Clinical variable-based cluster analysis identifies novel subgroups with a distinct genetic signature, lipidomic pattern and cardio-renal risks in Asian patients with recent-onset type 2 diabetes,Diabetologia

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Clinical variable-based cluster analysis identifies novel subgroups with a distinct genetic signature, lipidomic pattern and cardio-renal risks in Asian patients with recent-onset type 2 diabetes
Diabetologia ( IF 8.4 ) Pub Date : 2022-06-28 , DOI: 10.1007/s00125-022-05741-2
Jiexun Wang ₁ , Jian-Jun Liu ₁ , Resham L Gurung ₁ , Sylvia Liu ₁ , Janus Lee ₁ , Yiamunaa M ₁ , Keven Ang ₁ , Yi Ming Shao ₁ , Justin I-Shing Tang ₂ , Peter I Benke ₃ , Federico Torta ₃ , Markus R Wenk ₃ , Subramaniam Tavintharan ₄ , Wern Ee Tang ₅ , Chee Fang Sum ₄ , Su Chi Lim _{4,

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Affiliation

Aims/hypothesis

We sought to subtype South East Asian patients with type 2 diabetes by de novo cluster analysis on clinical variables, and to determine whether the novel subgroups carry distinct genetic and lipidomic features as well as differential cardio-renal risks.

Methods

Analysis by k-means algorithm was performed in 687 participants with recent-onset diabetes in Singapore. Genetic risk for beta cell dysfunction was assessed by polygenic risk score. We used a discovery–validation approach for the lipidomics study. Risks for cardio-renal complications were studied by survival analysis.

Results

Cluster analysis identified three novel diabetic subgroups, i.e. mild obesity-related diabetes (MOD, 45%), mild age-related diabetes with insulin insufficiency (MARD-II, 36%) and severe insulin-resistant diabetes with relative insulin insufficiency (SIRD-RII, 19%). Compared with the MOD subgroup, MARD-II had a higher polygenic risk score for beta cell dysfunction. The SIRD-RII subgroup had higher levels of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (phosphatidylethanolamine and phosphatidylcholine), whereas the MARD-II subgroup had lower levels of sphingolipids and glycerophospholipids but higher levels of lysophosphatidylcholines. Over a median of 7.3 years follow-up, the SIRD-RII subgroup had the highest risks for incident heart failure and progressive kidney disease, while the MARD-II subgroup had moderately elevated risk for kidney disease progression.

Conclusions/interpretation

Cluster analysis on clinical variables identified novel subgroups with distinct genetic, lipidomic signatures and varying cardio-renal risks in South East Asian participants with type 2 diabetes. Our study suggests that this easily actionable approach may be adapted in other ethnic populations to stratify the heterogeneous type 2 diabetes population for precision medicine.

Graphical abstract

中文翻译：

基于临床变量的聚类分析确定了亚洲新发 2 型糖尿病患者具有独特遗传特征、脂质组学模式和心肾风险的新亚组

目标/假设

我们试图通过对临床变量的从头聚类分析对东南亚 2 型糖尿病患者进行亚型分类，并确定新的亚组是否具有不同的遗传和脂质组学特征以及不同的心肾风险。

方法

对新加坡 687 名新发糖尿病患者进行了 k 均值算法分析。通过多基因风险评分评估 β 细胞功能障碍的遗传风险。我们使用发现-验证方法进行脂质组学研究。通过生存分析研究心肾并发症的风险。

结果

聚类分析确定了三个新的糖尿病亚组，即轻度肥胖相关糖尿病（MOD，45%）、轻度年龄相关糖尿病伴胰岛素功能不全（MARD-II，36%）和重度胰岛素抵抗糖尿病伴胰岛素相对不足（SIRD- RII，19%）。与 MOD 亚组相比，MARD-II 具有更高的 β 细胞功能障碍多基因风险评分。SIRD-RII 亚组的鞘脂（神经酰胺和鞘磷脂）和甘油磷脂（磷脂酰乙醇胺和磷脂酰胆碱）水平较高，而 MARD-II 亚组的鞘脂和甘油磷脂水平较低，但溶血磷脂酰胆碱水平较高。在平均 7.3 年的随访中，SIRD-RII 亚组发生心力衰竭和进行性肾病的风险最高，