Details of Disease

General Information of Disease (ID: DISQKEHW)

• Disease Name: Alpha-1 antitrypsin deficiency
• Synonyms: AATD; alpha-1-antitrypsin deficiency; ALPHA-1-antitrypsin deficiency; Alpha 1 antitrypsin deficiency; A1AT deficiency; Alpha-1 antitrypsin deficiency; A1ATD; A-1ATD; deficiency in Alpa-1-proteinase inhibitor; emphysema-cirrhosis, due to AAT deficiency; A1AD; alpha 1-antitrypsin deficiency; Alpha-1 Antitrypsin Deficiency; emphysema due to AAT deficiency; hemorrhagic diathesis due to antithrombin pittsburgh; AAT deficiency
• Disease Class: 5C5A: Alpha-1-antitrypsin deficiency
• Definition: Alpha-1-antitrypsin deficiency is a hereditary disease that develops in adulthood and is characterized by chronic liver disorders (cirrhosis), respiratory disorders (emphysema), and rarely panniculitis.
• Disease Hierarchy:
  DIS6SVEE: Syndromic disease
  DISGGAGJ: Respiratory disease
  DISTR06F: Plasma protein metabolism disease
  DISQKEHW: Alpha-1 antitrypsin deficiency
• ICD Code:
  ICD-11: ICD-11: 5C5A
  ICD-10: ICD-10: E88.0, M79.3
  ICD-9: ICD-9: 273.4
  Expand ICD-11: '5C5A
  Expand ICD-10: 'E88.0; 'M79.3
  Expand ICD-9: 273.4
• Disease Identifiers:
  MONDO ID: MONDO_0013282
  MESH ID: D019896
  UMLS CUI: C0221757
  OMIM ID: 613490
  MedGen ID: 67461
  Orphanet ID: 60
  SNOMED CT ID: 30188007

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 2 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Alpha 1-PI	DMXC1K9	Approved	Small molecular drug	[1]
Prolastin	DMYSCIL	Approved	NA	[1]

This Disease is Treated as An Indication in 6 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Fazirsiran	DM772MW	Phase 3	RNA interference	[2]
TAK-999	DMDTU6I	Phase 3	RNAi	[2]
AGTC-0106	DMMKASG	Phase 2	NA	[3]
ARO-AAT	DM2UP6Z	Phase 2	Small interfering RNA	[4]
Belcesiran	DMLMIGI	Phase 2	RNA interference	[5]
ARC-AAT	DM9TTUM	Phase 1	NA	[6]

This Disease is Treated as An Indication in 1 Preclinical Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
CAT4001	DMDUKMR	Preclinical	Small molecular drug	[7]

This Disease is Treated as An Indication in 1 Investigative Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
RHuA1AT	DMIILCU	Investigative	NA	[8]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 6 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
CELA1	TT3NKIB	Limited	Altered Expression	[9]
ADRA1D	TT34BHT	moderate	Altered Expression	[10]
SERPING1	TTVQ6R9	moderate	Biomarker	[11]
BPI	TTXCSDR	Strong	Biomarker	[12]
MVK	TT5DFHW	Strong	Biomarker	[13]
SERPINA1	TTA7UJC	Strong	Autosomal recessive	[14]

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
TGM5	DEW8QEH	Strong	Genetic Variation	[15]

This Disease Is Related to 22 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
GCNA	OTIU3F9Y	moderate	Biomarker	[16]
HFE	OTDD93KB	moderate	Genetic Variation	[17]
SFXN1	OTL66767	moderate	Genetic Variation	[18]
ACADVL	OT50L4XB	Strong	Genetic Variation	[15]
AMELX	OTIN26MM	Strong	Biomarker	[19]
AMFR	OTQRX7LC	Strong	Altered Expression	[20]
CHRNA3	OTCZQY1U	Strong	Biomarker	[21]
DNAJB11	OTDDK2SY	Strong	Biomarker	[22]
EYS	OT0NBPL5	Strong	Genetic Variation	[15]
FEV	OTYEC4IR	Strong	Biomarker	[23]
HADHA	OTO557N2	Strong	Genetic Variation	[15]
HERPUD1	OT9EROL6	Strong	Genetic Variation	[17]
IREB2	OT747D24	Strong	Biomarker	[21]
KLF10	OT4F4UGS	Strong	Altered Expression	[24]
MAN1B1	OTI780UB	Strong	Genetic Variation	[25]
MYO15A	OTVR4DV8	Strong	Genetic Variation	[26]
OTOA	OTBTEFIE	Strong	Genetic Variation	[15]
PROP1	OT8GF6N8	Strong	Genetic Variation	[15]
SELENOS	OTUEWIU9	Strong	Altered Expression	[27]
SERPINA1	OTACYW9J	Strong	Autosomal recessive	[14]
SVIP	OTVKVR34	Strong	Biomarker	[20]
TMBIM4	OT8712PP	Strong	Genetic Variation	[28]

