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Identification of LEF1 as a Susceptibility Locus for Kawasaki Disease in Patients Younger than 6 Months of Age.

ABSTRACT: Kawasaki disease (KD) is an acute febrile vasculitis predominately affecting infants and children. The dominant incidence age of KD is from 6 months to 5 years of age, and the incidence is unusual in those younger than 6 months and older than 5 years of age. We tried to identify genetic variants specifically associated with KD in patients younger than 6 months or older than 5 years of age. We performed an age-stratified genome-wide association study using the Illumina HumanOmni1-Quad BeadChip data (296 cases vs. 1,000 controls) and a replication study (1,360 cases vs. 3,553 controls) in the Korean population. Among 26 candidate single nucleotide polymorphisms (SNPs) tested in replication study, only a rare nonsynonymous SNP (rs4365796: c.1106C?T, p.Thr369Met) in the lymphoid enhancer binding factor 1 (LEF1) gene was very significantly associated with KD in patients younger than 6 months of age (odds ratio [OR], 3.07; pcombined = 1.10 × 10-5), whereas no association of the same SNP was observed in any other age group of KD patients. The same SNP (rs4365796) in the LEF1 gene showed the same direction of risk effect in Japanese KD patients younger than 6 months of age, although the effect was not statistically significant (OR, 1.42; p = 0.397). This result indicates that the LEF1 gene may play an important role as a susceptibility gene specifically affecting KD patients younger than 6 months of age.

SUBMITTER: Kim HJ

PROVIDER: S-EPMC6187808 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Identification of LEF1 as a Susceptibility Locus for Kawasaki Disease in Patients Younger than 6 Months of Age.

Kim Hea-Ji HJ Yun Sin Weon SW Yu Jeong Jin JJ Yoon Kyung Lim KL Lee Kyung-Yil KY Kil Hong-Ryang HR Kim Gi Beom GB Han Myung-Ki MK Song Min Seob MS Lee Hyoung Doo HD Ha Kee Soo KS Sohn Sejung S Ebata Ryota R Hamada Hiromichi H Suzuki Hiroyuki H Kamatani Yoichiro Y Kubo Michiaki M Ito Kaoru K Onouchi Yoshihiro Y Hong Young Mi YM Jang Gi Young GY Lee Jong-Keuk JK

Genomics & informatics 20180630 2

Kawasaki disease (KD) is an acute febrile vasculitis predominately affecting infants and children. The dominant incidence age of KD is from 6 months to 5 years of age, and the incidence is unusual in those younger than 6 months and older than 5 years of age. We tried to identify genetic variants specifically associated with KD in patients younger than 6 months or older than 5 years of age. We performed an age-stratified genome-wide association study using the Illumina HumanOmni1-Quad BeadChip da ...[more]

PMID: 30304924

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Project description:BackgroundKawasaki disease (KD) is a systematic vasculitis that occurs predominantly in young children, and is the leading cause of acquired heart disease in children younger than five-years-old in developed countries. Although the etiology of KD is unknown, it is believed to be an inflammatory disease resulting from abnormal immune responses to possible environmental or infectious stimuli in genetically predisposed individuals. Breast milk contains numerous anti-inflammatory factors which may protect against allergic and autoimmune diseases. In this study we tried to examine the effect of breastfeeding for 6 months or more on disease outcomes in patients with Kawasaki disease.MethodsA retrospective cohort study of 249 KD patients admitted from 1999- 2013 who were older than 6 months at time of diagnosis and had data regarding breastfeeding in the first 6 months of life. Demographic, clinical and laboratory data was collected by chart review. Continuous data was compared using Student's t-test and categorical variables were compared using Chi-square. Stepwise multivariate regression of all demographic factors was performed.ResultsBreastfeeding for 6 months or more was associated with a shorter total duration of fever (5.980± 1.405 Vs. 6.910 ± 2.573 days, p = 0.001) and a lower risk of developing persistent coronary artery lesions (CALs) (7.8% Vs. 20.2%, p-value = 0.039) on univariate analysis. Multivariate regression of all factors associated with CALs including breastfeeding for 6 months found that only the presence of CALs at baseline (β-coefficient = 0.065, p < 0.001) and white blood count (β-coefficient = 0.065, p = 0.018) remained significant after regression analysis.ConclusionsBreastfeeding for 6 months or more was associated with a shorter duration of fever and a lower risk of persistent CAL formation in patients with KD on univariate analysis, although this effect may be modest when other factors such as the presence of CALs at baseline and white blood cell count are also taken into consideration.

Project description:BackgroundKawasaki disease (KD) is a systemic vasculitis which may be associated with coronary artery aneurysms. A notable risk factor for the development of coronary artery aneurysms is resistance to intravenous immunoglobulin (IVIG) therapy, which comprises standard treatment for the acute phase of KD. The cause of IVIG resistance in KD is largely unknown; however, the contribution of genetic factors, especially variants in immune-related genes, has been suspected.MethodsTo explore genetic variants related to IVIG-unresponsiveness, we designated KD patients who did not respond to both first and second courses of IVIG therapy as IVIG-unresponsive patients. Using genomic DNA from 30 IVIG-unresponsive KD patients, we performed pooled genome sequencing targeting 39 immune-related cytokine receptor genes.ResultsThe single nucleotide variant (SNV), rs563535954 (located in the IL4R locus), was concentrated in IVIG-unresponsive KD patients. Individual genotyping showed that the minor allele of rs563535954 was present in 4/33 patients with IVIG-unresponsive KD, compared with 20/1063 individuals in the Japanese genome variation database (odds ratio = 7.19, 95% confidence interval 2.43-21.47). Furthermore, the minor allele of rs563535954 was absent in 42 KD patients who responded to IVIG treatment (P = 0.0337), indicating that a low-frequency variant, rs563535954, is associated with IVIG-unresponsiveness in KD patients. Although rs563535954 is located in the 3'-untranslated region of IL4R, there was no alternation in IL4R expression associated with the mior allele of rs563535954. However, IVIG-unresponsive patients that exhibited the minor allele of rs563535954 tended to be classified into the low-risk group (based on previously reported risk scores) for prediction of IVIG-resistance. Therefore, IVIG-unresponsiveness associated with the minor allele of rs563535954 might differ from IVIG-unresponsiveness associated with previous risk factors used to evaluate IVIG-unresponsiveness in KD.ConclusionThese findings suggest that the SNV rs563535954 could serve as a predictive indicator of IVIG-unresponsiveness, thereby improving the sensitivity of risk scoring systems, and may aid in prevention of coronary artery lesions in KD patients.

Dataset Information

Identification of LEF1 as a Susceptibility Locus for Kawasaki Disease in Patients Younger than 6 Months of Age.

Publications

Identification of LEF1 as a Susceptibility Locus for Kawasaki Disease in Patients Younger than 6 Months of Age.

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