Polymorphisms in alpha 7 nicotinic acetylcholine receptor gene, CHRNA7, and its partially duplicated gene, CHRFAM7A, associate with increased inflammatory response in human peripheral mononuclear cells.
CHRFAM7A
CHRNA7
alpha 7 nicotinic acetylcholine receptor
immune response
inflammation
polymorphisms
α7nAChR
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
revised:
14
02
2022
received:
09
12
2021
accepted:
11
03
2022
entrez:
28
3
2022
pubmed:
29
3
2022
medline:
23
4
2022
Statut:
ppublish
Résumé
The vagus nerve can, via the alpha 7 nicotinic acetylcholine receptor (α7nAChR), regulate inflammation. The gene coding for the α7nAChR, CHRNA7, can be partially duplicated, that is, CHRFAM7A, which is reported to impair the anti-inflammatory effect mediated via the α7nAChR. Several single nucleotide polymorphisms (SNPs) have been described in both CHRNA7 and CHRFAM7A, however, the functional role of these SNPs for immune responses remains to be investigated. In the current study, we set out to investigate whether genetic variants of CHRNA7 and CHRFAM7A can influence immune responses. By investigating data available from the Swedish SciLifeLab SCAPIS Wellness Profiling (S3WP) study, in combination with droplet digital PCR and freshly isolated PBMCs from the S3WP participants, challenged with lipopolysaccharide (LPS), we show that CHRNA7 and CHRFAM7A are expressed in human PBMCs, with approximately four times higher expression of CHRFAM7A compared with CHRNA7. One SNP in CHRFAM7A, rs34007223, is positively associated with hsCRP in healthy individuals. Furthermore, gene ontology (GO)-terms analysis of plasma proteins associated with gene expression of CHRNA7 and CHRFAM7A demonstrated an involvement for these genes in immune responses. This was further supported by in vitro data showing that several SNPs in both CHRNA7 and CHRFAM7A are significantly associated with cytokine response. In conclusion, genetic variants of CHRNA7 and CHRFAM7A alters cytokine responses. Furthermore, given that CHRFAM7A SNP rs34007223 is associated with inflammatory marker hsCRP in healthy individuals suggests that CHRFAM7A may have a more pronounced role in regulating inflammatory processes in humans than previously been recognized.
Identifiants
pubmed: 35344211
doi: 10.1096/fj.202101898R
doi:
Substances chimiques
Chrna7 protein, human
0
Cytokines
0
Receptors, Nicotinic
0
alpha7 Nicotinic Acetylcholine Receptor
0
C-Reactive Protein
9007-41-4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e22271Informations de copyright
© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
Références
Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458-462.
Huston JM, Ochani M, Rosas-Ballina M, et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med. 2006;203:1623-1628.
Bonaz B, Sinniger V, Hoffmann D, et al. Chronic vagus nerve stimulation in Crohn's disease: a 6-month follow-up pilot study. Neurogastroenterol Motil. 2016;28:948-953.
Koopman FA, Chavan SS, Miljko S, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016;113:8284-8289.
Fujii T, Mashimo M, Moriwaki Y, et al. Expression and function of the cholinergic system in immune cells. Front Immunol. 2017;8:1085.
Hoover DB. Cholinergic modulation of the immune system presents new approaches for treating inflammation. Pharmacol Ther. 2017;179:1-16.
Zoheir N, Lappin DF, Nile CJ. Acetylcholine and the alpha 7 nicotinic receptor: a potential therapeutic target for the treatment of periodontal disease? Inflamm Res. 2012;61:915-926.
Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384-388.
Kiss A, Tratsiakovich Y, Mahdi A, et al. Vagal nerve stimulation reduces infarct size via a mechanism involving the alpha-7 nicotinic acetylcholine receptor and downregulation of cardiac and vascular arginase. Acta Physiol (Oxf). 2017;221:174-181.
van Westerloo DJ, Giebelen IA, Florquin S, et al. The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology. 2006;130:1822-1830.
Pena G, Cai B, Liu J, et al. Unphosphorylated STAT3 modulates alpha 7 nicotinic receptor signaling and cytokine production in sepsis. Eur J Immunol. 2010;40:2580-2589.
Johansson ME, Ulleryd MA, Bernardi A, et al. alpha7 Nicotinic acetylcholine receptor is expressed in human atherosclerosis and inhibits disease in mice-brief report. Arterioscler Thromb Vasc Biol. 2014;34:2632-2636.
Ulleryd MA, Mjörnstedt F, Panagaki D, et al. Stimulation of alpha 7 nicotinic acetylcholine receptor (α7nAChR) inhibits atherosclerosis via immunomodulatory effects on myeloid cells. Atherosclerosis. 2019;287:122-133.
Sinkus ML, Graw S, Freedman R, Ross RG, Lester HA, Leonard S. The human CHRNA7 and CHRFAM7A genes: a review of the genetics, regulation, and function. Neuropharmacology. 2015;96:274-288.
Gault J, Robinson M, Berger R, et al. Genomic organization and partial duplication of the human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7). Genomics. 1998;52:173-185.
