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

Abstract 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 (rs563555492 T ), carried by 1 in 12 south Asians, has been associated with a nonglycemic 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 rs563555492 T 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 Research in Context Evidence before this study We searched PubMed from database inception to Nov 1, 2025, for studies examining PIEZO1, Glycated Haemoglobin (HbA1c) and type 2 diabetes (T2D) related outcomes. Search terms included “PIEZO1”, “haemoly*”, “hemol*”, “erythrocyte*”, “HbA1c”, “glycated haemoglobin”, “glycated hemoglobin”, “type 2 diabetes”, “prediabetes”, “retinopathy”, and related terms. HbA1c is widely used to guide prevention, diagnosis, and management of T2D, but variants affecting erythrocyte structure or lifespan can alter its relationship with glycaemia. A missense variant in PIEZO1 (rs563555492 T ), carried by one in twelve south Asians, has been associated with lower HbA1c and erythrocytic biomarkers without differences in fasting glucose and with older age at T2D diagnosis, suggesting delayed diagnosis in UK-based cohorts. However, uncertainties remain. Associations have not been replicated outside the UK to confirm generalisability. Experimental animal models suggest PIEZO1 channels may influence pancreatic insulin secretion, but this has not been evaluated in human cohorts. Finally, the potential clinical and health-economic consequences associated with this variant remain largely unexplored. Added value of this study We replicated associations between rs563555492 T , lower HbA1c, and erythrocytic changes in a geographically distinct south Asian cohort based in South India. We found no association with fasting glucose, postprandial glucose, or C-peptide concentrations, supporting a predominantly erythrocytic mechanism. We examined the clinical and economic consequences of this variant on south Asians in a large UK population-based cohort, following introduction of HbA1c-based diagnostic criteria. Carriers experienced delayed diagnosis of prediabetes and T2D, and there was some evidence of increased risk of diabetic eye disease. In a modelled population aged 40-50 years, the variant was associated with approximately 1,019 missed prediabetes diagnoses and 303 missed T2D diagnoses per 100,000 adults over 10 years. Because prediabetes diagnosis initiates referral to prevention programmes, missed diagnoses represent lost opportunities for disease prevention. In a UK NHS setting, we estimated the associated opportunity cost to be between £970,000 - £1,390,000 per 100,000 individuals over a 10-year horizon. Implications of all the available evidence A south Asian ancestry enriched PIEZO1 variant can disrupt the relationship between HbA1c and glycaemia and delay detection of prediabetes and T2D. Reliance on HbA1c alone may underestimate glycaemic risk in a substantial minority of individuals of south Asian ancestry, with potential implications for prevention strategies, risk of complications and health care costs. Alternative biomarkers of glycaemia or individualisation of HbA1c may help ensure timely and accurate diabetes detection in populations where this variant is common.