A low-frequency IL4R locus variant in Japanese patients with intravenous immunoglobulin therapy-unresponsive Kawasaki disease

• Published in: Pediatric rheumatology online journal Vol. 17; no. 1; p. 34
• Main Authors: Amano, Yuji, Akazawa, Yohei, Yasuda, Jun, Yoshino, Kazuhisa, Kojima, Katsuhiko, Kobayashi, Norimoto, Matsuzaki, Satoshi, Nagasaki, Masao, Kawai, Yosuke, Minegishi, Naoko, Ishida, Noriko, Motoki, Noriko, Hachiya, Akira, Nakazawa, Yozo, Yamamoto, Masayuki, Koike, Kenichi, Takeshita, Toshikazu
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.07.2019; BioMed Central; BMC
• Subjects: Aneurysm; Care and treatment; Child; Child, Preschool; Coronary Artery Disease - genetics; Cytokine receptors; DNA; DNA sequencing; Dosage and administration; Drug Resistance - genetics; Female; Gene Expression Profiling; Gene Frequency; Genes; Genetic aspects; Genome-Wide Association Study; Genomes; Genomics; Health aspects; Humans; Immunoglobulins; Immunoglobulins, Intravenous - therapeutic use; Immunotherapy; Infant; Interleukin-4; Interleukin-4 receptor; Interleukin-4 Receptor alpha Subunit - genetics; Interleukins; Intravenous immunoglobulins; IVIG-resistance; Japan - ethnology; Kawasaki disease; Kawasaki syndrome; Male; Medical schools; Mucocutaneous Lymph Node Syndrome - drug therapy; Mucocutaneous Lymph Node Syndrome - genetics; Patient outcomes; Pediatric research; Polymorphism, Single Nucleotide - genetics; Risk factors; RNA, Messenger - genetics; Sequence Analysis, RNA; Single nucleotide variant; Treatment Failure; Vasculitis; Japan; Interleukin-4 receptor; Kawasaki disease; IVIG-resistance; Single nucleotide variant
• ISSN: 1546-0096; 1546-0096
• DOI: 10.1186/s12969-019-0337-2

Kawasaki 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. To 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. The 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. These 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.