Araud T, Graw S, Berger R, et al. The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of alpha7*nAChR function. Biochem Pharmacol. 2011;82:904-914.
Costantini TW, Dang X, Coimbra R, Eliceiri BP, Baird A. CHRFAM7A, a human-specific and partially duplicated alpha7-nicotinic acetylcholine receptor gene with the potential to specify a human-specific inflammatory response to injury. J Leukoc Biol. 2015;97:247-257.
Dang X, Eliceiri BP, Baird A, Costantini TW. CHRFAM7A: a human-specific α7-nicotinic acetylcholine receptor gene shows differential responsiveness of human intestinal epithelial cells to LPS. FASEB J. 2015;29:2292-2302.
Costantini TW, Chan TW, Cohen O, et al. Uniquely human CHRFAM7A gene increases the hematopoietic stem cell reservoir in mice and amplifies their inflammatory response. Proc Natl Acad Sci U S A. 2019;116:7932-7940.
Freedman R, Olincy A, Ross RG, et al. The genetics of sensory gating deficits in schizophrenia. Curr Psychiatry Rep. 2003;5:155-161.
Hoskin JL, Al-Hasan Y, Sabbagh MN. Nicotinic acetylcholine receptor agonists for the treatment of Alzheimer's dementia: an update. Nicotine Tob Res. 2019;21:370-376.
Kunii Y, Zhang W, Xu Q, et al. CHRNA7 and CHRFAM7A mRNAs: co-localized and their expression levels altered in the postmortem dorsolateral prefrontal cortex in major psychiatric disorders. Am J Psychiatry. 2015;172:1122-1130.
Quik M, Zhang D, McGregor M, Bordia T. Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease. Biochem Pharmacol. 2015;97:399-407.
Severance EG, Yolken RH. Novel alpha7 nicotinic receptor isoforms and deficient cholinergic transcription in schizophrenia. Genes Brain Behav. 2008;7:37-45.
Villiger Y, Szanto I, Jaconi S, et al. Expression of an alpha7 duplicate nicotinic acetylcholine receptor-related protein in human leukocytes. J Neuroimmunol. 2002;126:86-98.
The FO, Boeckxstaens GE, Snoek SA, et al. Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice. Gastroenterology. 2007;133:1219-1228.
Baird A, Coimbra R, Dang X, Eliceiri BP, Costantini TW. Up-regulation of the human-specific CHRFAM7A gene in inflammatory bowel disease. BBA Clin. 2016;5:66-71.
Costantini TW, Dang X, Yurchyshyna MV, Coimbra R, Eliceiri BP, Baird A. A human-specific alpha7-nicotinic acetylcholine receptor gene in human leukocytes: identification, regulation and the consequences of CHRFAM7A expression. Mol Med. 2015;21:323-336.
Courties A, Do A, Leite S, et al. The role of the non-neuronal cholinergic system in inflammation and degradation processes in osteoarthritis. Arthritis Rheumatol. 2020;72:2072-2082.
Maldifassi MC, Martin-Sanchez C, Atienza G, et al. Interaction of the alpha7-nicotinic subunit with its human-specific duplicated dupalpha7 isoform in mammalian cells: Relevance in human inflammatory responses. J Biol Chem. 2018;293:13874-13888.
Russo P, Kisialiou A, Moroni R, Prinzi G, Fini M. Effect of genetic polymorphisms (SNPs) in CHRNA7 gene on response to acetylcholinesterase inhibitors (AChEI) in patients with Alzheimer's disease. Curr Drug Targets. 2017;18:1179-1190.
Weng PH, Chen JH, Chen TF, et al. CHRNA7 polymorphisms and response to cholinesterase inhibitors in Alzheimer's disease. PLoS One. 2013;8:e84059.
Weng PH, Chen JH, Chen TF, et al. CHRNA7 polymorphisms and dementia risk: interactions with apolipoprotein epsilon4 and cigarette smoking. Sci Rep. 2016;6:27231.
Sinkus ML, Lee MJ, Gault J, et al. A 2-base pair deletion polymorphism in the partial duplication of the alpha7 nicotinic acetylcholine gene (CHRFAM7A) on chromosome 15q14 is associated with schizophrenia. Brain Res. 2009;1291:1-11.
Stephens SH, Logel J, Barton A, et al. Association of the 5'-upstream regulatory region of the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7) with schizophrenia. Schizophr Res. 2009;109:102-112.
Bergstrom G, Berglund G, Blomberg A, et al. The Swedish CArdioPulmonary BioImage Study: objectives and design. J Intern Med. 2015;278:645-659.
Tebani A, Gummesson A, Zhong W, et al. Integration of molecular profiles in a longitudinal wellness profiling cohort. Nat Commun. 2020;11:4487.
Zhong W, Gummesson A, Tebani A, et al. Whole-genome sequence association analysis of blood proteins in a longitudinal wellness cohort. Genome Med. 2020;12:53.
Stranneheim H, Engvall M, Naess K, et al. Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism. BMC Genom. 2014;15:1090.
