Download Gene_air polution

Gene Environment Interactions
With Air Pollution
María Eugenia Vargas Camaño M. D.
Chief of Allergy and Clinical Immunology Service
CMN 20 de Noviembre ISSSTE México, D. F.
Asthma:
Chronic,
Inflammatory
Multifactorial disease.
Represents a huge socioeconomic burden
Public health: probably the most important allergyrelated disease.
Interaction of genetic and environmental
factors lead to its clinical expression
Casual Model for Asthma
Choudhry, Seibold, Borrell, et al.: Latinos, Epidemiology and Asthma Proc Am Thorac Soc 2007; 4: 226–233,
Genetics of Asthma
• Multiple genes identified and involved
• Each gene has a modest effect in the
disease
• Genetic variation often differs between
races and ethnic groups
• Difficulty in identifying a consistent
phenotype across population groups
• Clearly defining disease phenotype is a
central issue.
• There is no uniform phenotypic definition for
asthma
• It iss useful to evaluate phenotypes
associated with the disease
Individual
Environmental
Genetics
Gene-by-environment interactions: ‘‘because of their genetic
differences, two or more individuals, families or genotypic lines
respond differently, or to different extents, to changes in the
environment.’’
Caligari PD, Mather K. Genotype–environment interaction, III: interactions in Drosophila
melanogaster. Proc R Soc Lond B Biol Sci 1975;191:387-411.
Phenotypes associated with asthma
Atopic sensitization: High levels of IgE antibodies or
skin-test responsiveness to common allergens.
Wheeze: Noisy, labored breathing due to air moving
through narrowed tracheobronchial airways.
Bronchial hyperresponsiveness: state where bronchi
constrict easily and excessively, on exposure
to specific (allergen) and non-specific
(chemical and physical) stimuli.
Other allergic disorders: Characterized by an
immunologically mediated adverse reaction to a foreign
substance.
Sadeghnejad A, Bleecker E, Meyers DA Principles of Genetics in Allergic Diseases
and Asthma Adkinson: Middleton's Allergy: Principles and Practice, 7th ed.2008
pp.59-69
Phenotypes associated with asthma
Wardlaw AJ, Dunnette S, Gleich GJ, et al. Eosinophils and mast cells in bronchoalveolar lavage in
subjects with mild asthma: Relationship to bronchial hyperreactivity. Am Rev Respir Dis 1988;
137:62–69.
Asthma: Genome-Wide Screens1
Identify chromosomal regions linked with disease in families from which
candidate genes or positionally cloned genes are identified.
First study published in 19962.
Most of the studies used asthma-affected sibling pairs for the
identification of regions linked to the phenotypes of interest.
Phenotype studied
Total IgE
Ascertainment
Chromosomes linked
Siblings pairs with asthma
1, 7, 11 3
BHR
Asthmatic probands and their families
3p 5q4
FEV1% VC
Asthmatic probands and their families
2q5
1.Hayden,Le
Souëf.Clin Pulm Med 2007; 14:249-257
Daniels SE, Bhattacharrya S, James A, et al.. Nature. 1996;383:247–250.
3 Altmuller J, Seidel C, Lee YA, et al. BMC Pulm Med. 2005;5:1.
4 Meyers DA, Postma DS, Stine OC, et al.. J Allergy Clin Immunol. 2005; 115: 1169 –1175.
5 Postma DS, Meyers DA,. Am J Respir Crit Care Med. 2005;172:446–452.
2
Asthma: Candidate Gene/Association Studies1
In genome-wide screens chromosomal regions linked with asthma are identified. Candidate
genes within those regions can be screened for polymorphisms that may then be associated
with asthma-related phenotypes via association studies
1.Hayden,Le
Souëf.Clin Pulm Med 2007; 14:249-257 2 Van Eerdewegh P, Little RD, Dupuis J, et al.. Nature.2002;418:426–430. 3 Noguchi E, Yokouchi
Y, Zhang J, et al.. Am J Respir Crit Care Med. 2005;172:183–188. 4 Allen M, Heinzmann A, Noguchi E, Nat Genet. 2003;35: 258–263.5 Laitinen T,
Polvi A, Rydman P, et al. Science. 2004;304:300304. 6 Nicolae D, Cox NJ, Lester LA, et al.. Am J Hum Genet. 2005;76:349 –357 7 Zhang Y, Leaves
NI, Anderson GG, et al. Nat Genet. 2003;34:181–186. 8 Brasch-Andersen C, Tan Q, Borglum AD, et al. Thorax. 2006;61:874–879
Genome Wide Association Studies
First study in asthma1
>300 000 SNPs map association with childhood
asthma 994 patients and 1243 non-asthmatics
Multiple markers on chromosome 17q21 strongly
associated with childhood-onset asthma
1 Moffatt
M.F., Kabesch M., Liang L., et al: Genetic variants regulating ORMDL3 expression
contribute to the risk of childhood asthma. Nature 2007; 448:470-473.
Gene-environment interactions with air pollution
Convincing evidence
Air pollutants (fine particles and ozone):
1) Exacerbate existing asthma,
2) Increase the risk for asthma hospitalization and
emergency department visits,
3) Impair lung function 1-3 .
