ASTHMA, GENOMICS & FAMILY HEALTH HISTORIES:

A New Strategy for Disease Prevention, Education and Treatment

Paul G. Eberle, Ph.D(abd), RRTAssoc. Professor of Respiratory

TherapyWeber State University

It has been predicted that genomics will “revolutionize” public health as we know it today.

-Utah Dept. of Health/Asthma Taskforce

Genes & Family

Newsweek, Feb. 6, 2006What science can tell you about your

history and your health.

Asthma

A serious personal and public health issue with far reaching medical, economic, and psychosocial implications. It can be characterized by:

1) Airway inflammation2) Bronchial hyperreactivity3) Reversible airway obstruction4) Chronic eosinophilic bronchitis

Implications

Asthma results from a combination of environmental triggers and genetic predisposition.

Varying degrees of hypersensitivity between and among patients and the onset of symptoms complicates a consistent description for asthma.

Asthma Incidence

Most common chronic disease in U.S. Present in approx. 7.7% population

(22,771,528). 8.8% in children <18yrs. (26,024,731). ½ stricken before 10 yrs. of age.

(American Lung Assn. Nat’l Health Interview Survey-2003).

10.4 million hospital outpatient visits 2 million emergency dept. visits 465,000 hospitalizations 4,500 deaths

were attributed to asthma in 2000.

Asthma in the U.S.

Cost for treatment of asthma in the U.S. estimated to be 12.7 billion in 1998.

(Weiss & Sullivan, 2001).

Asthma in Utah

Cost in Utah for all providers was $2,972,061 (almost 3 million dollars).

Approx. 39% of all dollars spent on emergency department visits were due to asthma.

Cost of asthma for Utah emergency department visits, 2003.

11%

24%

3%

8%

1%

24%

9%

0%7%

0%13%

Medicare $327,110

Medicaid $723,542

Gov't $89,470

Commercial $240,307

Children's Health $17,901

Managed Care $722,714

Self Pay $252,020

Worker's Comp $3,975

Other $211,760

Charity $4,514

Blue Cross $378,748

Utah emergency department visit rates for females and males in years 2001, 2002, 2003 per 10,000 patients.

0

5

10

15

20

25

30

2001 2002 2003

Male

Female

Percentage of patient’s w/asthma seen in Utah emergency departments 2001 -2003.

0

10

20

30

40

50

60

Visits by age

Early-phase

IgE (antigen-antibody sensitivity) allergic reaction Attached to mast cell which release mediators

HistamineEosinophilic chemotactic factor of anaphylaxis

(ECF-A)Neutrophil chemotactic factor (NCF)ProstiglandinsPlatelet-activating factor

1) Vasodilatation2) Edema /irritation3) Mucus secretion4) Bronchoconstriction

Heightened Reactivity

LuekotrienesSlow reacting substance of

anaphylaxis (SRS-A)1) Vasodilatation2) Edema /irritation3) Mucus secretion4) Bronchoconstriction

Late-phase

Eosinophilic leukocytosisNegative airway effects

1) Thickening of the bronchial wall

2) Inflammation (use glucocorticosteroids)

3) Thickening of the basement membrane

4) De-nuding of respiratory epithelium

Triggers

IntrinsicOften no family history and onset later in life

1) Infection2) Emotion3) Cold air4) Exercise5) Smog 6) Irritants (tobacco smoke is the #1

modifiable factor i.e., 380,000 childhood cases of asthma can

be attributed to second-hand smoke).

Triggers

Extrinsic Allergic asthma triggers

1) Wind pollinating plants. i.e., trees, grass, weeds (40 µ).

2) Dry mold / Alter aria burnsii (1-2µ ).i.e., late summer- lower airway.

3) Animal dander (1-2 µ).4) House dust mites.

Non-allergic asthma1) Occupational exposures

Goal of Control Therapy

To restore lung function and return to “normal” activity. Effective tx. suggestive w/15-20% increase in Fev1

Mild <2/wk normal lung function tx. short acting bronchodilator (treat symptoms).

