HbA1c-based diagnosis of type 2 diabetes and complication risk are distorted in British south Asians due to HbE thalassaemia trait

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=7.8x10-8), 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=2.2x10-6) 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 hyperglycaemia, are needed, particularly on a global scale. This may be 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