Western Australian Institute for Medical Research (WAIMR)


Lung Institute of Western Australia (LIWA)
Genetics Unit

The Genetics Unit of the Lung Institute of Western Australia (LIWA), moved into the WAIMR laboratories in 2002, and was established primarily to study associations between asthma and mutations in asthma candidate genes.

Research in the genetics unit focuses primarily on the genetics of asthma and allergy, but also includes other respiratory diseases such as emphysema and chronic bronchitis. As one of the Australian National Cooperative Research Centres for Asthma and Airways (CRCAA) our work is focused on improving the health of asthmatics through providing new and improved treatments and advanced diagnostic and monitoring tools. More specifically, we aim to identify changes in the DNA of candidate genes and identify whether they contribute towards the clinical features, onset and severity of these diseases.

The basis of our experimental approach is through association studies linking the incidence of a particular disease with changes in the DNA of genes previously shown to be involved in inflammation and tissue repair. When an association is found, functional studies are conducted to determine whether the change has a direct effect the on the gene and its mode of action with respect to disease. In all cases our studies rely on volunteer recruitment and the use of human material from both test cases and healthy controls.

LIWA Mission Statement - our philosophy is that everyone who comes into contact with the Institute should be better informed and healthier for the experience.

Research Details

The majority of respiratory diseases are mainly as a result of either lung hyper-inflammation or tissue remodelling. It is now widely accepted that airway inflammation is the key factor underlying the pathogenesis of asthma. Inhaled corticosteroids remain the most important anti-inflammatory treatment for asthma. However, they are rather non-specific in their actions and their use raises concerns over side effects and compliance issues, particularly in children and adolescents. Moreover, a significant sub-group of asthmatic patients responds poorly or not at all to high-dose inhaled or systemic steroid treatment. Therefore, much effort is being made to develop novel more specific and safer therapy for asthma.

Abnormal remodelling of the airway wall is a characteristic feature of chronic asthma and is a dynamic process involving extracellular matrix (ECM) production, its degradation and altered structure. In this regard, the matrix metalloproteinases (MMPs), a family of proteases that degrade components of the ECM, and their specific inhibitors known as tissue inhibitors of metalloproteinases (TIMPs), have both been shown to be particularly important in this process.

With this background in mind our genetic studies focus on genes associated with the arachidonic acid pathway investigating the regulation of recognised inflammatory related genes and the MMP and TIMP family of genes association with ECM remodelling in asthma phenotypes.

Association Studies

Several ongoing studies in the lab investigate the presence of single nucleotide polymorphisms (SNPs) identified within specific inflammatory and remodelling family of genes and their link with asthma and/or asthma severity. With the assistance of adult asthmatic volunteers we are building a resource which enables us to screen specific gene SNPs across the different asthma phenotypes and identify whether there are association patterns between them.

MMP-9 and TIMP-1 SNP analysis

Several SNPs have been described in both the MMP-9 and TIMP-1 genes. For the purpose of our initial investigation into the association between SNPs in these genes and asthma phenotypes, we selected four of the five coding region polymorphisms reported by NCBI (www.ncbi.nlm.nih.gov) in the TIMP-1 gene as these may alter interactions with MMP-9, and four polymorphisms in the MMP-9 gene including one in the coding region and three promoter polymorphisms, the latter of which may be involved in altered gene expression.

In summary, we investigated the association between a number of polymorphisms in both MMP-9 and TIMP-1 genes and asthma, asthma severity and atopy using a large, carefully phenotyped white Australian population. Results from this study show that four MMP-9 and TIMP-1 polymorphisms were not associated with asthma, but a novel polymorphism in the TIMP-1 gene (536C.T (Ile158Ile)) was significantly associated with mild asthma in women and TIMP-1 haplotypes were also associated with asthma. The functional significance of the 536C.T polymorphism has still to be determined, but its association with asthma severity highlights the potential importance of proteases and antiproteases in this socioeconomically important disease. (Ref: Thorax. 2005 Aug; 60(8):623-8.)

We are continuing to investigate other SNPs within the tissue remodelling MMP family of genes in our asthma population in an effort to find candidates for improved drug therapy.

