Variable effects of environment due to genetics.

Turkish Thoracic Society 9th Annual Congress

Prof. Dr. Erika von Mutius

University Children‘s Hospital

Munich, Germany

Environmental factors for the development of childhood asthma.

Protective factors:Day careCertain infectionsFarming environment

Risk factors:High body mass indexParacetamol useTraffic exposurePassive smoking

Prevalence of asthma, hay fever and Prevalence of asthma, hay fever and atopy among farmers' children in the atopy among farmers' children in the ALEX StudyALEX Study

%

0

5

10

15

20

25

30

35

40

Asthmadiagnosis

Asthmasymptoms

Hay feverdiagnosis

Hay feversymptoms

Atopy

Non-Farmers (n=493)Farmers (n=319)

* * * *

*

* p< 0.05

Riedler et al. Lancet 2001

Exposure to stables and/or farm

milk in the 1. year of life.

11.8

1.4

14.8

2.8

16

3.2

19.8

5.1

32.9

12.4

0

5

10

15

20

25

30

35

Asthma diagnosisAsthma symptoms Hay feverdiagnosis

Hay feversymptoms

Atopy

No exposureMilk onlyStable onlyStable and milk

%

ALEX-StudyRiedler et al. Lancet 2001

Mattress levels of endotoxin and muramic

acid among farm and non-farm children.

0

20

40

60

80

100

120

140

160

180

Muramic acid µg /m2

0

5000

10000

15000

20000

25000

30000

Endotoxin EU/m2

FarmchildrenNon farmchildren

2 3 4 5

Endotoxin Load in Mattress [EU/m2] (log scale)

510

15A

dj. P

reva

lenc

e of

Hay

Fev

er (%

)

100 1000 10000 1000002 3 4 5

Endotoxin Load in Mattress [EU/m2] (log scale)

010

2030

Adj

.ust

ed P

reva

lenc

e of

Hay

Fev

er S

ympt

oms

(%)

100 1000 10000 1000002 3 4 5

Endotoxin Load in Mattress [EU/m2] (log scale)

1015

20A

dj. P

reva

lenc

e of

Ato

pic

Sen

sitiz

atio

n (%

)

100 1000 10000 100000

Hay fever Hay fever symptoms Atopy

Braun-Fahrländer et al. NEJM 2002

2 3 4 5

Endotoxin Load in Mattress [EU/m2] (log scale)

24

68

Ad

j. P

reva

len

ce o

f N

on

-Ato

pic

Wh

ee

ze (

%)

100 1000 10000 1000002 3 4 5

Endotoxin Load in Mattress [EU/m2] (log scale)

24

68

1012

Adj

. Pre

vale

nce

of A

topi

c W

heez

e (%

)

100 1000 10000 100000

Atopic wheeze Non-atopic wheeze

Braun-Fahrländer et al. NEJM 2002

LPS: Lipopolysaccharide

LBP: LPS-binding protein

MA: muramic acid

Molecular Basis of LPS and Muramic Acid Interaction

Bacteria

LPS

LPS

TLR4

TLR2CD14

LBP

NF B

MA

LPS

NOD2

0

10

20

30

40

High endotoxin exposure and TLR4/+45982

Asthma diagnosis

Currentasthma

symptoms

Atopy Currenthay fever

symptoms

AA n=259 AG/GG n=45

%

0

10

20

30

40

Low endotoxin exposure and TLR4/+45982

Asthma diagnosis

Atopy Currenthay fever

symptoms

AA n=266 AG/GG n=39

%

Currentasthma

symptoms

P=0.031

Eder et al,JACI 2004

Farmers’ children and TLR2/-16933

0

10

20

30

40

Asthma diagnosis

Currentasthma

symptoms

Atopy Currenthay fever

symptoms

AA n=52 AT n=116 TT n=61

%

p=0.012 p=0.004

p=0.023

p=0.01

B Nonfarmers’ children (n=380)

0

10

20

30

40

Asthma diagnosis

Currentasthma

symptoms

Atopy Current hay fever

symptoms

%

TLR2/-16933 AA n=97 TT n=94AT n=189

Eder et al,

JACI 2004

Environmental factors for the development of childhood asthma.

Protective factors:Day careCertain infectionsFarming environment

Risk factors:High body mass indexParacetamol useTraffic exposurePassive smoking

Passive smoking and

lung function

decrements.

A meta-analysis.

Detoxification pathways

David, AJRCCM2003

GSTM1 deficiency, in utero ETS exposure and asthma in US children

Gilliland, AJRCCM 2002

GSTM1 Deficiency and ETS in the German ISAAC population

Kabesch, Thorax 2004

FVC FEV1 PEF MEF 25 MEF 50 MEF 75

% p

red

icte

d

60

70

80

90

100

110

no ETS in Utero & GST T1+no ETS in Utero & GST T1-ETS in Utero & GST T1+ETS in Utero & GST T1-

GSTT1 Deficiency and in utero ETS:impaired lung function development

Kabesch, Thorax 2004

Conclusions.

• Environmental factors are important determinants for the

development of childhood asthma.

• The environmental exposure may decrease or increase

the risk.

• People are not uniformely sensitive to environmental

influences depending on their genetic make up.

• Gene*environment interactions highlight underlying

pathomechanisms of disease inception.