Missense Variants in PAX4 Are Associated with Early-Onset Diabetes in Chinese
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ORIGINAL RESEARCH
Missense Variants in PAX4 Are Associated with EarlyOnset Diabetes in Chinese Aibo Gao . Bin Gu . Juan Zhang . Chen Fang . Junlei Su . Haorong Li . Rulai Han . Lei Ye . Weiqing Wang . Guang Ning . Jiqiu Wang . Weiqiong Gu
Received: September 15, 2020 / Accepted: October 27, 2020 Ó The Author(s) 2020
ABSTRACT 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 b-cells. The dysfunction-missense variants PAX4 R192H and PAX4 R192S are common in East Asians but rare in Europeans.
Aibo Gao and Bin Gu share joint first co-authorship.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13300020-00960-5) contains supplementary material, which is available to authorized users. A. Gao B. Gu J. Zhang J. Su H. Li R. Han L. Ye W. Wang G. Ning J. Wang (&) W. Gu (&) Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200025, China e-mail: [email protected] W. Gu e-mail: [email protected] A. Gao National Research Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China C. Fang The Second Affiliated Hospital of Soochow University, Soochow 215004, China
Therefore, we aim to investigate the diabetesassociated genes, including PAX4 R192H/S, in East Asians with early-onset diabetes. Methods: Exome variants of 80 Chinese earlyonset 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 earlyonset diabetes (R192H: OR 1.88, 95% CI 1.37–2.60, P = 8.41 9 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 earlyonset diabetes with decreased C-peptide levels may be one explanation of the discrepancy of diabetes between East Asians and Europeans.
Diabetes Ther
Clinical trial registration: ClinicalTrials.gov (NCT01938365). Keywords: C-peptide; East Asian; PAX4
Early-onset
diabetes;
Key Summary Points Why carry out the study? Ea
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