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

Kuo HC, Chang JC, Guo MM, Hsieh KS, Yeter D, Li SC, Yang KD - PLoS ONE (2015)

Bottom Line: 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).Our results suggest varying gene-gene associations respectively predispose individuals to KD risk or its complications of CAL.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.

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.

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Comparison cytokines levels between KD patients with high-risk genotypes and low-risk genotypes.KD patients possessing the high-risk (KD risk: 1) PDE2A (rs341058) and CYFIP2 (rs767007) genotypes of KD susceptibility (n = 49) presented with significantly lower plasma levels of TGF-β1 (9489 ± 1605 vs. 16133 ± 3015) compared to KD patients in the low-risk group (KD risk: 0, n = 24), with an odds ratio of 0.59 (p = 0.036). (A) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IL-2 (14.1 ± 1.6 vs. 9.6 ± 1.2) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 1.47 (p = 0.028). (B) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IL-6 (51.0 ± 14.3 vs. 18.4 ± 3.7) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 2.77 (p = 0.033). (C) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IFN-γ (119.2 ± 15.2 vs. 81.8 ± 10.1) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 1.46 (p = 0.041). (D).
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pone.0143056.g003: Comparison cytokines levels between KD patients with high-risk genotypes and low-risk genotypes.KD patients possessing the high-risk (KD risk: 1) PDE2A (rs341058) and CYFIP2 (rs767007) genotypes of KD susceptibility (n = 49) presented with significantly lower plasma levels of TGF-β1 (9489 ± 1605 vs. 16133 ± 3015) compared to KD patients in the low-risk group (KD risk: 0, n = 24), with an odds ratio of 0.59 (p = 0.036). (A) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IL-2 (14.1 ± 1.6 vs. 9.6 ± 1.2) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 1.47 (p = 0.028). (B) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IL-6 (51.0 ± 14.3 vs. 18.4 ± 3.7) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 2.77 (p = 0.033). (C) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IFN-γ (119.2 ± 15.2 vs. 81.8 ± 10.1) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 1.46 (p = 0.041). (D).

Mentions: High-risk allele combinations of the PDE2A and CYFIP2 SNPs accounted for 67.1% of our KD cases. As shown in Fig 3A, we observed that these high-risk genotypes in KD patients were significantly associated with reduced plasma levels of TGF-β1 (9489 ± 1605 vs. 16133 ± 3015 pg/ml; p = 0.036) compared to KD patients in the low-risk group. High-risk allele combinations of the LOC100133214 and IL2RA SNPs accounted for 47.9% of our KD cases. We found significantly elevated plasma levels of interleukin (IL)-2 (14.1 ± 1.6 vs. 9.6 ± 1.2 pg/ml; p = 0.028), IL-6 (51.0 ± 14.3 vs. 18.4 ± 3.7 pg/ml; p = 0.033), and Interferon-γ (119.2 ± 15.2 vs. 81.8 ± 10.1 pg/ml; p = 0.041) in KD patients with the high-risk genotypes of CAL formation compared to KD patients in the low-risk CAL formation genotype group, as shown in Fig 3B, 3C and 3D. No significant differences were found between high- and low-risk genotypes in KD patients with levels of IL-3, IL-4, IL-5, IL-10, or IL-17A.


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

Kuo HC, Chang JC, Guo MM, Hsieh KS, Yeter D, Li SC, Yang KD - PLoS ONE (2015)

Comparison cytokines levels between KD patients with high-risk genotypes and low-risk genotypes.KD patients possessing the high-risk (KD risk: 1) PDE2A (rs341058) and CYFIP2 (rs767007) genotypes of KD susceptibility (n = 49) presented with significantly lower plasma levels of TGF-β1 (9489 ± 1605 vs. 16133 ± 3015) compared to KD patients in the low-risk group (KD risk: 0, n = 24), with an odds ratio of 0.59 (p = 0.036). (A) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IL-2 (14.1 ± 1.6 vs. 9.6 ± 1.2) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 1.47 (p = 0.028). (B) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IL-6 (51.0 ± 14.3 vs. 18.4 ± 3.7) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 2.77 (p = 0.033). (C) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IFN-γ (119.2 ± 15.2 vs. 81.8 ± 10.1) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 1.46 (p = 0.041). (D).
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pone.0143056.g003: Comparison cytokines levels between KD patients with high-risk genotypes and low-risk genotypes.KD patients possessing the high-risk (KD risk: 1) PDE2A (rs341058) and CYFIP2 (rs767007) genotypes of KD susceptibility (n = 49) presented with significantly lower plasma levels of TGF-β1 (9489 ± 1605 vs. 16133 ± 3015) compared to KD patients in the low-risk group (KD risk: 0, n = 24), with an odds ratio of 0.59 (p = 0.036). (A) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IL-2 (14.1 ± 1.6 vs. 9.6 ± 1.2) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 1.47 (p = 0.028). (B) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IL-6 (51.0 ± 14.3 vs. 18.4 ± 3.7) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 2.77 (p = 0.033). (C) KD patients possessing the high-risk LOC100133214 (rs2517892) and IL2RA (rs3118470) genotypes of CAL formation (CAL risk: 1, n = 35) presented with significantly elevated plasma levels of IFN-γ (119.2 ± 15.2 vs. 81.8 ± 10.1) compared to KD patients in the low-risk group (CAL risk: 0, n = 38), with an odds ratio of 1.46 (p = 0.041). (D).
Mentions: High-risk allele combinations of the PDE2A and CYFIP2 SNPs accounted for 67.1% of our KD cases. As shown in Fig 3A, we observed that these high-risk genotypes in KD patients were significantly associated with reduced plasma levels of TGF-β1 (9489 ± 1605 vs. 16133 ± 3015 pg/ml; p = 0.036) compared to KD patients in the low-risk group. High-risk allele combinations of the LOC100133214 and IL2RA SNPs accounted for 47.9% of our KD cases. We found significantly elevated plasma levels of interleukin (IL)-2 (14.1 ± 1.6 vs. 9.6 ± 1.2 pg/ml; p = 0.028), IL-6 (51.0 ± 14.3 vs. 18.4 ± 3.7 pg/ml; p = 0.033), and Interferon-γ (119.2 ± 15.2 vs. 81.8 ± 10.1 pg/ml; p = 0.041) in KD patients with the high-risk genotypes of CAL formation compared to KD patients in the low-risk CAL formation genotype group, as shown in Fig 3B, 3C and 3D. No significant differences were found between high- and low-risk genotypes in KD patients with levels of IL-3, IL-4, IL-5, IL-10, or IL-17A.

Bottom Line: 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).Our results suggest varying gene-gene associations respectively predispose individuals to KD risk or its complications of CAL.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.

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.

Show MeSH
Related in: MedlinePlus