Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6XKVVA)

• DOT Name: Complement C1q subcomponent subunit A (C1QA)
• Gene Name: C1QA
• Related Disease:
  Alzheimer disease
  Amyloidosis
  Autoimmune disease
  Autosomal systemic lupus erythematosus type 16
  B-cell lymphoma
  Breast neoplasm
  C1Q deficiency
  Complement deficiency
  Cutaneous lupus erythematosus
  Dense deposit disease
  IgA nephropathy
  Multiple sclerosis
  Neoplasm
  Renal fibrosis
  Subacute cutaneous lupus erythematosus
  Type III hypersensitivity disease
  Exanthem
  Periodontitis
  Advanced cancer
  Follicular lymphoma
  Nephritis
  Rett syndrome
• UniProt ID: C1QA_HUMAN
• PDB ID: 1PK6; 2JG8; 2JG9; 2WNU; 2WNV; 5HKJ; 5HZF; 6FCZ; 6Z6V
• Pfam ID: PF00386 ; PF01391
• Sequence:
  MEGPRGWLVLCVLAISLASMVTEDLCRAPDGKKGEAGRPGRRGRPGLKGEQGEPGAPGIR
  TGIQGLKGDQGEPGPSGNPGKVGYPGPSGPLGARGIPGIKGTKGSPGNIKDQPRPAFSAI
  RRNPPMGGNVVIFDTVITNQEEPYQNHSGRFVCTVPGYYYFTFQVLSQWEICLSIVSSSR
  GQVRRSLGFCDTTNKGLFQVVSGGMVLQLQQGDQVWVEKDPKKGHIYQGSEADSVFSGFL
  IFPSA
• Function: C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proenzyme complex, and efficient activation of C1 takes place on interaction of the globular heads of C1q with the Fc regions of IgG or IgM antibody present in immune complexes.
• KEGG Pathway:
  Efferocytosis (hsa04148)
  Complement and coagulation cascades (hsa04610)
  Alcoholic liver disease (hsa04936)
  Prion disease (hsa05020)
  Pertussis (hsa05133)
  Chagas disease (hsa05142)
  Staphylococcus aureus infection (hsa05150)
  Coro.virus disease - COVID-19 (hsa05171)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Classical antibody-mediated complement activation (R-HSA-173623)
  Regulation of Complement cascade (R-HSA-977606)
  Initial triggering of complement (R-HSA-166663)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
Amyloidosis	DISHTAI2	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Biomarker	[3]
Autosomal systemic lupus erythematosus type 16	DIS9RKY9	Strong	SusceptibilityMutation	[4]
B-cell lymphoma	DISIH1YQ	Strong	Genetic Variation	[5]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[6]
C1Q deficiency	DISWV4KU	Strong	Autosomal recessive	[7]
Complement deficiency	DISGN469	Strong	Biomarker	[8]
Cutaneous lupus erythematosus	DISOIX6L	Strong	Genetic Variation	[9]
Dense deposit disease	DISLWJSE	Strong	Biomarker	[10]
IgA nephropathy	DISZ8MTK	Strong	Biomarker	[11]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Renal fibrosis	DISMHI3I	Strong	Genetic Variation	[14]
Subacute cutaneous lupus erythematosus	DIS6XDK0	Strong	Genetic Variation	[9]
Type III hypersensitivity disease	DISFL6YG	Strong	Biomarker	[10]
Exanthem	DISAFOQN	moderate	Biomarker	[15]
Periodontitis	DISI9JOI	moderate	Altered Expression	[16]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[13]
Follicular lymphoma	DISVEUR6	Limited	Genetic Variation	[17]
Nephritis	DISQZQ70	Limited	Biomarker	[18]
Rett syndrome	DISGG5UV	Limited	Altered Expression	[19]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Complement C1q subcomponent subunit A (C1QA).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Complement C1q subcomponent subunit A (C1QA).	[22]

