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BPCO e carenza ereditaria di AAT. Ilaria Ferrarotti Centro per la Diagnosi del Deficit di Alfa1-Antitripsina Fondazione IRCCS Policlinico S. Matteo Dipartimento di Medicina Molecolare Università di Pavia. Alpha-1 antitrypsin Deficiency. Common genetic disease among Caucasians (1/5000)

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slide1

BPCO e carenza ereditaria di AAT

Ilaria Ferrarotti

Centro per la Diagnosi del Deficit di Alfa1-Antitripsina

Fondazione IRCCS Policlinico S. Matteo

Dipartimento di Medicina Molecolare

Università di Pavia

alpha 1 antitrypsin deficiency
Alpha-1 antitrypsinDeficiency
  • Common genetic disease among Caucasians (1/5000)
  • Autosomalco-dominant heredity
  • Reduced or complete lack of alpha-1-antitrypsin secretion from hepatocytes into the bloodstream
  • Severe AAT deficiency is most often associated with homozygous Z-mutation (PiZZ); over 120 genetic variants of the Pi gene are currently known
  • Lung, liver, and skin (very rare) can be affected
  • Often remains unrecognized or is wrongly diagnosed as COPD
slide3

CASE-FINDING

Severe AATD is clearly associated with disease risk accounting for 1-2% of all COPD cases.

slide5

Nevertheless...

.... large genome-wide association studies (GWAS) on these pulmonary outcomes have so far failed to point to this chromosomal region.

slide6

Missingheritability

Manolio TA et al, Nature 2009

slide7

The first GWAS on AAT serum concentration in a subset of the SAPALDIA (Swiss Cohort Study of Air Pollution and Lung Disease in Adults) general population sample

  • Fine mapping of the SERPINA1 locus (genotyping of additional SNPs in the whole study sample - exon sequencing in subjects with unexplained low levels of circulating AAT ).

Detection ofassociatedchromosomal loci

Addictionallyasssessmentofcontributionofthis locus to the trait’s variability

slide8

Conclusions:

  • GWAS on AAT blood levels, not yet present in the literature, identified a region that includes the gene SERPINA1 as the only associated locus in the genome.
  • Strong signals of common variants completely disappeared after conditioning on two low frequent causal variants
  • Rare SERPINA1 alleles much rather than common alleles contribute to the further variability of this blood marker.

Manhattan-Plot of genome-wide P-values for association with

blood AAT levels

Manhattan-Plot of genome-wide p-values for association with blood AAT levels conditioning on S and Z alleles.

p<5*10-8

14q32.1

slide9

Inference:

  • this locus is suggestive to contribute to the missing heritability of pulmonary outcomes.
  • The absence of this locus among the statistically significantly associated signals in corresponding GWAS may reflect
  • small effect sizes of the common variants in combination with insufficient sample size and stringent correction for multiple testing leading to a high risk of type II errors
  • poor tagging of the underlying causal variants by nearby SNPs in the chip arrays would further reduce the chance to find this locus among the significantly associated results.
slide10

LOSS OF FUNCTION

Normallung

AATD lung

degradation

degradation

HNE

HNE

AAT

AAT

slide13

Alpha1-antitrypsin serumlevel, SERPINA1 genotype , and riskfor COPD

Dahl & Nordestgaard, Int J COPD 2008;4:157-167

slide14

GAIN OF FUNCTION

AATD asconformationaldisease

Gooptu B, Lomas D, AnnRevBiochem, 2009

slide15

Polymers in the lung

McElvaney, Lung 2007

slide20

AnnualCongress, EuropeanRespiratory Society, Vienna, 1-5 Settembre, 2012

Effect of augmentation therapy on immune function of patients with severe Alpha1-antitrypsin deficiency

Ferrarotti I1, Carroll TP2, Inghilleri S1, Ottaviani S1, Luisetti M1, McElvaney NG2

1Center for Diagnosis of Inherited Alpha1-antitrypsin Deficiency, Dept of Molecular Medicine, Section of Pneumology, IRCCS San Matteo Hospital Foundation, University of Pavia, Italy;

2Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.

‘We acknowledge the support of the European Respiratory Society (ERS) and the National Society (AIMAR), joint ERS/AIMAR Fellowship STRTF 87-2010’

Augmentation therapy appeared to attenuate IL-6 and IL-8 production from ZZ and Q0/Q0 monocytes. (***p<0.001, **p<0.01)

Relative IL-8 and IL-6 levels measured by ELISA in monocyte supernatants collected after 24h incubation in the presence (+) or absence of LPS.

A-B. Comparison among MM, ZZ and ZZ treated with aumentation therapy (ZZa.t.).

C-D. ComparisonamongMM, M/Q0 and Q0/Q0treatedwithaumentationtherapy (Q0/Q0a.t.)

A

C

D

B

slide21

Reduced chemotactic activity of AATD individuals (PI*ZZ) receiving augmentation therapy in comparison to untreated PI*ZZ patients and controls.

P< 0.005

p=0.005

p=0.009

PatientPI*ZZ:

male, 42y, 20pack/y FEV1%31-FVC%60,

aug.therapy 2 years

PatientPI*ZZ:

male, 49y, 20pack/y FEV1%29 - FVC%68

no aug. therapy

MMcontrols: healthy, matchedforage and gender

slide22

Reduced superoxide production from AATD individuals (PI*ZZ and PI*Q0/Q0) on augmentation therapy in comparison to untreated PI*ZZ and controls.

slide25

AATD subjectsenrolled 5,511

(Update 20th August 2013)

slide26

DISTRIBUTION OF DIFFERENT CLINICAL RESPIRATORY PHENOTYPES ACCORDING TO GENOTYPES

* R denotes non-Z and non-Sdeficiencyvariants

slide27

DISTRIBUTION OF EARLY-ONSET EMPHYSEMA ACCORDING TO GENOTYPES

% ofearly-onsetemphysema

* R denotes non-Z and non-Sdeficiencyvariants

slide28

Severe AATD ItalianRegistry

413 patients (december 2013)

Genotype

slide29

IRCCS San Matteo Hospital Foundation,

University of Pavia:

Pulmonology Unit

Head of Department: Maurizio Luisetti

Laboratory of Biochemistry and Genetics of Lung Disease

StefaniaOttaviani

Marina Gorrini

Michele Zorzetto

Ilaria Campo

SimonaInghilleri

Simona Ferrari

Unit of Pulmonology

Francesca Mariani

ZamirKadija

Elena Paracchini