Chen X, Schulz-Trieglaff O, Shaw R, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016;32:1220-1222.
Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15:565-574.
Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7.
Maston GA, Evans SK, Green MR. Transcriptional regulatory elements in the human genome. Annu Rev Genomics Hum Genet. 2006;7:29-59.
Hammarlund ME, Darsalia V, Mjornstedt F, et al. The selective alpha7 nicotinic acetylcholine receptor agonist AR-R17779 does not affect ischemia-reperfusion brain injury in mice. Biosci Rep. 2021;41:BSR20210736.
Taylor SC, Laperriere G, Germain H. Droplet Digital PCR versus qPCR for gene expression analysis with low abundant targets: from variable nonsense to publication quality data. Sci Rep. 2017;7:2409.
Kuhlmann K, Cieselski M, Schumann J. Relative versus absolute RNA quantification: a comparative analysis based on the example of endothelial expression of vasoactive receptors. Biol Proced Online. 2021;23:6.
García-Moreno A, López-Domínguez R, Ramirez-Mena A, et al. GeneCodis 4: Expanding the modular enrichment analysis to regulatory elements. bioRxiv. 2021;2021.2004.2015.439962
Leonard S, Bertrand D. Neuronal nicotinic receptors: from structure to function. Nicotine Tob Res. 2001;3:203-223.
De Rosa MJ, Esandi Mdel C, Garelli A, Rayes D, Bouzat C. Relationship between alpha 7 nAChR and apoptosis in human lymphocytes. J Neuroimmunol. 2005;160:154-161.
van der Zanden EP, Hilbers FW, Verseijden C, et al. Nicotinic acetylcholine receptor expression and susceptibility to cholinergic immunomodulation in human monocytes of smoking individuals. NeuroImmunoModulation. 2012;19:255-265.
Courties A, Boussier J, Hadjadj J, et al. Regulation of the acetylcholine/alpha7nAChR anti-inflammatory pathway in COVID-19 patients. Sci Rep. 2021;11:11886.
Corradi J, Bouzat C. Understanding the bases of function and modulation of alpha7 nicotinic receptors: implications for drug discovery. Mol Pharmacol. 2016;90:288-299.
Shen JX, Yakel JL. Functional alpha7 nicotinic ACh receptors on astrocytes in rat hippocampal CA1 slices. J Mol Neurosci. 2012;48:14-21.
Hua S, Ek CJ, Mallard C, Johansson ME. Perinatal hypoxia-ischemia reduces alpha 7 nicotinic receptor expression and selective alpha 7 nicotinic receptor stimulation suppresses inflammation and promotes microglial Mox phenotype. Biomed Res Int. 2014;2014:718769.
Liu Y, Hu J, Wu J, et al. alpha7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation. J Neuroinflammation. 2012;9:98.
Cedillo JL, Arnalich F, Martin-Sanchez C, et al. Usefulness of alpha7 nicotinic receptor messenger RNA levels in peripheral blood mononuclear cells as a marker for cholinergic antiinflammatory pathway activity in septic patients: results of a pilot study. J Infect Dis. 2015;211:146-155.
Yang L, Lu X, Qiu F, et al. Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer. Eur J Hum Genet. 2015;23:1019-1024.
de Lucas-Cerrillo AM, Maldifassi MC, Arnalich F, et al. Function of partially duplicated human alpha77 nicotinic receptor subunit CHRFAM7A gene: potential implications for the cholinergic anti-inflammatory response. J Biol Chem. 2011;286:594-606.
Chan T, Williams E, Cohen O, Eliceiri BP, Baird A, Costantini TW. CHRFAM7A alters binding to the neuronal alpha-7 nicotinic acetylcholine receptor. Neurosci Lett. 2019;690:126-131.
Robert F, Pelletier J. Exploring the impact of single-nucleotide polymorphisms on translation. Front Genet. 2018;9:507.
Feher A, Juhasz A, Rimanoczy A, Csibri E, Kalman J, Janka Z. Association between a genetic variant of the alpha-7 nicotinic acetylcholine receptor subunit and four types of dementia. Dement Geriatr Cogn Disord. 2009;28:56-62.
Hong CJ, Lai IC, Liou LL, Tsai SJ. Association study of the human partially duplicated alpha7 nicotinic acetylcholine receptor genetic variant with bipolar disorder. Neurosci Lett. 2004;355:69-72.
Iwata Y, Nakajima M, Yamada K, et al. Linkage disequilibrium analysis of the CHRNA7 gene and its partially duplicated region in schizophrenia. Neurosci Res. 2007;57:194-202.
Jin Y, Zhang Y, Wang H, et al. Genomic polymorphisms within alpha 7 nicotinic acetylcholine receptor and severe sepsis in Chinese Han population. Int J Immunogenet. 2010;37:361-365.
Huang W, Kabbani N, Brannan TK, et al. Association of a functional polymorphism in the CHRFAM7A gene with inflammatory response mediators and neuropathic pain after spinal cord injury. J Neurotrauma. 2019;36:3026-3033.