital diagnosis of β-thalassemia heterozygosity in the national UK registries (ICD-10 code D56.3), we found that hospital diagnosed β-thalassemia carriers were at markedly increased risk of chronic kidney disease (HR 2.31;95%CI 1.55-3.46), cholelithiasis (2.73;1.69-4.39), diabetes (2.74;2.10-3.58), ischemic stroke (2.25;1.07-4.73), pulmonary embolism (3.56; 1.77-7.13), and heart failure (2.31;1.41-3.78). Conclusion:When studying consecutively genotyped general population individuals, β-thalassemia carriers were not at increased risk of death or comorbidities. Importantly, we could not confirm the increased risk of chronic kidney disease, cholelithiasis, liver cirrhosis, and diabetes reported in previous studies, and we even found a decreased risk of chronic kidney disease in β-thalassemia carriers when compared to non-carriers. Given the high global prevalence of β-thalassemia, this provides evidence-based reassurance for millions of carriers worldwide. Our findings underscore the importance of using consecutively genotyped individuals when studying risk of death and disease in β-thalassemia carriers, as analyses based on β-thalassemia carrier diagnoses from hospital registries are likely to suffer from selection bias caused by oversampling individuals who have been genotyped specifically because of hospital contacts due to health problems.