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Association of the IL16 Asn1147Lys polymorphism with intravenous immunoglobulin resistance in Kawasaki disease

Journal of Human Genetics volume 65, pages 421–426 (2020)Cite this article

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Abstract

Kawasaki disease (KD) is an acute, self-limited vasculitis, mainly affecting children younger than 5 years old, with accompanying fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) is the standard treatment for KD; however, ~15% of patients are resistant to IVIG treatment. To identify protein coding genetic variants influencing IVIG resistance, we re-analyzed our previous genome-wide association study (GWAS) data from 296 patients with KD, including 101 IVIG non-responders and 195 IVIG responders. Five nonsynonymous SNPs (nsSNPs) in five immune-related genes, including a previously reported SAMD9L nsSNP (rs10488532; p.Val266Ile), were associated with IVIG non-response (odds ratio [OR] = 1.89–3.46, P = 0.0109–0.0035). In a replication study of the four newly-identified nsSNPs, only one in the interleukin 16 (IL16) gene (rs11556218, p.Asn1147Lys) showed a trend of association with IVIG non-response (OR = 1.54, P = 0.0078). The same IL16 nsSNP was more significantly associated with IVIG non-response in combined analysis of all data (OR = 1.64, P = 1.25 × 10−4). Furthermore, risk allele combination of the IL16 CT and SAMD9L TT nsSNP genotypes exhibited a very strong effect size (OR = 9.19, P = 3.63 × 10−4). These results implicate IL16 as involved in the mechanism of IVIG resistance in KD.

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Acknowledgements

We thank all patients and their families for participating in this study. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (2019R1F1A1061238).

Korean Kawasaki Disease Genetics Consortium

Jeong Jin Yu3, In-Sook Park3, Soo-Jong Hong3, Kwi-Joo Kim3, Jong-Keuk Lee1, Jae-Jung Kim1, Young Mi Hong12, Sejung Sohn12, Gi Young Jang11, Kee Soo Ha11, Hyo-Kyoung Nam11, Jung-Hye Byeon11, Sin Weon Yun2, Myung-Ki Han8, Hyun Ok Jun8, Kyung-Yil Lee5, Ja-Young Hwang5, Jung-Woo Rhim5, Min Seob Song9, Hyoung Doo Lee10, Dong Soo Kim13, Kyung Lim Yoon4, Hong-Ryang Kil6, Gi Beom Kim7, Jae-Moo Lee14, Jong-Duk Kim14

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Author notes

  1. These authors contributed equally: Young Mi Hong, Gi Young Jang, Jong-Keuk Lee

Authors and Affiliations

  1. Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea

    Hea-Ji Kim, Jae-Jung Kim, Jong-Keuk Lee, Jong-Keuk Lee & Jae-Jung Kim

  2. Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea

    Sin Weon Yun & Sin Weon Yun

  3. Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

    Jeong Jin Yu, Jeong Jin Yu, In-Sook Park, Soo-Jong Hong & Kwi-Joo Kim

  4. Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea

    Kyung Lim Yoon & Kyung Lim Yoon

  5. Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary’s Hospital, Daejeon, Korea

    Kyung-Yil Lee, Kyung-Yil Lee, Ja-Young Hwang & Jung-Woo Rhim

  6. Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea

    Hong-Ryang Kil & Hong-Ryang Kil

  7. Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea

    Gi Beom Kim & Gi Beom Kim

  8. Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea

    Myung-Ki Han, Myung-Ki Han & Hyun Ok Jun

  9. Department of Pediatrics, Inje University Paik Hospital, Busan, Korea

    Min Seob Song & Min Seob Song

  10. Department of Pediatrics, Pusan National University Hospital, Busan, Korea

    Hyoung Doo Lee & Hyoung Doo Lee

  11. Department of Pediatrics, Korea University Hospital, Seoul, Korea

    Kee Soo Ha, Gi Young Jang, Gi Young Jang, Kee Soo Ha, Hyo-Kyoung Nam & Jung-Hye Byeon

  12. Department of Pediatrics, Ewha Woman’s University Hospital, Seoul, Korea

    Young Mi Hong, Young Mi Hong & Sejung Sohn

  13. Department of Pediatrics, Severance Children’s Hospital, Seoul, Korea

    Dong Soo Kim

  14. Seoul Clinical Laboratories, Seoul, Korea

    Jae-Moo Lee & Jong-Duk Kim

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The Korean Kawasaki Disease Genetics Consortium

  • Jeong Jin Yu
  • , In-Sook Park
  • , Soo-Jong Hong
  • , Kwi-Joo Kim
  • , Jong-Keuk Lee
  • , Jae-Jung Kim
  • , Young Mi Hong
  • , Sejung Sohn
  • , Gi Young Jang
  • , Kee Soo Ha
  • , Hyo-Kyoung Nam
  • , Jung-Hye Byeon
  • , Sin Weon Yun
  • , Myung-Ki Han
  • , Hyun Ok Jun
  • , Kyung-Yil Lee
  • , Ja-Young Hwang
  • , Jung-Woo Rhim
  • , Min Seob Song
  • , Hyoung Doo Lee
  • , Dong Soo Kim
  • , Kyung Lim Yoon
  • , Hong-Ryang Kil
  • , Gi Beom Kim
  • , Jae-Moo Lee
  •  & Jong-Duk Kim

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Correspondence to Jong-Keuk Lee.

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Members of the Korean Kawasaki Disease Genetics Consortium are listed below Acknowledgements.

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Kim, HJ., Kim, JJ., Yun, S.W. et al. Association of the IL16 Asn1147Lys polymorphism with intravenous immunoglobulin resistance in Kawasaki disease. J Hum Genet 65, 421–426 (2020). https://doi.org/10.1038/s10038-020-0721-2

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