Alternative Splicing

In addition to the SNP association approach towards investigating genetic influences in respiratory disease, we have chosen several candidate genes to study the influence of aberrant spliced gene products in relation to asthma and airway disease. This recent advance is in its early stages, however we are hopeful results will provide additional opportunities for the design of new therapies for respiratory disease.

Education Outreach

The Genetics Unit has continued to place an emphasis on science education for high school students in 2006. We are currently formally involved with 4 science education programs and have held 5 workshops including 3 work experience students for 40 hours each this year. The enthusiasm and appreciation shown by the students is testament to the perceived benefits gained. We have also maintained contact with several of these students and continue to play a supportive mentoring role as they progress in to the tertiary education setting.

Through this series of outreach programs we aim to inspire our next generation of medical scientists and increase community awareness of the importance of the research done here at LIWA.

CRC Asthma and Airways 2005-2011 - The genetics unit is one of 7 nodes of the Cooperative Research Centre for Asthma and Airway disease, a Commonwealth Government funded initiative to support the development of new diagnostic tests and novel treatment for asthma and airways disease.

State Wide High School Student Workshops
WorkshopNumber of StudentsGrade
Lesmurdie30Yr 10
Double helix (SciTech/CSIRO)8
CRCAA/LIWA Annual High School Workshop11Yr 10-12
SRS CSIRO Work Experience (40 hrs)2Yr 10
Structured Workplace learning Work Experience1Yr 11

Notable Publications

  1. Kedda MA, Duffy DL, Bradley B, O'Hehir RE, Thompson PJ. 2006. ADAM33 haplotypes are associated with asthma in a large Australian population. European Journal of Human Genetics 14(9):1027-36. [NCBI PubMed Entry]
  2. Lose F, Thompson PJ, Duffy D, Stewart GA, Kedda MA. 2005. A novel tissue inhibitor of metalloproteinase-1 (TIMP-1) polymorphism associated with asthma in Australian women. Thorax 60(8):623-8. [NCBI PubMed Entry]
  3. Shi J, Misso NL, Duffy DL, Bradley B, Beard R, Thompson PJ, Kedda MA. 2005. Cyclooxygenase-1 gene polymorphisms in patients with different asthma phenotypes and atopy. The European Respiratory Journal 26(2):249-56. [NCBI PubMed Entry]
  4. Kedda MA, Worsley P, Shi J, Phelps S, Duffy D, Thompson PJ. 2005. Polymorphisms in the 5-lipoxygenase activating protein (ALOX5AP) gene are not associated with asthma in an Australian population. Clinical and Experimental Allergy 35(3):332-8. [NCBI PubMed Entry]
  5. Akesson LS, Duffy DL, Phelps SC, Thompson PJ, Kedda MA. 2005. A polymorphism in the promoter region of the human interleukin-16 gene is not associated with asthma or atopy in an Australian population. Clinical and Experimental Allergy 35(3):327-31. [NCBI PubMed Entry]
  6. Kedda MA, Lose F, Duffy D, Bell E, Thompson PJ, Upham J. 2005. The CD14 C-159T polymorphism is not associated with asthma or asthma severity in an Australian adult population. Thorax 60(3):211-4. [NCBI PubMed Entry]
  7. Shi J, Misso NL, Duffy DL, Thompson PJ, Kedda MA. 2004. A functional polymorphism in the promoter region of the cyclooxygenase-2 gene is not associated with asthma and atopy in an Australian population. Clinical and Experimental Allergy 34(11):1714-8. [NCBI PubMed Entry]
  8. Kedda MA, Shi J, Duffy D, Phelps S, Yang I, O'Hara K, Fong K, Thompson PJ. 2004. Characterization of two polymorphisms in the leukotriene C4 synthase gene in an Australian population of subjects with mild, moderate, and severe asthma. The Journal of Allergy and Clinical Immunology 113(5):889-95. [NCBI PubMed Entry]
  9. O'Hara KA, Kedda MA, Thompson PJ, Knight DA. 2003. Oncostatin M: an interleukin-6-like cytokine relevant to airway remodelling and the pathogenesis of asthma. Clinical and Experimental Allergy 33(8):1026-32. [NCBI PubMed Entry]