Elsevier

Human Immunology

Volume 70, Issue 6, June 2009, Pages 468-471
Human Immunology

Lack of association between E148Q MEFV variant and Kawasaki disease

https://doi.org/10.1016/j.humimm.2008.10.017Get rights and content

Abstract

We investigated a possible association between Kawasaki disease (KD), a systemic vasculitis of unknown etiology, or its coronary artery lesions (CAL) and MEFV gene variants including E148Q, the most common and mild mutation in the MEFV gene for familial Mediterranean fever or vasculitis-related disorders. The study population comprised a total of 138 Japanese patients with KD, including 45 patients with CAL and 93 patients without CAL and 170 normal controls. Sequence variations for the MEFV gene were detected by direct sequencing, followed by the TaqMan SNP genotyping assay. The genotype and allele frequencies of MEFV gene variants (E148Q, L110P, R202Q, P369S, R408Q) were compared between KD patients with and without CAL or between KD patients with CAL and controls. E148Q heterozygotes and homozygotes were observed in 37.1 and 5.5% of healthy controls, 33.3 and 5.1% of KD patients, and 37.8 and 4.4% of KD patients with CAL. No significant differences were observed in the genotype and allele frequencies of other MEFV gene variants (L110P, R202Q, P369S, R408Q) between KD patients with and without CAL or between KD patients with CAL and controls. No associations were detected between the MEFV gene variants and the development of KD or CAL formation in KD.

Introduction

Kawasaki disease (KD) is an acute, self-limited systemic vasculitis that occurs predominantly in infants and young children. Coronary artery aneurysm or ectasia develops in <5 to 25% of untreated children with the disease [1], [2]. Its etiology remains unknown; however, clinical and epidemiological features strongly indicate that it is caused by one or several widely distributed infectious agents [2]. It is likely that KD results from an abnormal immunologic response to certain microbial agents in genetically susceptible individuals. The higher rate of KD in the siblings of KD patients and the racial difference in its incidence support this consideration [2]. Recently, several host genetic factors have been identified in the development of KD and coronary artery lesions (CAL) [3], [4], [5], [6].

Familial Mediterranean fever (FMF) is an inherited inflammatory disease that is common in Arabs, non-Ashkenazi Jews, Armenians, and Turks, whereas it is uncommon in east Asia, including Japan. FMF is characterized by self-limited periodic fever and various symptoms such as peritonitis, arthritis, rash, pleurisy, and pericarditis. The MEFV gene is responsible for FMF [7], [8]. Among the MEFV mutations, the role of E148Q (c.442 G>C) is still controversial. Although some reports indicated that E148Q was only one of the gene polymorphisms, other reports indicated that E148Q was associated with the mildest disease with a low penetrance or usually required another additional MEFV mutation to cause the classical manifestation of FMF [9], [10]. Although FMF is an uncommon disorder in Japan, the frequency of E148Q is higher in Japanese than in European or Arab populations [11], [12], [13]. MEFV was predominantly expressed in granulocytes and monocytes [7], both of which play major roles in the pathophysiology of KD at the acute phase [2]. Several reports revealed that MEFV mutations were associated with vasculitis-related disorders such as Behçet's disease, Henoch–Schönlein purpura, and polyarteritis nodosa [14], [15], [16], suggesting that MEFV gene mutations contribute to the development of a broader spectrum of vasculitis. Furthermore, it was reported that MEFV mutations might increase the baseline of inflammation, induce the development of rheumatic diseases, and affect the clinical course of inflammatory disorders [17].

To clarify the role of the MEFV gene in the development of KD as one of the host genetic factors, we investigated the associations between KD and MEFV gene variants, particularly E148Q, which is common in Japanese populations.

Section snippets

Subjects and methods

One hundred thirty-eight KD patients who were treated with oral aspirin plus intravenous immunoglobulin (IVIG:1–2 g/kg/total in CAL patients and 3–4 g/kg/total in CAL+ patients) at Kyushu University Hospital or its affiliated hospitals from 1991 through 2003 were enrolled. Informed consent was obtained from their parents, and the Ethical Committees of Kyushu University approved the study. All patients were Japanese and met the appropriate diagnostic criteria for KD [18]. The study population

Results

We first analyzed the allelic frequency of E148Q (c.442 G>C), which is a common SNP in Japanese populations [21] compared with other populations, in 138 KD patients and 170 controls by Taqman genotyping assay. E148Q heterozygotes and homozygotes were observed in 37.1 and 5.5% of healthy controls, 33.3 and 5.1% of KD patients, and 37.8 and 4.4% of KD patients with CAL (Table 2). The genotype and allele frequencies of E148Q variant between KD patients and healthy controls, KD patients with and

Discussion

Ozen et al. [17] reported that among 70 individuals with MEFV gene mutations, 28 (40.0%) had some form of rheumatic complaints and 15 (21.4%) developed rheumatic diseases or vasculitis, including Behçet's disease. They also reported that 30.5% of the children with rheumatic diseases and 25.4% of patients with juvenile idiopathic arthritis had mutations of the MEFV gene [17]. FMF and Behçet's disease are not rare disorders in the eastern Mediterranean and it was suggested that the MEFV mutation

Acknowledgments

This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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