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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2022

Open Access 01-12-2022 | Amyotrophic Lateral Sclerosis | Research

The associations between plasma soluble Trem1 and neurological diseases: a Mendelian randomization study

Authors: Xiaolei Shi, Tao Wei, Yachun Hu, Meng Wang, Yi Tang

Published in: Journal of Neuroinflammation | Issue 1/2022

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Abstract

Background

Triggering receptor expressed on myeloid cell 1 (Trem1) is an important regulator of cellular inflammatory responses. Neuroinflammation is a common thread across various neurological diseases. Soluble Trem1 (sTrem1) in plasma is associated with the development of central nervous system disorders. However, the extent of any causative effects of plasma sTrem1 on the risk of these disorders is still unclear.

Method

Genetic variants for plasma sTrem1 levels were selected as instrumental variables. Summary-level statistics of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), epilepsy, cerebrovascular diseases, and migraine were collected from genome-wide association studies (GWASs). Whether plasma sTrem1 was causally associated with neurological disorders was assessed using a two-sample Mendelian randomization (MR) analysis, with false discovery rate (FDR)-adjusted methods applied.

Results

We inferred suggestive association of higher plasma sTrem1 with the risk of AD (odds ratio [OR] per one standard deviation [SD] increase = 1.064, 95% CI 1.012–1.119, P = 0.014, PFDR = 0.056). Moreover, there was significant association between plasma sTrem1 level and the risk of epilepsy (OR per one SD increase = 1.044, 95% CI 1.016–1.072, P = 0.002, PFDR = 0.032), with a modest statistical power of 41%. Null associations were found for plasma sTrem1 with other neurological diseases and their subtypes.

