title: [DEFI-ALPHA cohort and POLYGEN DEFI-ALPHA clinical research hospital programme. A study about clinical, biological and genetics factors associated with the occurrence and the evolution of hepatic complications in children with alpha-1 antitrypsin deficiency].
abstract: BACKGROUND
  The alpha-1 antitrypsin (α1-AT) deficiency, most frequently caused by homozygosity for the Z variant (SERPINA1: c.1096 G>A; Glu342Lys), can give rise to two clinical patterns: (i) respiratory impairment with emphysema (mainly in adulthood) because of a pulmonary quantitative defect in anti-elastase activity; (ii) hepatic impairment (mainly in childhood) due to the misfolding of the PiZ protein which accumulates in hepatocytes thus providing cytotoxicity.
  
  
  BACKGROUND
  To date, the clinical and genetic factors responsible for the development of major hepatic injuries (fibrosis and portal hypertension) during childhood in PiZ patients are not known.
  
  
  METHODS
  The DEFI-ALPHA cohort, created in 2008, aims to inventory and prospectively study all α1-AT deficient children diagnosed and included after occurrence of a hepatic sign. The POLYGEN DEFI-ALPHA PHRC has recently (2013) been added to the project to identify modifiers genes by two complementary approaches: (i) the candidate genes strategy with the SERPINA1, CFTR (cystic fibrosis gene), MAN1B1 and SORL1 genes, these two latter being implied in the degradation of misfolding proteins; (ii) the whole exome sequencing (WES) strategy in families in which the PiZ proband has a PiZ brother or sister free of any hepatic sign.
  
  
  RESULTS
  The clinical parameter we want to explain is the apparition of a portal hypertension in PiZ children. In the DEFI-ALPHA project, three criteria will be tested: (i) age of inclusion in the cohort, (ii) the way of inclusion (neo-natal icterus or later hepatic impairment) and (iii) treatment or not with ursodesoxycholic acid and, if so, its duration. Genetically, polymorphisms on the SERPINA1 and MAN1B1 genes have already been associated in the literature with different clinical evolutions of the A1ATD but very inconstantly. Our study thus aims to confirm or not this association. The CFTR and SORL1 genes have never been studied in the α1-AT deficiency. Finally, the whole exome sequencing strategy could allow the discovery of new unexpected modifiers genes in this disease.
authors.affiliation: Unité de pathologie moléculaire du globule rouge, fédération de biochimie et de biologie spécialisée, hôpital Édouard-Herriot, hospices civils & université Claude-Bernard-Lyon 1, 69003 Lyon, France; Laboratoire CRIS EA 647, section « Vascular Biology and Red Blood Cell », université Claude-Bernard Lyon 1, Lyon, France.
authors.forename: P
authors.initials: P
authors.lastname: Joly
authors.affiliation: Service de gastroentérologie, hépatologie et nutrition pédiatrique, hôpital Femme-Mère-Enfant, université de Lyon 1, 59, boulevard Pinel, 69677 Bron, France.
authors.forename: L
authors.initials: L
authors.lastname: Restier
authors.affiliation: Institut de biochimie et génétique cellulaires (IBGC), UMR 5095, université Segalen de Bordeaux, 33077 Bordeaux, France.
authors.forename: M
authors.initials: M
authors.lastname: Bouchecareilh
authors.affiliation: Unité de pathologie moléculaire du globule rouge, fédération de biochimie et de biologie spécialisée, hôpital Édouard-Herriot, hospices civils & université Claude-Bernard-Lyon 1, 69003 Lyon, France.
authors.forename: P
authors.initials: P
authors.lastname: Lacan
authors.affiliation: Service d'endocrinologie moléculaire et maladies rares, centre de biologie et pathologie Est, groupement hospitalier Est, hospices civils & université Claude-Bernard-Lyon 1, 69677 Bron, France.
authors.forename: F
authors.initials: F
authors.lastname: Cabet
authors.affiliation: Laboratoire d'immunologie, centre de biologie Sud, centre hospitalier Lyon-Sud, hospices civils & université Claude-Bernard-Lyon 1, 69310 Pierre-Bénite, France.
authors.forename: C
authors.initials: C
authors.lastname: Chapuis-Cellier
authors.affiliation: Unité de pathologie moléculaire du globule rouge, fédération de biochimie et de biologie spécialisée, hôpital Édouard-Herriot, hospices civils & université Claude-Bernard-Lyon 1, 69003 Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Francina
authors.affiliation: Service de gastroentérologie, hépatologie et nutrition pédiatrique, hôpital Femme-Mère-Enfant, université de Lyon 1, 59, boulevard Pinel, 69677 Bron, France. Electronic address: alain.lachaux@chu-lyon.fr.
authors.forename: A
authors.initials: A
authors.lastname: Lachaux
mesh_terms: D000293:Adolescent; D035843:Biomedical Research; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D006761:Hospitals / Q000706:statistics & numerical data; D006801:Humans; D006975:Hypertension, Portal / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D008297:Male; D018579:Patient Selection; D012107:Research Design / Q000592:standards; D012307:Risk Factors; D019896:alpha 1-Antitrypsin Deficiency / Q000453:epidemiology / Q000235:genetics / Q000473:pathology
keywords: Alpha-1 antitrypsin; Alpha-1 antitrypsine; Cirrhose; Cirrhosis; Cohorte multicentrique pédiatrique; Gènes modificateurs; Hypertension portale; Modifying genes; Pediatric multicentric cohort; Portal hypertension