An Investigation of the Role of the Innate Immune Response in Kawasaki Disease

Investigator: Neil Edward Bowles, M.D.

Location: University of Utah School of Medicine, Salt Lake City, Utah

Timeline: January 1, 2008 - December 31, 2008

Abstract:  Kawasaki disease (KD) is the most common systemic vasculitis syndrome particularly affecting the coronary artery, but the etiology remains unknown. It is widely believed that KD is due to one or more common infectious agent(s), which evoke an abnormal immunological response in genetically susceptible individuals. Most patients respond to treatment, although 25-45% will develop coronary artery lesions (CAL). The role of the innate immune response has been widely investigated in a number of infectious diseases, with data showing that variants (mutations or polymorphisms) in genes encoding proteins of innate immune response signaling pathways can result in worse outcomes following infections with bacteria or viruses. We hypothesize that variations in genes encoding proteins involved in the innate immune response will be associated with the development of KD and/or with the development of CAL. In order to test this hypothesis we propose the following aims.

1)         To enroll patients with KD (with or without CAL), collect blood samples and isolate DNA for genetic analyses.

2)         To use Taqman technology to determine the frequency of non-synonymous single nucleotide polymorphisms (SNPs) in genes encoding proteins of the innate immune response The frequency of SNPs in patients with and without CAL will be compared with the frequencies in the normal population.

3)         To perform mutation analysis of a group of these genes by analysis of amplified gene products using Lightscanner technology and direct DNA sequencing.

            Identification of defects in these signaling pathways could be significant. In the era of pharmacogenetics, interventions tailored to bolster the innate immune response may offer novel therapeutic options for the treatment of KD-associated vasculitis. Identifying variations in a specific component could also shed light on the etiologies of KD, since variations in TLR2 would implicate bacteria, while variations in TLR3 would implicate RNA viruses.

Lay Person Summary:  Kawasaki disease (KD) is a common disease in children, who experience a fever for more than 5 days, along with other symptoms, including swelling and rashes.  While most children recover after treatment, up to 20% will develop problems in the blood vessels of their hearts. It is believed that KD is caused by infection with an unknown virus or bacteria. It also appears that some people are more susceptible to develop KD and heart problems.  This is probably because they have changes in genes which make key proteins that protect them from bacterial or viral infections. We believe that changes in the proteins that are involved in the initial defense of the body against bacteria and viruses may cause these individuals to be at greater risk.  To investigate this we propose to collect blood samples from KD patients and to isolate DNA, which is the chemical that makes up genes.  We will look for changes in the DNA structure (known as the DNA or gene sequence).  Initially, we will look for changes that are already known to exist in some people to see if these changes occur more frequently in KD patients than in normal people. Then we will investigate some of these genes in detail to look for changes that have not been seen before and that do not occur in normal people. If we find any changes this may mean that the protein made by this gene is important in protecting people against the virus or bacteria that causes KD. In the future, these studies may allow us to identify which individuals are more likely to develop KD, which KD patients are more likely to develop heart problems, and could provide clues as to which viruses or bacteria cause KD.