表观遗传标记与西非人群2型糖尿病因果关系的孟德尔随机化分析
本研究利用加纳和尼日利亚人群的DNA甲基化数据，通过两样本孟德尔随机化分析，识别出cg00036588和cg16759041两个CpG位点可能是西非人群2型糖尿病的因果表观遗传标记，纵向分析显示基线甲基化与随访HbA1c相关。
要点
- cg00036588和cg16759041在孟德尔随机化中显示与2型糖尿病存在因果证据。
- 基线甲基化水平与随访HbA1c相关，提示潜在早期检测价值。
- cg00036588与骨骼肌FAM83C表达呈顺式相关（FDR=3.3×10-4）。
核心结论
- 研究识别出两个CpG位点（cg00036588和cg16759041）可能是西非人群2型糖尿病的因果表观遗传标记。
研究设计与样本
- 研究纳入879名加纳个体（RODAM研究）和332名尼日利亚个体（AADM研究），均未使用降糖药物。
- 使用Illumina EPIC DNA甲基化芯片对外周血白细胞DNA进行甲基化谱分析。
- 对EWAS识别的CpG及HbA1c和HOMA-S的EWAS结果进行两样本孟德尔随机化分析。
- 利用AADM研究4120名参与者的全基因组关联分析获取SNP-结局关联。
- 纵向数据（n=138）和RNA-seq数据（n=77血液、49脂肪、55肌肉）用于后续分析。
主要发现
- 共识别28个与2型糖尿病相关的CpG、26个与HbA1c相关的CpG和3个与HOMA-S相关的CpG（总计57个）。
- 49个CpG在血液中有meQTL（AADM数据），4个在非洲裔美国人原代肝细胞中有meQTL。
- 孟德尔随机化分析为cg00036588（血液meQTL）和cg16759041（肝细胞meQTL）与2型糖尿病的因果关系提供了证据。
- 纵向分析显示这些CpG的基线甲基化与随访时HbA1c相关。
- RNA-seq数据显示cg00036588与骨骼肌FAM83C表达顺式相关（FDR=3.3×10-4），与EIF6相关（FDR=0.13）。
临床怎么用
- 这些有因果证据的CpG可作为西非人群2型糖尿病早期检测的潜在生物标志物。
- 这些CpG也可能作为药物开发靶点，但需进一步验证。
以上解读依据论文摘要（全文未开放获取或许可不允许翻译转载）。
原文
AIMS/HYPOTHESIS: Evidence for a causal role of DNA methylation sites (CpGs) in type 2 diabetes and glycaemic traits is limited due to the cross-sectional nature of many epigenome-wide association studies (EWAS). In addition, epigenetic studies in West African populations are particularly sparse, despite the high and rising burden of type 2 diabetes in these populations. Hence, we aimed to identify CpGs causally associated with type 2 diabetes among West Africans by leveraging Mendelian randomisation (MR) analysis and longitudinal data. METHODS: We used the Illumina EPIC DNA methylation array to profile the methylation of DNA extracted from white blood cells collected from 879 Ghanaian individuals (the Research on Obesity and Diabetes among African Migrants [RODAM] study) and 332 Nigerian individuals (the Africa America Diabetes Mellitus [AADM] study) who were not on glucose-lowering medication. We carried forwards CpGs identified in EWAS for type 2 diabetes and meta-analysed EWAS for HbA1c and homeostatic model assessment estimates of insulin sensitivity (HOMA-S) as exposures to two-sample MR analysis. Independent cis methylation quantitative trait loci (meQTLs) were calculated using methylation data from blood and primary hepatocytes and subsequently used as instrumental variables (SNP-exposure associations). Genome-wide association analyses for type 2 diabetes on 4120 participants from the AADM study were used to derive the SNP-outcome associations. Longitudinal trait data (n=138) and RNA-seq data (n=77 blood, 49 adipose, 55 muscle) available for a subset of Nigerians were used for follow-up analyses. RESULTS: We identified 28 CpGs associated with type 2 diabetes, 26 with HbA1c and three with HOMA-S (total CpGs: 57), of which 49 had meQTLs in blood (AADM study data) and four had meQTLs in primary hepatocytes from African American individuals. MR analysis provided evidence for causality for cg00036588 and cg16759041 in type 2 diabetes using blood and hepatocyte meQTLs, respectively. Longitudinal analyses showed an association between baseline methylation of these CpGs with HbA1c at follow-up. RNA-seq data revealed a cis correlation of cg00036588 with FAM83C (false discovery rate [FDR]=3.3 × 10-4) and EIF6 (FDR=0.13) in skeletal muscle. CONCLUSIONS/INTERPRETATION: Our study identified two epigenetic markers as likely to be causal for type 2 diabetes in West African populations. In addition to enhancing our understanding of disease mechanisms, these CpGs with evidence of causal associations could be prioritised as potential biomarkers for early detection of disease or as drug development targets.
引用
- Meeks KAC, van der Linden EL, Bentley AR, et al. Causal relationship between epigenetic markers and type 2 diabetes in West African populations: a Mendelian randomisation analysis. Diabetologia. 2026. PMID: 42032377. doi:10.1007/s00125-026-06716-3
供执业医师工作参考，不替代临床判断；数值与分级以指南原文为准。