Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt-Jakob disease

被引：15

作者：

C. Dabin, Luke ^{[1
]}

Guntoro, Fernando ^{[1
]}

Campbell, Tracy ^{[1
]}

Belicard, Tony ^{[2
,3
,4
]}

Smith, Adam R. ^{[5
]}

Smith, Rebecca G. ^{[5
]}

Raybould, Rachel ^{[6
]}

Schott, Jonathan M. ^{[7
]}

Lunnon, Katie ^{[5
]}

Sarkies, Peter ^{[2
,3
,4
]}

Collinge, John ^{[1
]}

Mead, Simon ^{[1
]}

Vire, Emmanuelle ^{[1
]}

机构：

[1] UCL Inst Prion Dis, MRC Prion Unit UCL, Courtauld Bldg,33 Cleveland St, London W1W 7FF, England

[2] MRC London Inst Med Sci, Du Cane Rd, London W12 0NN, England

[3] Imperial Coll London, Inst Clin Sci, Du Cane Rd, London W12 0NN, England

[4] Imperial Coll London, London W12 0NN, England

[5] Exeter Univ, Univ Exeter Med Sch, Coll Med & Hlth, Royal Devon & Exeter Hosp, RILD Bldg,Level 4,Barrack Rd, Exeter EX2 5DW, Devon, England

[6] Cardiff Univ, Inst Psychol Med & Clin Neurosci, UHW Main Bldg,Heath Pk, Cardiff CF14 4XN, Wales

[7] UCL Inst Neurol, Dementia Res Ctr, 8-11 Queen Sq, London WC1N 3AR, England

来源：

ACTA NEUROPATHOLOGICA | 2020年 / 140卷 / 06期

基金：

英国医学研究理事会;

关键词：

Prion disease; sCJD; DNA methylation; Blood; Disease duration; Neurodegeneration; PRION PROTEIN; OUTCOME MEASURE; NEURODEGENERATION; POLYMORPHISMS; INFLAMMASOME; DEGRADATION; SURVIVAL; CELLS; FKBP5;

D O I：

10.1007/s00401-020-02224-9

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Prion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we profiled genome-wide blood DNA methylation in the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). Our case-control study (n = 219), when accounting for differences in cell type composition between individuals, identified 38 probes at genome-wide significance (p < 1.24 x 10(-7)). Nine of these sites were taken forward in a replication study, performed in an independent case-control (n = 186) cohort using pyrosequencing. Sites in or close toFKBP5, AIM2(2 probes), UHRF1, KCNAB2successfully replicated. The blood-based DNA methylation signal was tissue- and disease-specific, in that the replicated probe signals were unchanged in case-control studies using sCJD frontal-cortex (n = 84), blood samples from patients with Alzheimer's disease, and from inherited and acquired prion diseases. Machine learning algorithms using blood DNA methylation array profiles accurately distinguished sCJD patients and controls. Finally, we identified sites whose methylation levels associated with prolonged survival in sCJD patients. Altogether, this study has identified a peripheral DNA methylation signature of sCJD with a variety of potential biomarker applications.

引用

页码：863 / 879

页数：17