Mod >2/wk normal lung function tx. inhaled corticosteroid w/bronchodilator.Mod/Persistent include Noc awakening, signs of impaired lung function, i.e., Fev1 <60% tx. steroid + long acting beta agonist &/or luekotriene inhibitor.Severe hypersensitivity w/ Noc awakening, Fev1 <50%

tx. mast cell stabilizer, inhaled corticosteroid/beta agonist & leukotriene inhibitor w/long acting theophylline.

Mortality in General Population 1.4/100,000 in 1982 2.0/100,000 in 1991

Mortality by race:Black

39/1000 pt’s w/asthma in 198262/1000 pt’s w/asthma in 1993

White35/1000 pt’s w/asthma in 198251/1000 pt’s w/asthma in 1993

Asthma prevalence is elevated in low-income populations with substantially higher fatality rates, hospital admissions, and emergency department visits.

Gene Expression & the Environment It is generally understood that a complex

relationship exists between gene expressions and environmental interactions (Kleeberger & Peden, 2005) in respiratory diseases.

Goals of Genomics

Genetic linkages in studies that range from replicating one gene at a time to complex multi-variant studies conclude that over 25 asthma or allergy susceptible loci have been identified.

(Ober, 2005).

Goals of these studies:1) Identify susceptible individuals.2) Intervene before the onset of disease.3) Design drugs that are genospecific.

Gene Exposure Phenotype Comment Reference

LTC4S Aspirin Asthma 2 444C allele ↑ w/ aspirin induced asthma

Sanak et al.

ADRB 2 Cigarette smoke Asthma ↑ risk among smokers w/Arg16 genotype

Wang et al.

ADRB 2 Physical activity Asthma ↑ risk among sedentary women w/Gly16 genotype

Barr et al.

TIM 1 Hep A Atopy HAV protects against atopy

McIntire et al.

TLR 4 Endotoxins Asthma

↑ levels of endotoxins (carriers of Gly299 and Ille399) reduce risk of asthma

Werner et al.

CD 14 Dog ownership Atopic dermatitis (AD)

2 159TT genotype is protective against AD

Gern et al.

GSTM 1 Diesel exhaust IgE / histamine response

↑ response among GSTM 1 – null individuals

Gilliland et al.

GSTP 1 Diesel exhaust IgE / histamine response

↑ response among individuals w/ lle105 allele

Gilliland

NOS 3 Day-care changes in TH2

cytokine response in first yr. of life

↑ T H2 response in children not attending day care

Hofjan et al.

FCERB 1 Day-care IL5 response at 1 year

Gly237 associated w/ ↑ IL5 responsiveness for children not attending day care

Hofjan

IL4RA Day-care IFN-g response at 1 yr. of age

↑ Val50 homozygosity in children not attending day care

Hofjan

HLAG Maternal Bronchial hyperresponsiveness (BHR)

Asthma-BHR in child

964G allele is associated w/asthma is ↑ with mothers w/BHR

Nicolae et al.

The genotype effects at these loci were modified by the environment such that the same genotype was associated with protection from or risk for a phenotype depending upon an early life exposure.

(Ober, 2005).

Interaction between gene variants and environmental exposures hold great promise for developing new strategies for diagnosing, managing, and perhaps preventing or curing asthma.

-U of Washington: Center of Genomics and Public Health

Q: So, what do we do with this genetic information?

A: Develop protocols to address and participate in education, prevention and treatment strategies that minimize risk!

Family Health History

Knowing your family history can save your life!

-Dr. Richard Carmona, U.S. Surgeon General

10 Questions to ask your family at Thanksgiving

What traits seem to run in your family? Did any of my family have health problems? Were there any miscarriages? How old were my family members when

problems arose? How old were my family members when they

died? What were the reasons they died? Where were my family members born? Did any of my family members smoke? What other lifestyle habits did they have? What types of allergies, reactions to food or

medications did they have?

When or who should get a genetic consultation? Health problems that occur at an earlier

age. A health problem in more than one close

family member. A health problem that does not usually affect

a certain gender. Certain combinations of health problems

within a family. Birth defects, growth, or development

problems, pregnancy concerns, and other known genetic conditions in the family.

What will I learn?

Asses your risk for a health problem based on your family health history.

Diagnose a health problem and cause for it.