Conclusions

Taken together, this study indicates suggestive association between plasma sTrem1 and AD. Moreover, higher plasma sTrem1 was associated with the increased risk of epilepsy. The findings support the hypothesis that sTrem1 may be a vital element on the causal pathway to AD and epilepsy.
Appendix
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Literature
1.
Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s Dementia. 2018;4:575–90.PubMedPubMedCentralCrossRef
2.
Brambilla R. Neuroinflammation, the thread connecting neurological disease. Acta Neuropathol. 2019;137(5):689–91.PubMedCrossRef
3.
4.
Hu X, Leak RK, Thomson AW, Yu F, Xia Y, Wechsler LR, Chen J. Promises and limitations of immune cell-based therapies in neurological disorders. Nat Rev Neurol. 2018;14(9):559–68.PubMedPubMedCentralCrossRef
5.
Bleharski JR, Kiessler V, Buonsanti C, Sieling PA, Stenger S, Colonna M, Modlin RL. A role for triggering receptor expressed on myeloid cells-1 in host defense during the early-induced and adaptive phases of the immune response. J Immunol. 2003;170(7):3812–8.PubMedCrossRef
6.
Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 2000;164(10):4991–5.PubMedCrossRef
7.
Tammaro A, Derive M, Gibot S, Leemans JC, Florquin S, Dessing MC. TREM-1 and its potential ligands in non-infectious diseases: from biology to clinical perspectives. Pharmacol Ther. 2017;177:81–95.PubMedCrossRef
8.
Lu Q, Liu R, Sherchan P, Ren R, He W, Fang Y, Huang Y, Shi H, Tang L, Yang S, et al. TREM (Triggering Receptor Expressed on Myeloid Cells)-1 inhibition attenuates neuroinflammation via PKC (Protein Kinase C) & CARD9 (Caspase Recruitment Domain Family Member 9) signaling pathway after intracerebral hemorrhage in mice. Stroke. 2021;52(6):2162–73.PubMedPubMedCentralCrossRef
9.
Molloy EJ. Triggering receptor expressed on myeloid cells (TREM) family and the application of its antagonists. Recent Pat Anti-Infect Drug Discov. 2009;4(1):51–6.CrossRef
10.
Jiang T, Zhang Y-D, Gao Q, Zhou J-S, Zhu X-C, Lu H, Shi J-Q, Tan L, Chen Q, Yu J-T. TREM1 facilitates microglial phagocytosis of amyloid beta. Acta Neuropathol. 2016;132(5):667–83.PubMedCrossRef
11.
Xu P, Zhang X, Liu Q, Xie Y, Shi X, Chen J, Li Y, Guo H, Sun R, Hong Y. Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke. Cell Death Dis. 2019;10(8):1–17.CrossRef
12.
Jiang T, Gong P-Y, Tan M-S, Xue X, Huang S, Zhou J-S, Tan L, Zhang Y-D. Soluble TREM1 concentrations are increased and positively correlated with total tau levels in the plasma of patients with Alzheimer’s disease. Aging Clin Exp Res. 2019;31(12):1801–5.PubMedCrossRef
13.
Hok-A-Hin YS, van der Flier WM, Lemstra AW, Del Campo M, Teunissen CE. Novel CSF inflammatory markers MIF and TREM-1 are increased in Alzheimer’s disease. Alzheimers Dement. 2021;17: e055184.
14.
Buckland KF, Ramaprakash H, Murray LA, Carpenter KJ, Choi ES, Kunkel SL, Lukacs NW, Xing Z, Aoki N, Hartl D. Triggering receptor expressed on myeloid cells-1 (TREM-1) modulates immune responses to Aspergillus fumigatus during fungal asthma in mice. Immunol Invest. 2011;40(7–8):692–722.PubMedPubMedCentralCrossRef
15.
Huh JW, Lim C-M, Koh Y, Oh YM, Shim TS, Lee SD, Kim WS, Kim DS, Kim WD, Hong S-B. Diagnostic utility of the soluble triggering receptor expressed on myeloid cells-1 in bronchoalveolar lavage fluid from patients with bilateral lung infiltrates. Crit Care. 2008;12(1):1–7.CrossRef
16.
Wu Y, Wang F, Fan X, Bao R, Bo L, Li J, Deng X. Accuracy of plasma sTREM-1 for sepsis diagnosis in systemic inflammatory patients: a systematic review and meta-analysis. Crit Care. 2012;16(6):1–11.CrossRef
17.
Ait Oufella H, Gibot S, Danchin N, Derive M, Kotti S, Lemarie J, Ohlmann P, Heitz A, Joffre J, Darchis J. circulating levels of sTREM-1 and mortality in patients with an acute myocardial infarction. Circulation. 2014;130(suppl_2):A16204.
18.
Sun X-G, Ma Q, Jing G, Wang L, Hao X-D, Wang G-Q. Early elevated levels of soluble triggering receptor expressed on myeloid cells-1 in subarachnoid hemorrhage patients. Neurol Sci. 2017;38(5):873–7.PubMedCrossRef
19.
Lawlor DA, Harbord RM, Sterne JAC, Timpson N, Davey SG. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27(8):1133–63.PubMedCrossRef
20.
Verduijn M, Siegerink B, Jager KJ, Zoccali C, Dekker FW. Mendelian randomization: use of genetics to enable causal inference in observational studies. Nephrol Dial Transplant. 2010;25(5):1394–8.PubMedCrossRef
21.
22.
Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, Burgess S, Jiang T, Paige E, Surendran P, et al. Genomic atlas of the human plasma proteome. Nature. 2018;558(7708):73–9.PubMedPubMedCentralCrossRef
23.
Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019;51(3):414–30.PubMedPubMedCentralCrossRef
24.
Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, Tan M, Kia DA, Noyce AJ, Xue A, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2019;18(12):1091–102.PubMedPubMedCentralCrossRef
25.
Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, Dominov JA, Kenna BJ, Nalls MA, Keagle P, et al. Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron. 2018;97(6):1268–83.PubMedPubMedCentralCrossRef
26.
Patsopoulos NA, Baranzini SE, Santaniello A, Shoostari P, Cotsapas C, Wong G, Beecham AH, James T, Replogle J, Vlachos IS, et al. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019;365(6460):eaav7188.CrossRef
27.
