PAX4基因的错义变异与中国人群早发型糖尿病相关。

Missense Variants in PAX4 Are Associated with Early-Onset Diabetes in Chinese.

作者信息

Gao Aibo, Gu Bin, Zhang Juan, Fang Chen, Su Junlei, Li Haorong, Han Rulai, Ye Lei, Wang Weiqing, Ning Guang, Wang Jiqiu, Gu Weiqiong

机构信息

Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China.

National Research Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

出版信息

Diabetes Ther. 2021 Jan;12(1):289-300. doi: 10.1007/s13300-020-00960-5. Epub 2020 Nov 20.

DOI:10.1007/s13300-020-00960-5

PMID:33216280

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7843779/

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 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; 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).

摘要

引言

东亚人比欧洲人更容易患早发性糖尿病，并且在疾病早期阶段胰岛素分泌就会减少。PAX4在β细胞的发育中起着关键作用。功能障碍错义变体PAX4 R192H和PAX4 R192S在东亚人中很常见，但在欧洲人中很少见。因此，我们旨在研究早发性糖尿病东亚患者中与糖尿病相关的基因，包括PAX4 R192H/S。

方法

通过覆盖32个已知糖尿病相关基因的定制基因检测板，检测80例排除1型糖尿病（T1D）的中国早发性糖尿病患者（发病年龄<35岁）的外显子变体。然后，对229例早发性糖尿病患者（排除T1D）和1679例中国人群对照进行基因分型，以验证PAX4 R192H/S与早发性糖尿病及相关表型的关联。

结果

基因检测板在80例早发性糖尿病患者中检测到11例单基因糖尿病患者，发现了5个新突变。亚洲人群中特异性富集的PAX4 R192H和R192S与早发性糖尿病相关（R192H：比值比1.88，95%置信区间1.37 - 2.60，P = 8.41×10；R192S：比值比1.71，95%置信区间1.17 - 2.51，P = 0.005）。在早发性糖尿病患者中，携带PAX4 R192H的患者糖化血红蛋白（HbA1c）水平较高（P = 0.030），口服葡萄糖耐量试验（OGTT）中2小时C肽水平较低（P = 0.040）；携带R192S的患者空腹C肽（FCP）水平较低（P = 0.011），OGTT中2小时C肽水平也低于非变体携带者（P = 0.033）。