is the mz carrier status clinically...
TRANSCRIPT
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Is the MZ carrier status clinically relevant?
Gerry McElvaneyIrish Centre for Genetic Lung DiseaseRoyal College of Surgeons in Ireland
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AAT Level vs. Phenotype in Irish TDP
Protective threshold
Norm range
MM MS MZ SS SZ ZZ0.0
0.5
1.0
1.5
2.0
2.5
AAT Phenotype
AA
T Le
vels
(g/L
)
Risk of lung disease
HighNone
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N. Gerry McElvaney,Respiratory Research Division,
Royal College of Surgeons in Ireland,Education and Research Centre,
Beaumont Hospital,Dublin 9
Do MZs have an increased risk for COPD?
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DEFINITION - COPD• COPD is a condition characterised by airflow
obstruction that is not fully reversible
• The airflow limitation is usually progressive and is associated with an enhanced inflammatory response of the lungs to noxious particles/gases, primarily tobacco smoke
• Heterogenous disease• Chronic Bronchitis• Emphysema
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DEFINITION - CHRONIC BRONCHITIS• Chronic Bronchitis is characterised by cough
productive of sputum on most days for at least 3 months for at least 2 consecutive years with no other attributable cardiac or respiratory cause
• Consequence of mucous hypersecretion
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DEFINITION - EMPHYSAEMA• Emphysaema is defined by abnormal and permanent
enlargement of the airways distal to the terminal bronchiole with gradual destruction of the alveolar septae and pulmonary capillary bed leading to a decreased ability to oxygenate blood
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Spirometry
• In COPD the amount of air you can blow out in 1 second (FEV1)is reduced compared to the total amount of air you can blow out (FVC)
• The ratio of FEV1/FVC is reduced
• Flow at various parts of expiration are also decreased (FEF25-75)
• All these values are compared to populations of the same age, height and sex
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Meta-analysis:PI MZ risk for lung disease
Difference in mean FEV1: PI MM – PI MZ-20 0 20
Study % WeightDifference in mean FEV1 (95% CI)
-10.00* (-16.79,-3.21)Webb 1973 10.0
-3.00* (-11.30,5.30)Hall 1976 7.9
1.49 (-3.06,6.04)Morse 1977 14.2
0.34 (-6.88,7.56)Girard 1978 9.3
3.00* (0.45,5.55)Eriksson 1985: Smokers 18.7
6.00* (-6.80,18.80)Ex-smokers 4.2
1.00* (-9.35,11.35)Non-smokers 5.8
10.00* (2.88,17.12)Horne 1986 9.5
-1.00* (-2.62,0.62)Dahl 2002 20.4
0.62 (-2.30,3.54)Overall (95% CI)
Figure 2: Meta-analysis of Quantitative FEV1 (% Pred)in PI MZ vs. PI MM Subjects
• Seven cross-sectional studies compared mean FEV1 (% predicted) in PMM and PI MZ individuals.
• There was no difference in mean FEV1 (% predicted) between PI MM and PI MZ individuals (summary difference PI MM -PIMZ=0.62% predicted, 95% CI-2.30%, 3.54%)
Hersh et al, Thorax 2004 Oct;59(10):843-9
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Larger studies?
• Sorheim et al.(Chest 2010)• Two large populations, case control study from Norway
(n=1669) and multicentre family based study from Europe/North America (n=2,707)
• PIMZ had lower FEV1/(F)VC ratio in both studies• In case control study PI MZ had more emphysema on
quantitative chest CT
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Other data
• Seersholm et al Am J Respir Crit Care Med 2000• Cohort of MZs retrieved from Danish AATD Registry• Ten matched controls for each MZ identified from Danish Central Population Registry• Cases and controls linked to Danish Hospital Discharge Registry• Of 1,551 PiMZ, 47 identified as discharge diagnosis of OPD• 206 with this Dx in control group• Significant only in age groups 40-79• Of the PiMZs 36% first degree relatives of symptomatic ZZs
• Problems• No smoking histories, , ? Higher in the MZs (92% of PiZZ index cases smokers)• Diagnosis of OPD included chronic bronchitis, emphysema and asthma• Increased risk of admission?, in younger ages 8 out of 9 for asthma
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Our Hypothesis
• A subset of Pi MZ siblings are at an increased risk for COPD due to additional genetic and environmental factors.
