1 型糖尿病患者 28 年来的 DNA 甲基化与增殖性视网膜病变的表观基因组关联研究

IF 3.2 Q1 OPHTHALMOLOGY Ophthalmology science Pub Date : 2024-02-28 DOI:10.1016/j.xops.2024.100497

Rachel G. Miller PhD , Josyf C. Mychaleckyj DPhil , Suna Onengut-Gumuscu PhD , Trevor J. Orchard MD, MMedSci , Tina Costacou PhD

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引用次数: 0

摘要

目的对 1 型糖尿病（T1D）患者的 DNA 甲基化（DNAm）和 28 年增殖性糖尿病视网膜病变（PDR）发病率进行前瞻性全表观基因组关联研究。方法在基线期、DNAm 测量后的 2、4、6、8、16、23 和 28 年，在 1、2 和 4 区拍摄立体眼底照片。照片采用改良的 Airlie House 系统进行分级。对基线时无 PDR 的患者（n = 265；基线时 T1D 平均持续时间为 18 年），在 Cox 模型中分析了 683 597 个 CpGs 的全血 DNAm（EPIC 阵列）与事件发生时间的关系。评估了重要 CpGs 与临床风险因素之间的关联；确定了与 DNAm 相关的遗传变异（甲基化定量性状位点 [meQTLs]）。采用孟德尔随机化方法检查 DNAm 与 PDR 之间因果关系的证据。主要结果测量增殖性糖尿病视网膜病变的定义是：至少有一只眼的视网膜病变分级≥60级，或首次因PDR而进行泛视网膜光凝。随访时间从可获得 DNAm 数据的研究访问（基线）开始计算，直至 PDR 发生或剔除（2018 年 12 月 31 日或最后一次随访）。cg27512687（KIF16B）的DNAm越大，PDR发病率越低（P = 6.3 × 10-9；假发现率[FDR]：< 0.01）；发现了113个顺式-meQTLs（P <5×10-8）。使用哨点 meQTL 作为工具变量的孟德尔随机分析支持 cg27512687 与 PDR 之间的潜在因果关系。Cg27512687 还与较低的脉搏率和白蛋白排泄率以及较高的估计肾小球滤过率有关，但在对这些因素进行调整后，它与 PDR 的关联仍具有独立显著性。结论KIF16B、FUT4、FKBP1A和RIN2的DNA甲基化与PDR发病率相关，支持铁清除、发育途径和自噬在PDR发病机制中的表观遗传调控作用。对这些基因位点的进一步研究可能会为预防或延缓T1D的PDR提供新的干预靶点。

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An Epigenome-Wide Association Study of DNA Methylation and Proliferative Retinopathy over 28 Years in Type 1 Diabetes

Purpose

To perform a prospective epigenome-wide association study of DNA methylation (DNAm) and 28-year proliferative diabetic retinopathy (PDR) incidence in type 1 diabetes (T1D).

Design

Prospective observational cohort study.

Participants

The Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (< 17 years) T1D.

Methods

Stereoscopic fundus photographs were taken in fields 1, 2, and 4 at baseline, 2, 4, 6, 8, 16, 23, and 28 years after DNAm measurements. The photos were graded using the modified Airlie House System. In those free of PDR at baseline (n = 265; mean T1D duration of 18 years at baseline), whole blood DNAm (EPIC array) at 683 597 CpGs was analyzed in Cox models for time to event. Associations between significant CpGs and clinical risk factors were assessed; genetic variants associated with DNAm were identified (methylation quantitative trait loci [meQTLs]). Mendelian randomization was used to examine evidence of causal associations between DNAm and PDR. Post hoc regional and functional analyses were performed.

Main Outcome Measures

Proliferative diabetic retinopathy was defined as the first instance of a grade of ≥ 60 in at least 1 eye or pan-retinal photocoagulation for PDR. Follow-up time was calculated from the study visit at which DNAm data were available (baseline) until PDR incidence or censoring (December 31, 2018 or last follow-up).

Results

PDR incidence was 53% over 28-years’ follow-up. Greater DNAm of cg27512687 (KIF16B) was associated with reduced PDR incidence (P = 6.3 × 10⁻⁹; false discovery rate [FDR]: < 0.01); 113 cis-meQTLs (P < 5 × 10⁻⁸) were identified. Mendelian randomization analysis using the sentinel meQTL as the instrumental variable supported a potentially causal association between cg27512687 and PDR. Cg27512687 was also associated with lower pulse rate and albumin excretion rate and higher estimated glomerular filtration rate, but its association with PDR remained independently significant after adjustment for those factors. In regional analyses, DNAm of FUT4, FKBP1A, and RIN2 was also associated with PDR incidence.

Conclusions

DNA methylation of KIF16B, FUT4, FKBP1A, and RIN2 was associated with PDR incidence, supporting roles for epigenetic regulation of iron clearance, developmental pathways, and autophagy in PDR pathogenesis. Further study of those loci may provide insight into novel targets for interventions to prevent or delay PDR in T1D.