title: Hereditary angioedema with F12 mutation: factors modifying the clinical phenotype.
abstract: BACKGROUND
  Hereditary angioedema (HAE) with normal C1 inhibitor (C1Inh) associated with the c.983C>A and c.983C>G mutations of the F12 gene (FXII-HAE) is a rare condition, and presents with highly variable clinical expression. On the basis of data gathered from a large carrier cohort, we assessed the modifiers affecting the clinical phenotype.
  
  
  METHODS
  We analyzed clinical and biological data recorded from 118 mutation carriers (80 symptomatic and 38 asymptomatic), 58 noncarrier relatives from 40 families, and 200 healthy donors. Disease severity was scored in relation to frequency and location of edema, as well as age at disease onset. To predict FXII-HAE disease severity, we analyzed the biological phenotype [C1Inh, C4, spontaneous amidase, angiotensin-I-converting enzyme (ACE), aminopeptidase P (APP), and carboxypeptidase N/M (CPN)] by means of logistic regression (Akaike information criterion) and odds ratio (OR).
  
  
  RESULTS
  Meaningful variables contributed to FXII-HAE, with the kinin catabolism enzymes ACE and CPN exhibiting a significant inverse relationship with disease severity (OR = 0.36, 95% CI 0.23-0.59, P < 0.001; OR = 0.58, 95% CI 0.36-0.91, P < 0.05, respectively). CPN activities were 37.5 (28.5-41.3) nmol/ml/min and 38.5 (32.8-45.6) for FXII-HAE asymptomatic and symptomatic carriers, respectively, and 37.9 (30.5-43.7) nmol/ml/min for noncarriers. Angiotensin-I-converting enzyme activities were 58 (44-76) and 49 (35-59) nmol/ml/min for FXII-HAE asymptomatic and symptomatic carriers, respectively, and 56 (49-66) nmol/ml/min for noncarriers.
  
  
  CONCLUSIONS
  The FXII-HAE is associated with modifiers, for example kinin catabolism enzymes, ACE and CPN, different from those recognized in HAE with C1Inh deficiency.
authors.affiliation: CREAK, Centre de Référence des Angioedèmes, Grenoble, France; GREPI/AGIM CNRS FRE 3405, Université Joseph Fourier, Grenoble, France.
authors.forename: D
authors.initials: D
authors.lastname: Charignon
authors.forename: A
authors.initials: A
authors.lastname: Ghannam
authors.forename: F
authors.initials: F
authors.lastname: Defendi
authors.forename: D
authors.initials: D
authors.lastname: Ponard
authors.forename: N
authors.initials: N
authors.lastname: Monnier
authors.forename: M
authors.initials: M
authors.lastname: López Trascasa
authors.forename: D
authors.initials: D
authors.lastname: Launay
authors.forename: T
authors.initials: T
authors.lastname: Caballero
authors.forename: K
authors.initials: K
authors.lastname: Djenouhat
authors.forename: O
authors.initials: O
authors.lastname: Fain
authors.forename: S
authors.initials: S
authors.lastname: Cichon
authors.forename: L
authors.initials: L
authors.lastname: Martin
authors.forename: C
authors.initials: C
authors.lastname: Drouet
mesh_terms: D000483:Alleles; D054179:Angioedemas, Hereditary / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism; D050718:Complement C1 Inhibitor Protein; D005091:Exons; D005174:Factor XII / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D016017:Odds Ratio; D010641:Phenotype; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; C469952:SERPING1 protein, human; D005174:Factor XII
keywords: angiotensin-I-converting enzyme; bradykinin; carboxypeptidase N/M; factor XII mutation; hereditary angioedema with normal C1 inhibitor