2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Complement C1q subcomponent subunit A (C1QA).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Complement C1q subcomponent subunit A (C1QA).	[23]

References

• [1] Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain.J Neuroinflammation. 2017 Mar 6;14(1):48. doi: 10.1186/s12974-017-0814-9.
• [2] Integrative approach to sporadic Alzheimer's disease:deficiency of TYROBPin cerebral A amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing A burden.Mol Psychiatry. 2019 Mar;24(3):431-446. doi: 10.1038/s41380-018-0255-6. Epub 2018 Oct 3.
• [3] Immuno-modulatory gene polymorphisms and outcome in breast and ovarian cancer.Immunol Invest. 2009;38(3-4):324-40. doi: 10.1080/08820130902910567.
• [4] The role of complement in the development of systemic lupus erythematosus.Annu Rev Immunol. 2004;22:431-56. doi: 10.1146/annurev.immunol.22.012703.104549.
• [5] Homozygous FCGR3A-158V alleles predispose to late onset neutropenia after CHOP-R for diffuse large B-cell lymphoma.Intern Med J. 2012 Oct;42(10):1113-9. doi: 10.1111/j.1445-5994.2011.02587.x.
• [6] The pattern of clinical breast cancer metastasis correlates with a single nucleotide polymorphism in the C1qA component of complement.Immunogenetics. 2006 Feb;58(1):1-8. doi: 10.1007/s00251-005-0077-y. Epub 2006 Feb 8.
• [7] Molecular basis of hereditary C1q deficiency--revisited: identification of several novel disease-causing mutations. Genes Immun. 2011 Dec;12(8):626-34. doi: 10.1038/gene.2011.39. Epub 2011 Jun 9.
• [8] C1q: A fresh look upon an old molecule.Mol Immunol. 2017 Sep;89:73-83. doi: 10.1016/j.molimm.2017.05.025. Epub 2017 Jun 7.
• [9] Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus.Lupus. 2003;12(2):124-32. doi: 10.1191/0961203303lu329oa.
• [10] Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family.Kidney Int. 1996 Aug;50(2):635-42. doi: 10.1038/ki.1996.359.
• [11] The molecular phenotype of endocapillary proliferation: novel therapeutic targets for IgA nephropathy.PLoS One. 2014 Aug 18;9(8):e103413. doi: 10.1371/journal.pone.0103413. eCollection 2014.
• [12] Complement is activated in progressive multiple sclerosis cortical grey matter lesions.J Neuroinflammation. 2016 Jun 22;13(1):161. doi: 10.1186/s12974-016-0611-x.
• [13] C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation.Nat Commun. 2016 Feb 1;7:10346. doi: 10.1038/ncomms10346.
• [14] Pericytes and immune cells contribute to complement activation in tubulointerstitial fibrosis.Am J Physiol Renal Physiol. 2017 Mar 1;312(3):F516-F532. doi: 10.1152/ajprenal.00604.2016. Epub 2017 Jan 4.
• [15] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [16] Amyloid beta (A4) precursor protein expression in human periodontitis-affected gingival tissues.Arch Oral Biol. 2014 Jun;59(6):586-94. doi: 10.1016/j.archoralbio.2014.03.004. Epub 2014 Mar 19.
• [17] A polymorphism in the complement component C1qA correlates with prolonged response following rituximab therapy of follicular lymphoma.Clin Cancer Res. 2008 Oct 15;14(20):6697-703. doi: 10.1158/1078-0432.CCR-08-0745.
• [18] Evaluation of C1q genomic region in minority racial groups of lupus.Genes Immun. 2009 Jul;10(5):517-24. doi: 10.1038/gene.2009.33. Epub 2009 May 14.
• [19] Transcriptome analysis of human brain tissue identifies reduced expression of complement complex C1Q Genes in Rett syndrome.BMC Genomics. 2016 Jun 6;17:427. doi: 10.1186/s12864-016-2746-7.
• [20] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [21] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [22] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [23] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.