Gene-Gene Associations with the Susceptibility of Kawasaki Disease and Coronary Artery Lesions.

Ho-Chang Kuo,Kuender D Yang,Sung-Chou Li,Deniz Yeter,Mindy Ming-Huey Guo,Jen-Chieh Chang,Kai-Sheng Hsieh,Weili Zhang

doi:10.1371/journal.pone.0143056

Abstract

Kawasaki disease (KD) is a systemic vasculitis primarily affecting children < 5 years old. Genes significantly associated with KD mostly involve cardiovascular, immune, and inflammatory responses. Recent studies have observed stronger associations for KD risk with multiple genes compared to individual genes. Therefore, we investigated whether gene combinations influenced KD susceptibility or coronary artery lesion (CAL) formation. We examined 384 single-nucleotide polymorphisms (SNPs) for 159 immune-related candidate genes in DNA samples from KD patients with CAL (n = 73), KD patients without CAL (n = 153), and cohort controls (n = 575). Individual SNPs were first assessed by univariate analysis (UVA) and multivariate analysis (MVA). We used multifactor dimensionality reduction (MDR) to examine individual SNPs in one-, two-, and three-locus best fit models. UVA identified 53 individual SNPs that were significantly associated with KD risk or CAL formation (p < 0.10), while 35 individual SNPs were significantly associated using MVA (p ≤ 0.05). Significant associations in MDR analysis were only observed for the two-locus models after permutation testing (p ≤ 0.05). In logistic regression, combined possession of PDE2A (rs341058) and CYFIP2 (rs767007) significantly increased KD susceptibility (OR = 3.54; p = 4.14 x 10−7), while combinations of LOC100133214 (rs2517892) and IL2RA (rs3118470) significantly increased the risk of CAL in KD patients (OR = 5.35; p = 7.46 x 10−5). Our results suggest varying gene-gene associations respectively predispose individuals to KD risk or its complications of CAL.

Highlights

Kawasaki disease (KD) is an acute febrile illness that predominately affects children under 5 years of age
We identified 22 individual single-nucleotide polymorphisms (SNPs) for 21 genes that were significantly associated with coronary artery lesions (CAL) formation in KD patients using univariate analysis (UVA) (p < 0.10), as shown in S3 Table
This method of multifactor dimensionality reduction (MDR) analysis is able to identify a high order of evidence for gene-gene interactions in diseases when there is a lack of any primary individual genes that influence susceptibility [21], including autoimmune disorders and certain malignancies[22]

Summary

Introduction

Kawasaki disease (KD) is an acute febrile illness that predominately affects children under 5 years of age. KD is characterized by the development of an autoimmune-like vasculitis involving the small- to medium-sized arteries, and has a predilection for the coronary arteries. Up to 25 to 30% of untreated KD patients develop coronary artery lesions (CAL) including coronary artery dilation, aneurysms, or fistula formation. Prompt detection of acute KD is crucial and must be followed by timely treatment before the 10th day after disease onset, as delayed treatment with intravenous immunoglobulin (IVIG) is significantly associated with an increased risk of CAL formation in KD patients. Approximately 10% of all KD patients do not respond to IVIG treatment, which is significantly associated with a higher risk of CAL formation[3]

Methods

Results

Conclusion