Hi everyone my name is Sean and I will be talking about genetics and how it links to the respiratory illness, asthma.
So as most of you would know, asthma is caused by the inflammation of smooth muscles in the bronchial tube which leads to the narrowing of the airways. This narrowing of the airways then causes the observable symptoms of breathlessness and wheezing.
Research into asthma and how it is linked to genetic mutations was first proposed in the 1980s and 1990s and since then many genes had been identified as potential candidates for causing asthma. Through numerous studies and tests by many independent groups the locations of some of these genes have been found.
In 2007 research into asthma took a major step forward with the first ever genome wide association study (GWA). This study sequenced the genomes of 994 people with asthma and also 1243 people without asthma who were related to the asthma sufferers. So for example if a child was an asthma sufferer, his or her parents would also have had their genome sequence as well. From this study a gene located on chromosome 17q21 was found to be potentially linked to the onset of childhood asthma, as 62%, or 617 of the 994 asthmatics expressed this gene.
Continuing on from the GWA the specific gene was found to be ORMDL3. However now the issue was that at this point in 2007, the function of ORMDL3 still hadn’t been figured out. Further research by another group in 2009, found the ORMDL3 is a transmembrane protein which interacts with another pump called SERCA which controls calcium levels inside the cell. Calcium levels are important as it allows proteins in the endoplasmic reticulum of cells to fold properly and hence then allow them to function for other cellular processes.
From this paper it was furthermore discovered that the ORMDL3 gene in asthmatic was mutated which could be attributed to a person’s susceptibility to asthma. These mutations are called single nucleotide polymorphisms (SNPs) or called snips. These snips as you can see from this picture are simply single alterations in the coding sequence where one nucleotide has been replaced by another. Continuing research from the paper also showed that the ORMDL3 gene itself could have multiple snips, each snip is given a certain RS number to differentiate them.
One of the most studied snips is given the number RS7216389. This snip is a C/T polymorphism, so instead of having a cytosine and guanine base pair, it is replaced by a thymine and adenine base pair. This mutation affects how ORMDL3 works with the SERCA pump, and it has been found that it reduces the rate at which SERCA is able to operate at. This in turn means that the calcium levels in the cell fluctuate out their ideal levels and if the correct level isn’t re-established the proteins which are being folded can’t form their proper shapes and are ideally useless. This causes cells to be put under a large amount of stress and then lead to inflammation.
Asthma research is continuing and even more recent papers have found that some of the genes responsible for asthma are found in some races but not in others, further research is also occurring to see if certain combination of genes can definitely cause asthma, as most asthma sufferers have more than one gene present which contributes to their asthma susceptibility.