Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
J Hum Genet. 2022 Apr;67(4):203-208. doi: 10.1038/s10038-021-00987-x. Epub 2021 Nov 5.
Late-onset Alzheimer's disease (LOAD) is the most common form of dementia, and its pathogenesis is multifactorial. We previously reported a rare functional variant of SHARPIN (rs572750141, NP_112236.3:p.Gly186Arg) that was significantly associated with LOAD. In addition, several recent studies have suggested the potential role of SHARPIN in AD pathogenesis. In this study, we sought to identify additional functional variants of SHARPIN in Japanese population. Six highly deleterious variants of SHARPIN, comprising four missense variants, one frameshift variant, and one stop-gain variant were detected from whole-genome sequencing data for 180 patients with LOAD and 184 with mild cognitive impairment. One of these candidate variants (rs77359862, NP_112236.3:p.Arg274Trp) was significantly associated with an increased risk of LOAD in 5043 LOAD cases and 11984 controls (P = 0.0016, odds ratio = 1.43). Furthermore, this variant SHARPIN showed aberrant cellular localization and reduced the activation of NF-κB, a central mediator of inflammatory and immune responses. Further investigation of the physiologic role of SHARPIN may reveal the mechanism of onset of LOAD.
晚发性阿尔茨海默病 (LOAD) 是最常见的痴呆症形式，其发病机制是多因素的。我们之前报道了一种 SHARPIN 的罕见功能变体（rs572750141，NP_112236.3:p.Gly186Arg），它与 LOAD 显著相关。此外，最近的几项研究表明 SHARPIN 在 AD 发病机制中的潜在作用。在这项研究中，我们试图在日本人群中鉴定 SHARPIN 的其他功能变体。从 180 名 LOAD 患者和 184 名轻度认知障碍患者的全基因组测序数据中检测到 SHARPIN 的六个高度有害变体，包括四个错义变体、一个移码变体和一个终止增益变体。这些候选变体之一（rs77359862，NP_112236.3:p.Arg274Trp）与 5043 例 LOAD 病例和 11984 例对照者的 LOAD 风险增加显著相关（P = 0.0016，优势比 = 1.43）。此外，这种变体 SHARPIN 显示出异常的细胞定位，并降低了 NF-κB 的激活，NF-κB 是炎症和免疫反应的中心介质。对 SHARPIN 的生理作用的进一步研究可能揭示 LOAD 发病的机制。