• Lower FEV1 levels will be found in Pi MZ siblings compared to their Pi MM siblings in families of PIMZ COPD probands.
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National Alpha-1 Targeted Detection Programme
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What Groups are Targeted?
ATS/ERS (WHO) Guidelines• All COPD patients• All non-responsive asthmatics
(adults/adolescents)• All patients with cryptogenic cirrhosis/liver
disease• All first degree relatives of patients/carriers
with AAT deficiency
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Screening for Alpha-1 in Ireland to date
• Almost 19,000 tested; ~ 31% possess at least one abnormal Alpha-1 gene
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Methods• 1) Population Building:
• The people with MZ AATD, referred to us with COPD are called probands (the affected individual through whom a family with a genetic disorder is ascertained). Enrolled parents and siblings of PI MZ COPD probands
• Perform spirometry testing, questionnaire and phlebotomy (for PI typing and future genetic modifier studies).
• 2) Family-based genetic association analysis:• Perform ~ of qualitative (presence/absence of COPD) and
quantitative (FEV1 % predicted) airflow obstruction phenotypes in PI MZ relatives and PI MM relatives of the PI MZ COPD probands.
• 3) Genotype-by-environment interaction studies:• Investigate the impact of active and passive cigarette smoke
exposure on the PI MZ risk for COPD as a genotype-by-interaction environment interaction.
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1) Study Individuals
• Inclusion criteria(PiMZ probands) :
• Age > 30 years
• GOLD Stage 2-4 COPD
• Confirmed carrier status(PI MZ genotype)
• No other lung disease affecting PFT
• Exclusion criteria (siblings):
• Interstitial lung diseases (except asthma)
• Pi types other than PI MM or PI MZ
• Half biological siblings of PI MZ COPD probands
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ResultsPatient Characteristics
Recruited247
Included239
Excluded8
Probands MM Relatives MZ Relatives P value
N 51 99 89 ….
Age (y), mean ± SD 64.82 ± 11.06 51.88 ± 14.46 53.42 ± 13.62 ns
Gender, % females 25 (49) 66 (66.67) 52 (58.4) ns
BMI (k/m2) mean ± SD) 25.21 ± 5.35 26.13 ± 4.64 26.72 ± 5.97 ns
AAT (g/L), mean ± SD) 0.88 ± 0.16 1.396 ± 0.275 0.921 ± 0.389 < 0.0001
% Ever Smokers 88.23(n = 45)
52.52(n = 52)
58.42(n = 52)
ns
% Current Smokers 29.41(n = 15)
29.29(n = 29)
32.58(n = 29)
ns
Pack Years 40(17, 67)
21.38(14.75, 36.50)
23.75(14.25, 45.75)
ns
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Baseline Pulmonary function data
Post-BDFEV1/FVC ratio
0.40(0.32, 0.59)
0.78(0.73, 0.83)
0.75(0.66, 0.79)
0.0037
FEV1 (L)0.96
(0.71, 1.24)2.692
(2.146, 3.136)2.5420
(1.838, 3.189)ns
FEV1 (% predicted)
38.84(27.17, 68.71)
98.63(85.49, 109.70)
91.98(75.58, 105.40)
0.0428
FEF 25-75 (L/s)0.12
(0.08, 0.24)2.422
(1.860, 3.332)2.1380
(1.011, 2.888)0.0094
FEF 25-75 (% predicted)
12.14(8.40, 23.87)
72.84(55.50, 97.74)
63.84(38.45, 84.35)
0.0013
Probands MM Relatives MZ Relatives P value
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Results: FEV1/FVC
FEV1/FVC Ratio (median, interquartile range)MM MZ P value
Never Smoked 0.81 (0.75,0.85) 0.77 (0.73,0.83) nsEver Smoked 0.77 (0.72,0.81) 0.71 (0.58,0.77) 0.0013
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Results: FEV1 (%predicted)
FEV1 % predicted (median, interquartile range)MM MZ P value
Never Smoked 101.3 (88.7,110.6) 102.2 (88.3,108.4) nsEver Smoked 94.8 (82.1,102.4) 82.34 (63.1, 94.4) 0.0009
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Results: FEF25-75 (%predicted)
