An ancestry-enriched PIEZO1 missense variant biases HbA1c-based diagnosis of prediabetes and type 2 diabetes in South Asians

Background Glycated haemoglobin (HbA1c) underpins type 2 diabetes (T2D) and prediabetes management worldwide and reflects both glycaemia and erythrocyte biology. A missense variant in PIEZO1 (rs563555492T), carried by 1 in 12 South Asians, has been associated with a nonglycaemic reduction in HbA1c. We aimed to further characterise this association and evaluate its clinical consequences. Methods We undertook genetic and linked health data analyses across two cohorts: 19,898 (37.4% female) South Indians from the Madras Diabetes Research Foundation (MDRF) and 43,011 (54.4% female) British Bangladeshis and British Pakistanis in Genes & Health. In MDRF, we tested associations with glycaemic and erythrocytic traits using additive genetic models. In Genes & Health we modelled diagnosis of prediabetes, T2D, and diabetic eye disease using flexible parametric survival models. Ten-year absolute risks were estimated for a population aged 40-50 years. Findings PIEZO1 rs563555492T was associated with erythrocytic traits and lower HbA1c, but not with fasting glucose, postprandial glucose, or C-peptide. This variant reduced risk of prediabetes (HR 0.63, 95% CI 0.58-0.69) and T2D (0.85, 0.78-0.93) diagnosis, and increased risk of diabetic eye disease among individuals with T2D (1.20, 1.01-1.43). Modelling suggested approximately 1,019 missed prediabetes and 303 missed T2D diagnoses per 100,000 adults over 10 years. Interpretation An ancestry-enriched PIEZO1 variant is associated with lower HbA1c independent of glycaemia, reduced prediabetes and T2D diagnosis suggesting delayed detection, and increased complication risk. Reliance on HbA1c may systematically underestimate glycaemic risk in a substantial minority of South Asians. Funding The Wellcome Trust; NIHR