Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad, Pakistan.
BGI-Europe, Copenhagen, Denmark.
PLoS One. 2019 Jan 10;14(1):e0210114. doi: 10.1371/journal.pone.0210114. eCollection 2019.
PPP1R3B has been suggested as a candidate gene for monogenic forms of diabetes as well as type 2 diabetes (T2D) due to its association with glycaemic trait and its biological role in glycogen synthesis.
To study if rare missense variants in PPP1R3B increase the risk of maturity onset diabetes of the young (MODY), T2D or affect measures of glucose metabolism.
Targeted resequencing of PPP1R3B was performed in 8,710 samples; MODY patients with unknown etiology (n = 54), newly diagnosed patients with T2D (n = 2,930) and population-based control individuals (n = 5,726, of whom n = 4,569 had normal glucose tolerance). All population-based sampled individuals were examined using an oral glucose tolerance test.
Among n = 396 carriers, we identified twenty-three PPP1R3B missense mutations, none of which segregated with MODY. The burden of likely deleterious PPP1R3B variants was significantly increased with a total of 17 carriers among patients with T2D (0.58% (95% CI: 0.36-0.93)) compared to 18 carriers among non-diabetic individuals (0.31% (95% CI: 0.20-0.49)), resulting in an increased risk of T2D (OR (95% CI) = 2.57 (1.14-5.79), p = 0.02 (age and sex adjusted)). Furthermore, carriers with diabetes had less abdominal fat and a higher serum concentration of LDL-cholesterol compared to patients with T2D without rare missense PPP1R3B variants. In addition, non-diabetic carriers had a higher birth weight compared to non-carriers.
Rare missense PPP1R3B variants may predispose to T2D.
PPP1R3B 由于与血糖特征相关，并且在糖原合成中具有生物学作用，因此被认为是单基因形式糖尿病和 2 型糖尿病（T2D）的候选基因。
研究 PPP1R3B 中的罕见错义变体是否会增加青少年发病型糖尿病（MODY）、T2D 的风险，或者是否会影响葡萄糖代谢的测量指标。
对 8710 个样本进行 PPP1R3B 的靶向重测序；病因不明的 MODY 患者（n=54）、新诊断的 T2D 患者（n=2930）和基于人群的对照个体（n=5726，其中 n=4569 糖耐量正常）。所有基于人群的采样个体均接受口服葡萄糖耐量试验。
在 n=396 个携带者中，我们鉴定出 23 个 PPP1R3B 错义突变，没有一个与 MODY 分离。T2D 患者中共有 17 个携带者存在 PPP1R3B 可能有害变异的负担显著增加（0.58%（95%CI：0.36-0.93）），而非糖尿病个体中共有 18 个携带者（0.31%（95%CI：0.20-0.49）），导致 T2D 的风险增加（OR（95%CI）=2.57（1.14-5.79），p=0.02（年龄和性别调整））。此外，患有糖尿病的携带者的腹部脂肪较少，血清 LDL-胆固醇浓度较高，而患有 T2D 但没有罕见 PPP1R3B 错义变异的患者则没有。此外，非糖尿病携带者的出生体重高于非携带者。
罕见的 PPP1R3B 错义变异可能导致 T2D。