Decide if genetic testing is an option. Give you facts about treatment or

management of a problem. Refer you and your family members to

support groups and resources.

Where can I learn more?

Huntsman Cancer Institute, www.huntsmancancer.org.

Family Cancer Assessment Clinic, (801) 587-9555.

For other genetic questions, call (801) 585-0100 or toll-free at 866-275-0243.

Intermountain Healthcare, Clinical Genetics Institute

Genetic specialist, call (801) 408-5014. University of Utah Hospital

Genetic counseling and patient care issues, call (801) 581-8943.

References Barr, R.G., Cooper, D.M., Speizer, F.E., Drazen, J.M., Camargo, C.A., Jr. (2001). Beta(2)

adrenoceptor polymorphism and body mass index are associated with adult-onset asthma in sedentary but not active. Chest, 120, p. 1474-9.

Gern, J.E., Reardon, C.L., Hoffjan, S., Nicolae, D., Li, Z., Roberg, K.A., et al. (2004). Effects of dog ownership and genotype on immune development and atopy in infancy. Journal of Allergy and Clinical Immunology, 113, p. 307-14.

Gilliland, F.D., Li, Y.F., Saxon, A., Diaz-Sanchez, D. (2004). Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: Randomized, placebo-controlled crossover study. Lancet, 363, p. 119-25.

Hoffjan, S., Nicolae, D. Ostrovnaya, I., Roberg, K., Evans, M. Mirel, D,B., et al. (2005). Gene-environment interaction effects on the development of immune responses in the first year of life. American Journal of Human Genetics, 76, p. 696-704.

Kalb, C. (2006, Feb.). In our blood. Newsweek Magazine, p. 47 – 55.

Kleeberger, S.R. & Peden, D. (2005). Gene-environment interactions in asthma and other respiratory diseases. Annual Review of Medicine, 56, p. 383 – 400.

Marshall, R., Webb, S., Bellingham, G.J. et al. (2002). Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. American Journal of Respiratory Critical Care, 166, p. 646 – 50.

McIntire, J.J., Emetsu, S.E., Macaubas, C., Hoyte, E.G., Cinnioglu, C., Cavalli-Sforza, L.L.. et al. ( 2003). Immunology: Hepatitis A virus link to atopic disease. Nature, 425, p. 576.

Nicolae, D., Cox, N.J., Lester, L.A., Schneider, D. Tan, Z., et al. (2005). Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. American Journal of Human Genetics, 76, p. 349-57.

National Heart, Lung & Blood Institute. National asthma education and prevention program. http://www.nhbli.nih.gov/about/naep_pd.htm.

Ober, C. (2005). Perspectives on the past decade of asthma genetics. Journal of Allergy and Clinical Immunology, 116,(2), p. 274 – 278.

Sanak, M., Pierzchaiska, M., Bazan,-Socha, S. & Szczeklik, A. (2000). Enhanced expression of the leukotriene C(4) synthase due to overactive transcription of an allele variant associated with aspirin-intolerant asthma. American Journal of Respiratory Cell and Molecular Biology, 23, p. 290-6.

Utah Asthma Program, Bureau of Health Promotion (2005). Asthma Emergency Department Report. Salt Lake City, UT: Utah Department of Health.

Utah Department of Health. Make family health history a tradition. http://www.health.utah.gov/genomics.

Wang, Z., Chen, C., Niu, T., Yang, J., Wang, B., et al. (2001). Association of asthma with beta(2) adrenergic receptor gene polymorphism and cigarette smoking. American Journal of Respiratory and Critical Care Medicine, 163, p. 1404-9.

Weiss, K.B. & Sullivan, S.D. (2001). The health economics of asthma and rhinitis: Assessing the economic impact. Journal of Allergy & Clinical Immunology, 107,(1), p. 3-8.

Werner, M., Topp, R., Wimmer, K., Richter, K. Bischof, W., Wjst, M., et al. (2003). TLR4 gene variants modify exotoxin effects on asthma. Journal of Allergy and Immunology, 112, p. 323-30.

Thank You!

Utah Department of Health, Asthma Taskforce

Libbey Chuy, MPH, Health Program Specialist

Charrissa Wood, Program SpecialistJenny Johnson, CHES, Health Program

Specialist