A Genetic Clue into Asthma

A Small Change on Chromosome 17 Increases Asthma Risk by up to 2.3-fold

by George Wang, Stanford University

1 in 10 people in the U.S. suffers from asthma and it's on the rise. Some reports say up to 1 in 4 urban children have asthma.

Anyone who has ever seen an asthma attack knows how awful it is to see someone struggling to breathe. But the concern goes beyond personal discomfort.

Asthma attacks result in missed school and work. Plus severe cases can be life threatening.

Because of asthma's significance, scientists are trying to find its causes. One place they are looking is asthmatics' DNA. By comparing their DNA to the DNA of people without asthma, scientists, in a new study, were able to find a bit of DNA that increases someone's risk for developing asthma up to 2.3 times.

This means this part of DNA may play a role in asthma. Interestingly, it only affects people that get asthma before the age of 4. And the risk is even higher for these children if their parents smoke.

How to Find DNA Involved in a Trait or Disease

Geneticists found differences
between the genomes
of asthmatics and
non-asthmatics.

DNA is the instruction manual for life. It has the instructions for making someone who they are. How someone looks is in their DNA. As is their risk for developing diseases like cancer or asthma.

These instructions are written using only four letters—A, T, G, and C. The letters are strung together in a certain order that is called the human genome.

Everyone's genome has these letters arranged a bit differently. This is where all the wonderful diversity around us comes from. Including our risk for some diseases.

The human genome is made up of 3 billion letters. Most of the letters between humans are the same. But on average, there is a difference every 1,200 letters or so. These differences are called single nucleotide polymorphisms or SNPs.

For example whether or not someone thinks broccoli is bitter is the result of one of these SNPs. This difference in taste is due to a letter change from A to G at one certain spot in the DNA. In other words, one letter difference out of 3 billion makes some people think broccoli tastes bitter.

Bitter tasters have an A and non-tasters have a G at a certain spot in their DNA. How did scientists find this out?

First they gathered two groups of people. They split them up into tasters and non-tasters. The scientists made sure the two groups were big so the only similarity within each group was whether they could taste or not.

They looked at the genomes of every person.* They found many differences between them, which was expected.

Most of these differences didn't follow a pattern. In other words, most differences could be found in people in both groups.

But the scientists did find a SNP that was only in non-tasters. Tasters only had an A there and non-tasters only had a G there. Further testing confirmed that this was the critical difference between the two groups.

*Sequencing an entire genome would be expensive. And since most of the 3 billion letters are the same also a waste. Instead scientists just sequence the known differences between humans.

Finding Asthma DNA

The asthma study used the same strategy. The scientists looked at about 1,500 people from 400 families that lived in five French cities. The patients were placed into two groups: asthmatics and non-asthmatics.

The researchers compared the two groups' genomes and found 4 significant SNPs. Asthmatics tended to have CGCC and non-asthmatics had TATT at a certain position in their genome.

But the results weren't perfect. There were many cases of people without asthma who had the CGCC. So the scientists decided to dig a bit deeper.

The scientists looked more closely at the groups of people and found two more results. One was that having CGCC plays a role only in asthma before the age of 4. The second finding was that if a child's parents smoked, then that child was at an even greater risk of getting asthma if they also had CGCC.

The conclusion was that a person with CGCC was 1.7 times more likely to have asthma. The other result was that asthma risk increased to 2.3 times if they had parents that smoked.

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The Asthma Region is on Chromosome 17

A SNP on chromosome 17
can increase someone's
risk for developing asthma.

Human DNA is organized in 23 parts. Each part is called a chromosome and every chromosome comes as a pair. The exception is the sex chromosomes where males have an X paired with a Y.

Every chromosome is made up of a long string of connected DNA letters. The 4 asthma SNPs are all in the same region on chromosome 17. This result means that something in this region most likely plays a role in asthma.

Knowing that a SNP correlates with asthma means that people can find out if they are at a higher risk for asthma. This could be helpful because there are certain things people can do to lower their risk of asthma.

Even better though is the potential for finding a cure for asthma with these SNPs.

How a SNP Can Lead to a Cure

The human genome is the instruction manual for a human being. The manual has about 20,000 instructions that are called genes. These genes are typically a few hundred to a few thousand DNA letters long.

Each gene tells the body how to make a different protein. And it's these thousands of proteins that are the molecular machines in the body.

Certain proteins are important, for example, in order to feel hot and cold. Other proteins are what allow the immune system to fight off germs. And other proteins are what make muscles contract.

Some people have slightly different instructions in their genes because of certain SNPs*. Sometimes this can cause a molecular machine to act differently.

For example, the change might make a protein that overreacts to something resulting in an allergy. Or a change might make someone's blood less able to carry oxygen.

In this study the scientists were able to narrow down the increased risk for asthma down to 4 genes. Two of these genes, GSDML and ORMDL3, have interesting connections with asthma. GSDML may play a role in making the tissues of the lung. And ORMDL3 may be involved in respiratory infections, which lead to increased risk for asthma.

Now scientists can study these genes to see which is responsible for the increased asthma risk. Once they've figured that out, then they can try to use that knowledge to find a better asthma treatment.

For example, they may be able to make that protein in a lab and give it to the patients. Or after knowing what that protein does they can give patients a drug that mimics the protein's job. Or a drug that makes the protein behave correctly. Or...

There is hope for new asthma drugs in the future.

*Since most of the DNA in the human genome does not belong to a gene, many mutations don't matter. Moreover not all changes to genes mean a non-working protein.

George Wang

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Content provided by the Department of Genetics, Stanford University.