COPD Genetics

Overview

Many factors can contribute to the occurrence of COPD. While cigarette smoking is the number one risk factor in the development of COPD, recent research has pointed to the notion that genes may also play a significant role and could be responsible for why some people who smoke will develop COPD while others will not. COPD may be influenced by race, ethnicity, gender, and other genetic factors not yet known. The marked variability in lung function and risk of COPD in people with similar cigarette smoking histories, together with studies of familial aggregation, support an important role for genetics in COPD.

The graph above illustrates variation in COPD self-reported in the United States across race and gender, 1980-2000. The prevalence of COPD based on self-reports of emphysema or chronic bronchitis has generally been higher among whites and women.

A small but important fraction of COPD cases harbor a major genetic determinant, α1-antitrypsin deficiency (AATD). This condition is most common in populations of Northern European ancestry, although affected individuals in other populations can be found. Despite significant advancements in diagnosis and treatment, AATD remains highly under diagnosed.

Other genetic determinants of COPD have been more difficult to establish, as has been the case for many complex diseases

Performing a Genetic Study

In general, doing scientific research involves the use of multiple tools and techniques in order to find out information. Researchers employ different methods to conduct a study depending on what is being studied and what type of information is being sought. At the COPDGene® Study, we are looking for genes that might be involved in the development and disease progression of COPD. Finding genes that are associated with a disease is a very tedious and difficult process, and one that involves many steps.

The COPDGene® Study is a type of epidemiological study, called a genetic epidemiology study. Epidemiological research looks at a large population of individuals and tries to understand a disease process within that population. A genetic epidemiological study looks for genes that are suspected to be involved in a disease process for a population. The general goal of a genetic epidemiological study is to identify genes that affect the health and wellness of population.

Conducting a genetic epidemiological study like COPDGene® requires following a well-defined research method that will help reduce the collection of irrelevant or false data. The general method used in COPDGene® is outlined below.

1. Identify a population

When scientists attempt to look for genes that are associated with a particular trait, they first have to choose a population that expresses that trait. In order to do this, a population must be chosen that uniquely fits a physical or behavioral model that will help separate a population into groups that share more traits in common. For instance, men and women are often separated into two populations or groups in a study because of differences in physiological traits. People from different ethnic and racial backgrounds are also often studied as unique groups as some genes may be exclusively expressed for these groups. For instance, people of Northern European decent tend to carry the gene for alpha1-antitrypsin disorder more commonly than people from other racial groups.

Most studies need at least two distinct populations in order to conduct a study; a control group and a study group. A control group is chosen to serve as a ‘normal' or unchanged population where the study group is the population that shares a particular trait or feature of interest that is being studied. For instance, if a researcher wanted to understand how smoking affects the lungs, they would study the lungs of a group of smokers and the lungs of non-smokers and looking for differences between the two groups. In a genetic study, researchers look for people who share certain disease features and try to find genes that are common to that group but that may not be found in the general population. The traits that are used to collect a study group have been carefully selected and will help narrow the genetic diversity of the population, thus making finding genetic similarities more likely. The COPDGene® Study looks for people with specific smoking histories, age, race, gender, lung health, and several other factors. By gathering a specific population, genes that may be associated with a disease can be more easily found.

2. Measure the population

The next step after finding a group of people that fit a specified criteria is to measure them. Taking measurements will helps to further define a population and help to outline the specific traits and features that they share. In COPDGene®, measurements that relate to COPD, lung health, and general physical health are taken. These measurements can then be used to assess the severity of disease and begin to place study participants into smaller groups based on their lung health. At a COPDGene® Study visit, a CT scan is preformed to get a visual assessment of lung disease, a walk test is performed, spirometry data is collected, medical history is recorded, and blood is taken. The blood samples are used to extract DNA and look for genes.

Each of the measurements taken will help scientists see correlations between factors and draw conclusions about disease states. For instance, by measuring how much people smoke and the health of their lungs, it has been concluded that people who smoke cigarettes have a higher risk of developing a lung disease than non-smokers.

3. Look for genetic similarities

The next step in a genetic epidemiology study is to look for shared genes within the study population. This is no doubt the most difficult and tedious aspect of a genetic study and requires the aid of biostatisticians and molecular geneticists to find genetic trends. Most genes associated with diseases are not easy to find because each gene may only contribute a portion of the total genetic component of a disease. Unlike more clear-cut genes with one primary gene responsible for a trait (like those that are responsible for eye color or blood type), many disease-related genes contain multiple parts that function together to create a complex array of physiological processes leading to disease. Finding all the parts and assessing their importance with respect to the disease is difficult and often does not produce definitive results.

Further complicating matters is the problem of genes interacting with the environment which may change which genes are expressed. ‘The environment' refers to factors that a person is exposed to outside of their physical body that can change the way the body functions. For instance, if genetic factors are found for COPD, simply having the genes may not be enough to develop the disease. Smoking cigarettes however could interact with the COPD genes potentially causing COPD.

The way in which the COPDGene® Study looks for genes within the study population is though the use of a Genetic Wide Association Study, or GWAS for short. A genome-wide association study is a scientific approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease. GWAS studies are often used as a tool to find genes involved in complex diseases such as COPD, heart disease, and cancer. For more information on GWAS studies click here.

4. Make conclusions

After all the information is collected, scientists begin to make conclusions about what was found. In a genetics study, this often involves making conclusions about trends seen in the data. Discovering a trend or an association of a gene with a particular disease or eveen on easpect of a disease does not however mean that every individual that has that gene will develop the disease. This is where the idea of ‘risk factors' come into play. Say for instance, a random group of 100 people are studied for geneic similarities and it is found that 50 of the people studies have a particular set of genes in common. Of those 50 people, 40 also have COPD. The conclusion one might make is that these particular genes may be associated with COPD, though it could not be said that they difinitively cause COPD as 10 people in the group who have the genes do not have COPD. Drawing conclusions about genetic similarities works in the same way; genes are often assocaited with a disease but do not always absolutely cause it.

So what accounts for the differences then? While it is not completely understood why some people with a disease associated gene will get a disease when others may not, it is widely accepted that environmental factors play an important role. The process of genetic and environmental risk factors working together to cause an outcom is commonly reffered to as the gene-environment interaction. In short, genes may set the stage for a disease to occur, but only through environmental exposures acting in concert with the genes will a disease actually manafest.

Known Genetic Factors realted to COPD

Alpha1-antitrypsin defeciency is the most common and well understood genetic factor related to COPD. While other genetic factors that may contribute to COPD have been identified, the exact nature of their contributions are not clear. For a complete list and discussion of other genetic factors that have been identified along with their relationship to COPD, click here.