Few studies have addressed interactions between air
pollutants and genetics in relation to asthma.4-5
Downs SH, Schindler C, Liu LJ, Keidel D, Bayer-Oglesby L, Brutsche MH, et al. Reduced
exposure to PM10 and attenuated age-related decline in lung function. NEngl J Med
2007;357:2338-47.
2 Atkinson RW. Acute effects of air pollution on admissions: reanalysis of APHEA2. Am J
Respir Crit Care Med 2004;169:1257-8.
3 Atkinson RW, Anderson HR, Sunyer J, Ayres J, Baccini M, Vonk JM, et al. Acute effects of
particulate air pollution on respiratory admissions: results from APHEA 2 project. Air
Pollution and Health: a European Approach. Am J Respir Crit Care Med 2001;164:1860-6.
4 London SJ. Gene-air pollution interactions in asthma. Proc Am Thorac Soc 2007;4; 217-20.
5 Yang IA, Savarimuthu S, Kim ST, Holloway JW, Bell SC, Fong KM. Gene-environmental
interaction in asthma. Curr Opin Allergy Clin Immunol 2007;7:75-82.
1
Gene-environment interactions with air pollution
Acute exposure studies: 24 healthy volunteers
2-hour bicycle ride at ambient summer ozone concentrations, before
and after:
Decreases in lung function parameters > in subjects with the
combined GSTM1- null and the NAD(P):quinone oxidoreductase wildtype genotype 1
Similar results: cross-sectional study in a Mexico City population
High lifetime exposure to ozone.
The NAD(P):quinone oxidoreductase TT reduced activity genotype
was protective for asthma only among the GSTM1-null individuals2.
There is also some evidence that the GSTM1 and GSTP1 genotypes
alone or in combination may modify the acute respiratory response to
ozone in individuals with asthma 3
Bergamaschi E, De Palma G, Mozzoni P, Vanni S, Vettori MV, Broeckaert F, et al. Polymorphism of quinonemetabolizing enzymes and susceptibility to ozone inducedacute effects. Am J Respir Crit Care Med 2001;163:142631
2David GL, Romieu I, Sienra-Monge JJ, Collins WJ, Ramirez-Aguilar M, del Rio-Navarro BE, et al. Nicotinamide
adenine dinucleotide (phosphate) reduced:quinone oxidoreductase and glutathione S-transferase M1
polymorphisms and childhood asthma. Am J Respir Crit Care Med 2003; 168:1199-204.
3Romieu I, Ramirez-Aguilar M, Sienra-Monge JJ, Moreno-Macias H, del Rio-Navarro BE, David G, et al. GSTM1 and
GSTP1 and respiratory health in asthmatic children exposed to ozone. Eur Respir J 2006;28:953-9.
1
Gene-environment interactions with air pollution
Acute exposure studies: 51 individuals undergoing ozone challenge
Genotyped for 4 polymorphisms across the TNF gene.1
Mean reduction in FEV1 with ozone challenge > in TNF-308GG
individuals compared with the other genotypes.
TNF polymorphism in susceptibility to childhood asthma:
Large Child’s Health Study in the United States.2
Children with TNF-308 GG had decreased risk of asthma and lifetime
wheezing.
The protective effects of GG genotype on wheezing outcomes > in
lower than higher ozone communities.
The reduction of the protective effect from the -308 GG genotype with
higher ozone exposure was most marked in the GSTM1-null and GSTP1
Ile/Ile groups
Yang IA, Holz O, Jorres RA, Magnussen H, Barton SJ, Rodriguez S, et al. Association of tumor
necrosis factor-alpha polymorphisms and ozone-induced changein lung function. Am J Respir Crit
Care Med 2005;171:171-6.
2Cameron L, Webster RB, Strempel JM, Kiesler P, Kabesch M, Ramachandran H, et al. Th2 cellselective enhancement of human IL13 transcription by IL13- 1112C>T, a polymorphism associated
with allergic inflammation. J Immunol 2006; 177: 8633-42
1
205 non-asthmatic and asthmatic children, (9-12 ys) Detroit, Michigan:
• Environmental measures (indoor and outdoor air, vacuum dust)
• Biomarkers of exposure (cotinine, metals, total and allergen specific
Ig E, polycyclic aromatic hydrocarbons, volatile organic carbon
metabolites)
• Clinical indicators of health outcome (immunological, cardiovascular
and respiratory)
• Blood gene expression and candidate SNP analyses were conducted.
MICA study provides an opportunity to evaluate complex
relationships between environmental factors, physiological
biomarkers, genetic susceptibility and health outcomes
Thorax 2011;66:1043-1050
Is the process of urbanisation involved in differences in asthma
prevalence in transitional communities in north-eastern Ecuador?
This is an ecological study conducted in 59 communities in
Esmeraldas Province, Ecuador.
Indicators of urbanisation were grouped into three indices
representing the processes associated with urbanisation:
1) Socioeconomic
2) Lifestyle
3) Urban infrastructure.
Asthma Prevalence and Urbanisation
Significant associations
with community asthma
prevalence:
1) Socioeconomic (r=
0.295, p= 0. 023)
2) Lifestyle (r= 0.342, p=
0.008)
3) Summary urbanisation
index (r= 0.355, p=
0.006).
Socioeconomic
Summary Urbanisation
Lifestyle
Indices
von Mutius E. Gene-environment interactions in asthmaJ Allergy Clin Immunol
2009;123: 3-11.