Abou-Khalil B, Auce P, Avbersek A, Bahlo M, Balding DJ, Bast T, Baum L, Becker AJ, Becker F, Berghuis B, et al. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun. 2018;9(1):5269.CrossRef
28.
Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018;50(4):524–37.PubMedPubMedCentralCrossRef
29.
Wei T, Guo Z, Wang Z, Li C, Zhu W, Zheng Y, Yin Y, Mi Y, Xia X, Hou H, Tang Y. Five major psychiatric disorders and Alzheimer’s disease: a bidirectional mendelian randomization study. J Alzheimers Dis. 2022;87(2):675–84.PubMedCrossRef
30.
Zhuang Z, Yang R, Wang W, Qi L, Huang T. Associations between gut microbiota and Alzheimer’s disease, major depressive disorder, and schizophrenia. J Neuroinflamm. 2020;17(1):288.CrossRef
31.
Brion MJ, Shakhbazov K, Visscher PM. Calculating statistical power in Mendelian randomization studies. Int J Epidemiol. 2013;42(5):1497–501.PubMedCrossRef
32.
Staley JR, Blackshaw J, Kamat MA, Ellis S, Surendran P, Sun BB, Paul DS, Freitag D, Burgess S, Danesh J, et al. PhenoScanner: a database of human genotype-phenotype associations. Bioinformatics. 2016;32(20):3207–9.PubMedPubMedCentralCrossRef
33.
MacArthur J, Bowler E, Cerezo M, Gil L, Hall P, Hastings E, Junkins H, McMahon A, Milano A, Morales J, et al. The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Nucleic Acids Res. 2017;45(D1):D896-d901.PubMedCrossRef
34.
Burgess S, Davey Smith G, Davies NM, Dudbridge F, Gill D, Glymour MM, Hartwig FP, Holmes MV, Minelli C, Relton CL, Theodoratou E. Guidelines for performing Mendelian randomization investigations. Wellcome Open Res. 2019;4:186.PubMedCrossRef
35.
Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–14.PubMedPubMedCentralCrossRef
36.
Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017;46(6):1985–98.PubMedPubMedCentralCrossRef
37.
Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, Laurin C, Burgess S, Bowden J, Langdon R, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018;7:e34408.PubMedPubMedCentralCrossRef
38.
Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–8.PubMedPubMedCentralCrossRef
39.
40.
Matos AO, Dantas PHS, Silva-Sales M, Sales-Campos H. TREM-1 isoforms in bacterial infections: to immune modulation and beyond. Crit Rev Microbiol. 2021;47(3):290–306.PubMedCrossRef
41.
Klesney-Tait J, Turnbull IR, Colonna M. The TREM receptor family and signal integration. Nat Immunol. 2006;7(12):1266–73.PubMedCrossRef
42.
Menyhart O, Weltz B, Győrffy B. MultipleTesting.com: a tool for life science researchers for multiple hypothesis testing correction. PLoS ONE. 2021;16(6):e0245824.PubMedPubMedCentralCrossRef
43.
Korthauer K, Kimes PK, Duvallet C, Reyes A, Subramanian A, Teng M, Shukla C, Alm EJ, Hicks SC. A practical guide to methods controlling false discoveries in computational biology. Genome Biol. 2019;20(1):118.PubMedPubMedCentralCrossRef
44.
Duyckaerts C, Delatour B, Potier M-C. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118(1):5–36.PubMedCrossRef
45.
Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson EJ. β-amyloid1–42 induces neuronal death through the p75 neurotrophin receptor. J Neurosci. 2008;28(15):3941–6.PubMedPubMedCentralCrossRef
46.
Insel PS, Mattsson N, Donohue MC, Mackin RS, Aisen PS, Jack CR Jr, Shaw LM, Trojanowski JQ, Weiner MW, Initiative AsDN. Initiative AsDN The transitional association between β-amyloid pathology and regional brain atrophy. Alzheimers Dement. 2015;11(10):1171–9.PubMedCrossRef
47.
Wood H. Sequential amyloid-β and tau accumulation foreshadows cognitive decline. Nat Rev Neurol. 2019;15(8):433–433.PubMedCrossRef
48.
49.
Replogle JM, Chan G, White CC, Raj T, Winn PA, Evans DA, Sperling RA, Chibnik LB, Bradshaw EM, Schneider JA. A TREM 1 variant alters the accumulation of Alzheimer-related amyloid pathology. Ann Neurol. 2015;77(3):469–77.PubMedPubMedCentralCrossRef
50.
Liu Y-S, Yan W-J, Tan C-C, Li J-Q, Xu W, Cao X-P, Tan L, Yu J-T. Common variant in TREM1 influencing brain amyloid deposition in mild cognitive impairment and Alzheimer’s disease. Neurotox Res. 2020;37(3):661–8.PubMedCrossRef
51.
Garwood CJ, Cooper JD, Hanger DP, Noble W. Anti-inflammatory impact of minocycline in a mouse model of tauopathy. Front Psych. 2010;1:136.
52.
53.
Jacoby A, Snape D, Baker GA. Epilepsy and social identity: the stigma of a chronic neurological disorder. Lancet Neurol. 2005;4(3):171–8.PubMedCrossRef
54.
Rana A, Musto AE. The role of inflammation in the development of epilepsy. J Neuroinflamm. 2018;15(1):1–12.CrossRef
55.
Quirico-Santos T, Mello AN, Gomes AC, de Carvalho LP, de Souza JM, Alves-Leon S. Increased metalloprotease activity in the epileptogenic lesion—lobectomy reduces metalloprotease activity and urokinase-type uPAR circulating levels. Brain Res. 2013;1538:172–81.PubMedCrossRef
56.
Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med. 2004;10(7):S10–7.PubMedCrossRef
57.
Ross CA, Poirier MA. What is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol. 2005;6(11):891–8.PubMedCrossRef
58.
59.
Chaney A, Wilson E, Jain P, Cropper H, Swarovski M, Lucot K, Vogel H, Andreasson K, James ML: TREM1-PET imaging of pro-inflammatory myeloid cells distinguishes active disease from remission in Multiple Sclerosis. Soc Nuclear Med; 2020.
Metadata
Title
The associations between plasma soluble Trem1 and neurological diseases: a Mendelian randomization study
Authors
Xiaolei Shi
Tao Wei
Yachun Hu
Meng Wang
Yi Tang
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-022-02582-z

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