THE ROLE OF GENE-ENVIRONMENT INTERACTIONS
purely on population stratification, which can result from incomplete matching between cases and controls—including differences in ethnicity. No association studies in COPD have been re- ported which used family-based controls, a study design which is immune to such population strati- fication effects. More importantly, no linkage studies have been published in COPD to iden- tify regions of the genome which are likely to contain COPD susceptibility genes—regions in which association studies are likely to be more productive (Walter et al. 2000).
Despite the high prevalence of and mortality from COPD, extensive research on the underly- ing pathophysiology and specific therapeutics for this disease is, relatively, in its infancy. Sev- eral novel molecular targets are being investi- gated as potential treatments for the disease (Hay 2001). The most exciting new class of compounds is the phosphodiesterase 4 inhibitors; Ariflo (SB 207499)-a member of this class, and the most ad- vanced in development (Phase III)-was reported recently to have significant clinical efficacy in patients with chronic obstructive pulmonary dis- ease (Barnes 2001; Huang et al. 2001).
can also eventually damage lung tissue if not neutralized by AAT. If allowed to progress, this form of emphysema becomes chronic and lung tissue continues to be destroyed; eventually it is fatal if the progress is not slowed down or halted. While there are different causes of em- physema (such as smoking andAAT deficiency), the physical signs and symptoms in each case are similar.
AATD related emphysema is caused by an inherited lack of a protective protein called al- pha1-antitrypsin (AAT). Every person inherits two AAT genes, one from each parent. A person has AAT deficiency only if he or she inherits two abnormal genes. People who have only one abnormal gene and one normal AAT gene are “carriers” and do not have the disease. Their AAT levels may be lower than normal, but not as low as the deficiency state and are not generally thought to cause significant health problems. People who have AAT deficiency will pass on one abnormal gene to their children, but they will be “carriers” and will not have AAT deficiency. There is a test for determining if a person is a carrier or is AAT deficient.
Emphysema can best be characterized as the progressive destruction of the grape-like sacs that fulfill the lung’s basic function: exchanging oxygen in the air for carbon dioxide in the cardio- vascular system. Emphysema is the chief “cul- prit” in COPD. Emphysema begins with the de- struction of alveoli, small sac-like structures (re- sembling bunches of grapes) in the lungs where oxygen from the air is exchanged for carbon di- oxide in the blood. The walls of the alveoli are thin and fragile, and are easily damaged. The damage is irreversible and results in permanent “holes” in the tissues of the lower lungs. As alveoli are destroyed, the lungs are able to transfer less and less oxygen to the blood- stream,causing shortness of breath during exer- cise and eventually even at rest. The lungs also lose their elasticity, so the patient experiences great difficulty exhaling. The bronchial tubes lead- ing to the air sacs may collapse, which traps air in the lungs. This is the condition known as em- physema.
The marked variability in the development of COPD in response to cigarette smoking has been known for decades, but severe AAT deficiency (PI Z allele) remains the only proven genetic risk factor for COPD (Sigsgaard et al. 2000).With ciga- rette smoking, PI Z subjects tend to develop more severe pulmonary impairment at an earlier age than non-smoking PI Z individuals. However, PI Z individuals exhibit wide variability in pulmo- nary function impairment, even among individu- als with similar smoking histories. Therefore, other genes and environmental exposures are also likely involved.
Chronic bronchitis is a first step toward im-
pending emphysema/COPD. It often results from ordinary chest infections (colds, flu). Folks with „„ h i b hi i k h l c ron c ronc t s now t at every, or near y every, cold they get will “go straight to the lungs”. With proper care it need not lead to COPD; (2) in a COPD patient chronic bronchitis contrib-
utes to the gunk that we spit up regularly.
„ „ r o n i c a s t h m a i s t h e t h i r d
c o n s t i t u e n t o
Role of Alpha 1-Antitrypsin Deficiency (AATD) in Emphysema
In normal and healthy individuals, AAT pro- tects the lungs from a natural enzyme (called neu- trophil elastase) that helps fight bacteria and clean up dead lung tissue. However, this enzyme
COPD. Not all COPD patients have asthma, and most certainly most asthma patients do not have COPD. But many of us suffer from it greatly. Al- ready sick, our airways are easily constricted by all manner of airborne nasties. It is why we carry our inhalers. Some authorities do not consider asthma a component of COPD because unlike emphysema and chronic bronchitis, asthma can