创建皮克病国际联盟：H2单倍型与皮克病风险的关联研究。

Creating the Pick's disease International Consortium: Association study of H2 haplotype with risk of Pick's disease.

作者信息

Valentino Rebecca R, Scotton William J, Roemer Shanu F, Lashley Tammaryn, Heckman Michael G, Shoai Maryam, Martinez-Carrasco Alejandro, Tamvaka Nicole, Walton Ronald L, Baker Matthew C, Macpherson Hannah L, Real Raquel, Soto-Beasley Alexandra I, Mok Kin, Revesz Tamas, Warner Thomas T, Jaunmuktane Zane, Boeve Bradley F, Christopher Elizabeth A, DeTure Michael, Duara Ranjan, Graff-Radford Neill R, Josephs Keith A, Knopman David S, Koga Shunsuke, Murray Melissa E, Lyons Kelly E, Pahwa Rajesh, Parisi Joseph E, Petersen Ronald C, Whitwell Jennifer, Grinberg Lea T, Miller Bruce, Schlereth Athena, Seeley William W, Spina Salvatore, Grossman Murray, Irwin David J, Lee Edward B, Suh EunRan, Trojanowski John Q, Van Deerlin Vivianna M, Wolk David A, Connors Theresa R, Dooley Patrick M, Frosch Matthew P, Oakley Derek H, Aldecoa Iban, Balasa Mircea, Gelpi Ellen, Borrego-Écija Sergi, de Eugenio Huélamo Rosa Maria, Gascon-Bayarri Jordi, Sánchez-Valle Raquel, Sanz-Cartagena Pilar, Piñol-Ripoll Gerard, Molina-Porcel Laura, Bigio Eileen H, Flanagan Margaret E, Gefen Tamar, Rogalski Emily J, Weintraub Sandra, Redding-Ochoa Javier, Chang Koping, Troncoso Juan C, Prokop Stefan, Newell Kathy L, Ghetti Bernardino, Jones Matthew, Richardson Anna, Robinson Andrew C, Roncaroli Federico, Snowden Julie, Allinson Kieren, Green Oliver, Rowe James B, Singh Poonam, Beach Thomas G, Serrano Geidy E, Flowers Xena E, Goldman James E, Heaps Allison C, Leskinen Sandra P, Teich Andrew F, Black Sandra E, Keith Julia L, Masellis Mario, Bodi Istvan, King Andrew, Sarraj Safa-Al, Troakes Claire, Halliday Glenda M, Hodges John R, Kril Jillian J, Kwok John B, Piguet Olivier, Gearing Marla, Arzberger Thomas, Roeber Sigrun, Attems Johannes, Morris Christopher M, Thomas Alan J, Evers Bret M, White Charles L, Mechawar Naguib, Sieben Anne A, Cras Patrick P, De Vil Bart B, De Deyn Peter Paul P P, Duyckaerts Charles, Le Ber Isabelle, Seihean Danielle, Turbant-Leclere Sabrina, MacKenzie Ian R, McLean Catriona, Cykowski Matthew D, Ervin John F, Wang Shih-Hsiu J, Graff Caroline, Nennesmo Inger, Nagra Rashed M, Riehl James, Kovacs Gabor G, Giaccone Giorgio, Nacmias Benedetta, Neumann Manuela, Ang Lee-Cyn, Finger Elizabeth C, Blauwendraat Cornelis, Nalls Mike A, Singleton Andrew B, Vitale Dan, Cunha Cristina, Carvalho Agostinho, Wszolek Zbigniew K, Morris Huw R, Rademakers Rosa, Hardy John A, Dickson Dennis W, Rohrer Jonathan D, Ross Owen A

机构信息

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

Dementia Research Centre, Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, UK.

出版信息

medRxiv. 2023 Apr 24:2023.04.17.23288471. doi: 10.1101/2023.04.17.23288471.

DOI:10.1101/2023.04.17.23288471

PMID:37163045

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10168402/

Abstract

BACKGROUND

Pick's disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the gene. The H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between H2 and risk of PiD.

METHODS

We established the Pick's disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521).

FINDINGS

Our primary analysis found that the H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65).

INTERPRETATION

The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.

摘要

背景

匹克氏病（PiD）是一种罕见的、主要为散发性的额颞叶痴呆形式，被归类为原发性tau蛋白病。PiD在病理学上由嗜银性包涵体匹克小体以及额叶和颞叶脑叶中的气球样神经元所定义。PiD的特征是存在由聚集的、高度磷酸化的3重复tau蛋白形成的匹克小体，这些蛋白由该基因编码。H2单倍型一直与进行性核上性麻痹和皮质基底节变性这两种4重复tau蛋白病的疾病风险降低相关，然而其在PiD易感性中的作用尚不清楚。本研究的主要目的是评估H2与PiD风险之间的关联。

方法

我们成立了匹克氏病国际联盟（PIC），并从全球39个地点收集了338例（60.7%为男性）经病理证实的PiD脑标本。从佛罗里达州杰克逊维尔的梅奥诊所（N = 881）或明尼苏达州罗切斯特的梅奥诊所（N = 431）招募了1312名神经功能正常的临床对照。对于主要分析，对受试者直接进行H1 - H2单倍型定义变体rs8070723的基因分型。在次要分析中，我们对六个变体进行基因分型并构建H1亚单倍型（rs1467967、rs242557、rs3785883、rs2471738、rs8070723和rs7521）。

研究结果

我们的主要分析发现，H2单倍型与PiD风险增加相关（比值比：1.35，95%置信区间：1.12 - 1.64，P = 0.002）。在涉及H1亚单倍型的次要分析中，观察到H1f亚单倍型与PiD存在保护性关联（0.0%对1.2%，P = 0.049），H1b也有类似趋势（比值比：0.76，95%置信区间：0.58 - 1.00，P = 0.051）。4重复tau蛋白病风险单倍型H1c与PiD易感性无关（比值比：0.93，95%置信区间：0.70 - 1.25，P = 0.65）。