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [2] ClinicalTrials.gov (NCT05677971) A Randomized, Double-blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Fazirsiran in the Treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease With METAVIR Stage F2 to F4 Fibrosis. U.S.National Institutes of Health.
• [3] ClinicalTrials.gov (NCT01054339) Safety & Efficacy Study of rAAV1-CB-hAAT for Alpha-1 Antitrypsin Deficiency. U.S. National Institutes of Health.
• [4] ClinicalTrials.gov (NCT03362242) Study of ARO-AAT in Normal Adult Volunteers. U.S. National Institutes of Health.
• [5] ClinicalTrials.gov (NCT04764448) A Phase 2, Randomized, Double-blind, Placebo-Controlled Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Dose Levels of Belcesiran in Patients With Alpha-1 Antitrypsin Deficiency-Associated Liver Disease. U.S.National Institutes of Health.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019 Apr;18(4):295-317.
• [8] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [9] Role for Cela1 in Postnatal Lung Remodeling and Alpha-1 Antitrypsin-Deficient Emphysema.Am J Respir Cell Mol Biol. 2018 Aug;59(2):167-178. doi: 10.1165/rcmb.2017-0361OC.
• [10] The Role of Computed Tomography for the Evaluation of Lung Disease in Alpha-1 Antitrypsin Deficiency.Chest. 2018 May;153(5):1240-1248. doi: 10.1016/j.chest.2017.11.017. Epub 2017 Nov 23.
• [11] Characterisation of serpin polymers in vitro and in vivo.Methods. 2011 Mar;53(3):255-66. doi: 10.1016/j.ymeth.2010.11.008. Epub 2010 Nov 27.
• [12] The prevalence and clinical significance of alpha 1-antitrypsin deficiency (PiZ) and ANCA specificities (proteinase 3, BPI) in patients with ulcerative colitis.Inflamm Bowel Dis. 1999 Nov;5(4):246-52. doi: 10.1097/00054725-199911000-00002.
• [13] Mevalonate kinase deficiency masked by cytomegalovirus infection and obscure liver disease.Clin Chim Acta. 2019 Nov;498:122-125. doi: 10.1016/j.cca.2019.08.014. Epub 2019 Aug 17.
• [14] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [15] Exome-based search for recurrent disease-causing alleles in Russian population.Eur J Med Genet. 2019 Jul;62(7):103656. doi: 10.1016/j.ejmg.2019.04.013. Epub 2019 Apr 24.
• [16] Prevalence of alpha-1 antitrypsin deficiency in poorly controlled asthma--results from the ALA-ACRC low-dose theophylline trial. J Asthma. 2007 Oct;44(8):605-8. doi: 10.1080/02770900701540028.
• [17] ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency.PLoS One. 2017 Jun 15;12(6):e0179369. doi: 10.1371/journal.pone.0179369. eCollection 2017.
• [18] Alpha 1-antitrypsin-deficient variant Siiyama (Ser53[TCC] to Phe53[TTC]) is prevalent in Japan. Status of alpha 1-antitrypsin deficiency in Japan.Am J Respir Crit Care Med. 1995 Dec;152(6 Pt 1):2119-26. doi: 10.1164/ajrccm.152.6.8520784.
• [19] Tryptophan-kynurenine profile in pediatric autoimmune hepatitis.Immunol Res. 2019 Feb;67(1):39-47. doi: 10.1007/s12026-019-9068-1.
• [20] SVIP regulates Z variant alpha-1 antitrypsin retro-translocation by inhibiting ubiquitin ligase gp78.PLoS One. 2017 Mar 16;12(3):e0172983. doi: 10.1371/journal.pone.0172983. eCollection 2017.
• [21] Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency.Respir Res. 2012 Feb 22;13(1):16. doi: 10.1186/1465-9921-13-16.
• [22] Erdj3 Has an Essential Role for Z Variant Alpha-1-Antitrypsin Degradation.J Cell Biochem. 2017 Oct;118(10):3090-3101. doi: 10.1002/jcb.26069. Epub 2017 Jun 20.
• [23] Glutathione S-transferase P1 and lung function in patients with alpha1-antitrypsin deficiency and COPD.Chest. 2005 May;127(5):1537-43. doi: 10.1378/chest.127.5.1537.
• [24] Krppel-like zinc finger proteins in end-stage COPD lungs with and without severe alpha1-antitrypsin deficiency.Orphanet J Rare Dis. 2012 May 23;7:29. doi: 10.1186/1750-1172-7-29.
• [25] SERPINA1 and MAN1B1 polymorphisms are not linked to severe liver disease in a French cohort of alpha-1 antitrypsin deficiency children.Liver Int. 2017 Nov;37(11):1608-1611. doi: 10.1111/liv.13586. Epub 2017 Sep 15.
• [26] Neonatal cholestasis, hyperferritinemia, hypoglycemia and deafness: a diagnostic challenge.BMJ Case Rep. 2019 Dec 1;12(11):e231978. doi: 10.1136/bcr-2019-231978.
• [27] Is there a therapeutic role for selenium in alpha-1 antitrypsin deficiency?.Nutrients. 2013 Mar 11;5(3):758-70. doi: 10.3390/nu5030758.
• [28] Semiquantitation of Monomer and Polymer Alpha-1 Antitrypsin by Centrifugal Separation and Assay by Western Blot of Soluble and Insoluble Components.Methods Mol Biol. 2017;1639:227-234. doi: 10.1007/978-1-4939-7163-3_23.