Missense variant in TREML2 protects against Alzheimer's disease
NEUROBIOLOGY OF AGING
Authors: Benitez, Bruno A.; Jin, Sheng Chih; Guerreiro, Rita; Graham, Rob; Lord, Jenny; Harold, Denise; Sims, Rebecca; Lambert, Jean-Charles; Gibbs, J. Raphael; Bras, Jose; Sassi, Celeste; Harari, Oscar; Bertelsen, Sarah; Lupton, Michelle K.; Powell, John; Bellenguez, Celine; Brown, Kristelle; Medway, Christopher; Haddick, Patrick C. G.; van der Brug, Marcel P.; Bhangale, Tushar; Ortmann, Ward; Behrens, Tim; Mayeux, Richard; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Haines, Jonathan L.; Turton, Jim; Braae, Anne; Barber, Imelda; Fagan, Anne M.; Holtzman, David M.; Morris, John C.; Williams, Julie; Kauwe, John S. K.; Amouyel, Philippe; Morgan, Kevin; Singleton, Andy; Hardy, John; Goate, Alison M.; Cruchaga, Carlos
Abstract
TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p. R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p. R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p. S144G (rs3747742) as a potential driver of the metaanalysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD. (C) 2014 Elsevier Inc. All rights reserved.
A risk assessment model of acute liver allograft rejection by genetic polymorphism of CD276
MOLECULAR GENETICS & GENOMIC MEDICINE
Authors: Yu, Xiaobo; Wei, Bajin; Su, Rong; Yao, Jia; Feng, Xiaowen; Jiang, Guoping; Xie, Haiyang; Wu, Jian; Xu, Xiao; Zhang, Min; Zheng, Shusen; Zhou, Lin
Abstract
BackgroundLiver transplantation is an effective therapy for end-stage liver diseases and acute liver failure. After the operation, however, recipients may suffer grafts loss induced by alloimmune reaction, which is termed as acute allograft rejection. The interaction between costimulatory molecules, CD276, and its ligand, TREML2, promotes T cell-mediated immune response, as well as acute or chronic allograft rejection. Our research aimed at correlating genetic polymorphisms of CD276/TREML2 with acute rejection, and evaluating its prognostic value of acute rejection after liver transplantation. MethodsThe study enrolled a total of 388 recipients. Among them, acute allograft rejection was observed in 54 cases. We performed single nucleotide polymorphism genotyping of CD276, including rs11072431, rs11574495, rs12593558, rs12594627, rs2127015, rs3816661 and rs7176654, and TREML2, including rs4714431, rs6915083, rs7754593, and rs9394767 from preoperative peripheral blood genome DNA. ResultsWe found rs2127015 of CD276, rs6915083 and rs7754593 of TREML2, and HBV infection as well were associated with acute rejection. And, rs2127015 influences CD276 expression. Moreover, we established a risk assessment model, composited by statistically proved risk factors. ConclusionBy integrating both clinical and genetic variables, liver transplant recipients can be categorized into different risk groups, and might benefit from individualized therapies.
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