A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease

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Abstract

Kawasaki disease (KD), a systemic vasculitis of infants and children, manifests as fever and mucocutaneous inflammation. Although its etiology is largely unknown, the epidemiological data suggest that genetic factors are important in KD susceptibility. To identify genetic variants influencing KD susceptibility, we performed a genome-wide association study (GWAS) and replication study using a total of 915 children with KD and 4553 controls in the Korean population. Six single-nucleotide polymorphisms (SNPs) in three loci were associated significantly with KD susceptibility (P<1.0 × 10−5), including the previously reported BLK locus (rs6993775, odds ratio (OR)=1.52, P=2.52 × 10−11). The other two loci were newly identified: NMNAT2 on chromosome 1q25.3 (rs2078087, OR=1.33, P=1.15 × 10−6) and the human leukocyte antigen (HLA) region on chromosome 6p21.3 (HLA-C, HLA-B, MICA and HCP5) (rs9380242, rs9378199, rs9266669 and rs6938467; OR=1.33–1.51, P=8.93 × 10−6 to 5.24 × 10−8). Additionally, SNP rs17280682 in NLRP14 was associated significantly with KD with a family history (18 cases vs 4553 controls, OR=6.76, P=5.46 × 10−6). These results provide new insights into the pathogenesis and pathophysiology of KD.

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References

  1. 1

    Burns, J. C. & Glodé, M. P. Kawasaki syndrome. Lancet 364, 533–554 (2004).

  2. 2

    Kato, H., Sugimura, T., Akagi, T., Sato, N., