Is the MZ carrier status clinically relevant?

Gerry McElvaneyIrish Centre for Genetic Lung DiseaseRoyal College of Surgeons in Ireland

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

N. Gerry McElvaney,Respiratory Research Division,

Royal College of Surgeons in Ireland,Education and Research Centre,

Beaumont Hospital,Dublin 9

gmcelvaney@rcsi.ie

Do MZs have an increased risk for COPD?

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

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

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

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

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

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

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

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.

National Alpha-1 Targeted Detection Programme

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

Screening for Alpha-1 in Ireland to date

• Almost 19,000 tested; ~ 31% possess at least one abnormal Alpha-1 gene

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.

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

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

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

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

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

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

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

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

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

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

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

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.

Not just a double hit

Mehta , Occup Environ Med 2014

Two distinct diseases?

Lung disease: (loss of function)

Liver disease: (gain of toxic function)

Cirrhosis risk

Strnad GUT 2018

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

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

Go Raibh Maith Agaibh