FEF25-75 % predicted (median, interquartile range)MM MZ P value
Never Smoked 84.1 (70.7,100.8) 76.1 (63.6,99.4) nsEver Smoked 64.8 (52.2,90.2) 47.7 (22.7,66.8) 0.0002
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Results: FEV1/FVC ratio: high vs low exposure
FEV1 /FVC ratio(median, interquartile range)MM MZ P value
Low exposure 0.80 (0.76,0.83) 0.75 (0.67,0.77) 0.007High exposure 0.74 (0.69,0.78) 0.68 (0.56,0.78) 0.011
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Results: FEV1 (%predicted): high vs low exposure
FEV1 % predicted (median, interquartile range)MM MZ P value
Low exposure 96.2 (84,108.5) 87.4 (60.1,97.6) 0.011High exposure 89.9 (79.4,99.4) 81.7 (66.2,91.3) 0.027
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Results: FEF 25-75 (%predicted): high vs low exposure
FEF 25-75 % predicted (median, interquartile range)MM MZ P value
Low exposure 86.4 (60.8, 98.6) 55.4 (30.8,68.1) 0.002High exposure 56.6 (44.5,70.6) 41.4 (22.3,64.0) 0.02
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PBAT p values for MZ heterozygosity and post bronchodilator spirometry and COPD in non-probands.
Characteristic Model All
Relatives
Ever
Smoking
Relatives*
Never
Smoking
Relatives*
Direction of Effectof Z Alleleon Lung Function
Phenotypes
Post-BD FEV1/FVC ratio A 0.0003 0.006 0.025 Decrease
FEV1 (L) A 0.043 0.003 ns Decrease
FEV1 (%
predicted)
B 0.028 0.003 ns Decrease
FEF25-75 (L/s) A 0.002 0.006 ns Decrease
FEF25-75 (%
predicted)
B 0.006 0.020 ns Decrease
COPD * C 0.0005 0.0004 ns Increase
Model A: Adjusted for age, sex, height, ever smoking status and pack-years Model B: Adjusted for ever smoking status and pack-years. Model C: Adjusted for age, sex, ever smoking status and pack-years model
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Generalized estimating equations for the risk of COPD in al relatives and ever smoking relatives
All Relatives Ever Smokers
Co-variate O.R. (95% CI) p-value O.R. (95% CI) p-value
PI MZ Genotype 5.18 (1.27 - 21.15) 0.02 10.65 (2.17 - 52.29) 0.003
Age 1.04 (1.01 - 1.08) 0.02 1.05 (1.00 - 1.10) 0.03
Sex 1.35 (0.39 - 4.67) 0.63 1.84 (0.47 - 7.17) 0.38
Ever Smoker 6.33 (0.74 - 53.89) 0.09 NA NA
Pack Years of
smoking
1.02 (0.99 - 1.05) 0.14 1.02 (0.99 - 1.06) 0.17
Abbreviations: O.R. = Odds ratio; CI = Confidence Interval
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Conclusions• This is the first family based case control study to determine
the risk of COPD in PiMZ individuals.• Cigarette smoking in PiMZ individuals is associated with a
reduced:• FEV1/FVC ratio• FEV1 (% predicted)• FEF25-75 (% predicted)• An increased risk of COPD
• Conclusion:1. Smoking PiMZ’s are at an increased risk of COPD2. MZ individuals who don’t smoke do not develop
significant lung disease.
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Not just a double hit
Mehta , Occup Environ Med 2014
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Two distinct diseases?
Lung disease: (loss of function)
Liver disease: (gain of toxic function)
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Cirrhosis risk
Strnad GUT 2018
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Results
• The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p
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Not just lung and Liver Disease
• 246 patients with Rheumatoid arthritis
• No difference in prevalence of AATD and general population
• MZs increased ACPA titres• Associated with more
severe prognosis
McCarthy Arthritis Rheum 2017
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Go Raibh Maith Agaibh