LAUSR

Introduction East Asians are more susceptible to early-onset diabetes than Europeans and exhibit reduced insulin secretion at earlier stages. PAX4 plays a critical role in the development of β-cells. The dysfunction-missense variants PAX4 R192H and PAX4 R192S are common in East Asians but rare in Europeans. Therefore, we aim to investigate the diabetes-associated genes, including PAX4 R192H/S, in East Asians with early-onset diabetes. Methods Exome variants of 80 Chinese early-onset diabetes patients (onset age < 35 years) after the exclusion of type 1 diabetes (T1D) were detected by a customized gene panel covering 32 known diabetes-associated genes. Then, 229 subjects with early-onset diabetes (T1D excluded) and 1679 controls from the Chinese population were genotyped to validate the association of PAX4 R192H/S with early-onset diabetes and related phenotypes. Results The gene panel detected 11 monogenic diabetes patients with five novel mutations among the 80 early-onset diabetes patients. Asian-specifically enriched PAX4 R192H and R192S were associated with early-onset diabetes (R192H: OR 1.88, 95% CI 1.37–2.60, P  = 8.41 × 10 −5 ; R192S: OR 1.71, 95% CI 1.17–2.51, P  = 0.005). In early-onset diabetes patients, PAX4 R192H carriers had higher haemoglobin A1c (HbA1c) levels ( P  = 0.030) and lower 2 h C-peptide levels in the oral glucose tolerance test (OGTT) ( P  = 0.040); R192S carriers had lower fasting C-peptide (FCP) ( P  = 0.011) and 2 h C-peptide levels ( P  = 0.033) in OGTT than non-variant carriers. Conclusions The ethnic-specific enrichment of PAX4 R192H/S predisposing East Asians to early-onset diabetes with decreased C-peptide levels may be one explanation of the discrepancy of diabetes between East Asians and Europeans. Clinical trial registration ClinicalTrials.gov (NCT01938365).