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Abstract Background Genetic variants impacting red blood cell biology disrupt the relationship between glycaemia and glycated haemoglobin (HbA1c), with implications for diagnosis and management of type 2 diabetes (T2D). Thalassaemia trait is estimated to affect 350 million people globally, but its impact on T2D and related outcomes is not clear. Methods We explored associations between thalassaemia trait, HbA1c, and T2D diagnosis and complications in 43,088 British Bangladeshi and Pakistani participants in the Genes & Health study with linked multisource England National Health Service (NHS) electronic health record data and whole exome sequencing. Findings 2,490 participants (5.8%) were heterozygous carriers of ClinVar pathogenic / likely pathogenic thalassaemia variants, however 3 in 4 of these were not diagnosed with thalassaemia in their NHS health records. rs33950507, a common variant causal for HbE thalassaemia, was associated with increased HbA1c (beta=0.13, 95%CI:0.08-0.18, p=7.8×10 −8 ), but not glucose levels (beta=0.01, 95%CI:-0.04-0.06, P=0.72). rs33950507 was associated with increased hazards of prediabetes (HR=1.38, 95%CI:1.26-1.52, p=2.2×10 −6 ) and T2D (HR=1.11, 95%CI:1.01-1.22, p=0.03), and reduced hazards of diabetic eye disease (HR=0.74, 95%CI:0.56-0.96, p=0.02) and cerebrovascular disease (HR=0.44, 95%CI:0.20-0.94, p=0.03). Sensitivity analyses suggested mediation by overdiagnosis and overtreatment of T2D. Interpretation Alternatives to HbA1c, and/or precision medicine approaches to defining and managing pre-diabetes and T2D. These findings have global impact, and are particularly relevant to individuals from ancestral groups among whom erythrocytic traits are more common but often undiagnosed. Funding Wellcome Trust, MRC, NIHR, Barts Charity, Genes & Health Industry Consortium RESEARCH IN CONTEXT Evidence before this study The role of genetic variants that disrupt red blood cell biology in distorting the relationship between glycaemia and glycated haemoglobin (HbA1c) is increasingly recognised. Recently, variants in G6PD and PIEZO1, associated with lower HbA1c via red blood cell mechanisms independent of blood glucose, have been shown to associate with increased progression of diabetes complications. The clinical consequences of HbA1C disruption from thalassaemia trait remain poorly understood, despite thalassaemia trait affecting 350 million individuals worldwide, and being known to interfere with HbA1c measurement. We searched PUBMED and EMBASE for “thalass* & (diabet* | “hba1” | glycat*)” from inception to December 2025, identifying 984 studies. While several studies described distortion of HbA1c relative to blood glucose in thalassaemia trait, we identified none which reported on the clinical consequences, or on the diagnosis of diabetes or its complications. Added value of this study Thalassemia affects over 350 million people globally. We defined thalassaemia trait as individuals heterozygous for ClinVar pathogenic / likely pathogenic variants in whole exome sequence data in the Genes & Health study of British Pakistani and Bangladeshi individuals (n = 2,490 / 43,098). We highlight that only 1 in 4 of these genetically-defined thalassaemia trait carriers had a clinical diagnosis in their NHS health records, suggesting that thalassaemia is under-recognised in clinical practice in this population. A clinical prediction tool using routine. blood tests (ThalPred), was also only able to identify only one quarter of thalassaemia trait carriers. HbE thalassaemia trait was associated with increased HbA1c, contrasting to findings previously reported for G6PD and PIEZO1 which show opposite directionality. Thalassemia trait was also associated with increased hazards of prediabetes and type 2 diabetes (T2D) diagnosis, but was not associated with changes in serum glucose. HbE trait was associated with reduced hazards of complications including diabetic eye and cerebrovascular disease, but these associations were lost after adjustment for HbA1c, T2D diagnosis, and antidiabetic drug exposure. These findings suggest that the distortion of HbA1c leads to over-diagnosis and over-treatment, and this mediates the association with complications. Implications of all the available evidence This study adds further evidence to a growing literature emphasising the distortion between HbA1c and glycaemia in genetic conditions affecting red cell biology. Our findings suggest there is need for alternatives to HbA1c, and/or precision medicine approaches, to diagnose and manage prediabetes and type 2 diabetes accurately and equitably. These findings are particularly relevant in Asian ancestral groups, among whom poorer diabetes outcomes and red cell traits such as thalassaemia are common.