背景:Pick病是一种罕见且主要为散发性的额颞叶痴呆,被归类为原发性tau病。Pick的疾病在病理上由Pick身体的额叶和颞叶的存在来定义,由过度磷酸化组成,三重复tau蛋白,由MAPT基因编码。MAPT有两种不同的单倍型,H1和H2;MAPTH1单倍型是四重复tau蛋白病的主要遗传风险因素(例如,进行性核上性麻痹和皮质基底变性),MAPTH2单倍型对这些疾病有保护作用。这项研究的主要目的是评估MAPTH2与Pick疾病风险的关系,发病年龄,和疾病持续时间。
方法:在这项遗传关联研究中,我们使用了皮克疾病国际联合会的数据,我们建立的目的是为了收集全世界患有Pick病的患者的数据。对于这个分析,我们收集了来自北美35个地点(脑库和医院)的病理证实的Pick病个体的脑样本,欧洲,和澳大利亚在2020年1月1日至2023年1月31日之间。神经健康对照是从梅奥诊所(FL,美国,或MN,1998年3月1日至2019年9月1日之间的美国)。对于主要分析,对个体直接进行MAPTH1-H2单倍型定义变体rs8070723的基因分型。在次要分析中,我们基因分型并构建了六个变体定义的(rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521)MAPTH1亚单倍型。MAPT变异体和MAPT单倍型与Pick疾病风险的关联,发病年龄,使用逻辑和线性回归模型检查疾病持续时间;估计比值比(OR)和β系数,并对应于每个额外的次要等位基因或给定单倍型的每个额外拷贝.
结果:我们从338名经病理证实的Pick病患者(205[61%]男性和133[39%]女性;338[100%]白人)和1312名神经系统健康对照(611[47%]男性和701[53%]女性;1312[100%]白人)中获取了大脑样本。与H1单倍型相比,MAPTH2单倍型与Pick病的风险增加相关(OR1·35[95%CI1·12至1·64],p=0·0021)。MAPTH2与发病年龄无关(β-0·54[95%CI-1·94至0·87],p=0·45)或疾病持续时间(β0·05[-0·06至0·16],p=0·35)。尽管在多次测试校正后并不重要,在p小于0·05时观察到关联:具有H1f亚单倍型的Pick病风险(OR0·11[0·01至0·99],p=0·049);随着H1b的发病年龄(β2·66[0·63至4·70],p=0·011),H1(β-3·66[-6·83至-0·48],p=0·025),和H1u(β-5·25[-10·42至-0·07],p=0·048);疾病持续时间为H1x(β-0·57[-1·07至-0·07],p=0·026)。
结论:Pick病国际联合会提供了一个进行大型研究的机会,以提高我们对Pick病病理生物学的认识。这项研究表明,与四重复tau蛋白病变的风险降低相反,在欧洲血统的人中,MAPTH2单倍型与Pick病的风险增加有关。这一发现可能会为Tau蛋白病的同工型相关疗法的发展提供信息。
背景:惠康信托基金,RothaAbrahamTrust,英国大脑研究,杜比基金,痴呆症研究所(医学研究理事会),美国国立卫生研究院,和梅奥诊所基金会.
BACKGROUND: Pick\'s disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick\'s disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick\'s disease risk, age at onset, and disease duration.
METHODS: In this genetic association study, we used data from the Pick\'s disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick\'s disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick\'s disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick\'s disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and β coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype.
RESULTS: We obtained brain samples from 338 people with pathologically confirmed Pick\'s disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick\'s disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (β -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (β 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick\'s disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (β 2·66 [0·63 to 4·70], p=0·011), H1i (β -3·66 [-6·83 to -0·48], p=0·025), and H1u (β -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (β -0·57 [-1·07 to -0·07], p=0·026).
CONCLUSIONS: The Pick\'s disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick\'s disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick\'s disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies.
BACKGROUND: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.