Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China.
Diabetes Metab Res Rev. 2020 Feb;36(2):e3214. doi: 10.1002/dmrr.3214. Epub 2019 Sep 10.
To investigate the genetic factors contributing to early-onset type 2 diabetes (EOD) in the Chinese Hans populations.
For 2734 newly diagnosed type 2 diabetes patients and 4041 normal glycemic controls, 25 single nucleotide polymorphisms from 24 genomic loci linked to diabetes were successfully genotyped. Three genetic risk scores (GRSs) were constructed, including the weighted type 2 diabetes-related GRS (wT-GRS), the weighted β-cell function-related GRS (wB-GRS), and the weighted GRS constructed by risk alleles not related to β-cell function (wNB-GRS). For patients with diabetes, EOD, middle-age-onset type 2 diabetes (MOD), and late-onset type 2 diabetes (LOD) were defined by onset ages ≤40, 40 to 60, and ≥60 years, respectively.
From single marker analysis, different gene profiles were identified between EOD and LOD patients. EOD patients had greater wT-GRS and wB-GRS values than LOD patients. After adjustment for sex, elevated wT-GRS and wB-GRS values were significantly associated with an increased risk for EOD by 1.11- and 1.21-fold per allele (P = 1.69 × 10 ; 6.07 × 10 ). The wT-GRS and wNB-GRS were nominally related to an increased risk of LOD by 1.03-fold per allele (P = 1.03 × 10 , 1.78 × 10 ). In patients with diabetes, higher wT-GRS and wB-GRS were associated with younger onset age [wT-GRS: β (SE) = -0.0033(0.0016), P = 3.74 × 10 ; wB-GRS: -0.0076(0.0028), 7.45 × 10 ] and decreased insulinogenic index [wT-GRS: -0.0384(0.0098), 9.39 × 10 ; wB-GRS: -0.0722(0.0176), 4.21 × 10 ].
Our findings indicate a strong genetic predisposition for EOD, which can be mainly attributed to genetic variants linked to β-cell function, suggesting the β-cell dysfunction plays a key role in the pathogenesis of EOD in Chinese Han individuals.
研究中国汉族人群中导致早发 2 型糖尿病（EOD）的遗传因素。
对 2734 名新诊断的 2 型糖尿病患者和 4041 名血糖正常的对照者进行了 24 个与糖尿病相关的基因组位点的 25 个单核苷酸多态性的成功基因分型。构建了 3 种遗传风险评分（GRS），包括加权 2 型糖尿病相关 GRS（wT-GRS）、加权β细胞功能相关 GRS（wB-GRS）和不与β细胞功能相关的风险等位基因构建的加权 GRS（wNB-GRS）。对于糖尿病患者，EOD、中年发病 2 型糖尿病（MOD）和晚发 2 型糖尿病（LOD）的定义为发病年龄≤40、40 至 60 和≥60 岁。
从单标记分析来看，EOD 和 LOD 患者的基因谱不同。EOD 患者的 wT-GRS 和 wB-GRS 值高于 LOD 患者。经性别调整后，每个等位基因增加 1.11-1.21 倍，wT-GRS 和 wB-GRS 值显著与 EOD 风险增加相关（P=1.69×10-5；6.07×10-5）。wT-GRS 和 wNB-GRS 与 LOD 的风险增加呈名义相关，每个等位基因增加 1.03 倍（P=1.03×10-4，1.78×10-4）。在糖尿病患者中，较高的 wT-GRS 和 wB-GRS 与发病年龄较小相关[wT-GRS：β（SE）=-0.0033（0.0016），P=3.74×10-5；wB-GRS：-0.0076（0.0028），7.45×10-5]，胰岛素生成指数降低[wT-GRS：-0.0384（0.0098），9.39×10-5；wB-GRS：-0.0722（0.0176），4.21×10-5]。
我们的研究结果表明，EOD 存在强烈的遗传易感性，这主要归因于与β细胞功能相关的遗传变异，提示β细胞功能障碍在汉族人群 EOD 的发病机制中起关键作用。
