Department of Metabolic and Bariatric Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.
Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, China.
Diabetologia. 2023 Nov;66(11):2087-2100. doi: 10.1007/s00125-023-05978-5. Epub 2023 Aug 4.
AIMS/HYPOTHESIS: This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes.
We examined the causal relationship between VAT and type 2 diabetes using bidirectional Mendelian randomisation (MR) followed by multivariable MR. We conducted a transcriptome-wide association study (TWAS) leveraging prediction models and a large-scale type 2 diabetes genome-wide association study (74,124 cases and 824,006 controls) to identify candidate genes in VAT and used summary-data-based MR (SMR) and co-localisation analysis to map causal genes. We performed enrichment and single-cell RNA-seq analyses to determine the cell-specific localisation of the TWAS-identified genes. We also conducted knockdown experiments in 3T3-L1 pre-adipocytes.
MR analyses showed a causal relationship between genetically increased VAT mass and type 2 diabetes (inverse-variance weighted OR 2.48 [95% CI 2.21, 2.79]). Ten VAT-specific candidate genes were associated with type 2 diabetes after Bonferroni correction, including five causal genes supported by SMR and co-localisation: PABPC4 (1p34.3); CCNE2 (8q22.1); HAUS6 (9p22.1); CWF19L1 (10q24.31); and CCDC92 (12q24.31). Combined with enrichment analyses, clarifying cell-type specificity with single-cell RNA-seq data indicated that most TWAS-identified candidate genes appear more likely to be associated with adipocytes in VAT. Knockdown experiments suggested that Pabpc4 likely contributes to regulating differentiation and energy metabolism in 3T3-L1 adipocytes.
CONCLUSIONS/INTERPRETATION: Our findings provide new insights into the genetic basis and biological processes of the association between VAT accumulation and type 2 diabetes and warrant investigation through further functional studies to validate these VAT-specific candidate genes.
目的/假设：本研究旨在评估内脏肥胖与 2 型糖尿病之间的因果关系，进而筛选 2 型糖尿病的内脏脂肪组织（VAT）特异性靶点。
我们使用双向 Mendelian 随机化（MR），随后进行多变量 MR 来检验 VAT 与 2 型糖尿病之间的因果关系。我们利用预测模型和大规模 2 型糖尿病全基因组关联研究（74124 例病例和 824006 例对照）进行全转录组关联研究（TWAS），以鉴定 VAT 中的候选基因，并使用基于汇总数据的 MR（SMR）和共定位分析来映射因果基因。我们进行了富集和单细胞 RNA-seq 分析，以确定 TWAS 鉴定基因的细胞特异性定位。我们还在 3T3-L1 前脂肪细胞中进行了敲低实验。
MR 分析表明，遗传上增加的 VAT 质量与 2 型糖尿病之间存在因果关系（逆方差加权 OR 2.48 [95%CI 2.21, 2.79]）。在 Bonferroni 校正后，有 10 个 VAT 特异性候选基因与 2 型糖尿病相关，其中包括 SMR 和共定位支持的 5 个因果基因：PABPC4（1p34.3）；CCNE2（8q22.1）；HAUS6（9p22.1）；CWF19L1（10q24.31）；和 CCDC92（12q24.31）。结合富集分析，利用单细胞 RNA-seq 数据阐明细胞特异性表明，TWAS 鉴定的大多数候选基因似乎更可能与 VAT 中的脂肪细胞相关。敲低实验表明，Pabpc4 可能有助于调节 3T3-L1 脂肪细胞的分化和能量代谢。
结论/解释：我们的研究结果为 VAT 积累与 2 型糖尿病之间的关联的遗传基础和生物学过程提供了新的见解，并需要通过进一步的功能研究来验证这些 VAT 特异性候选基因。
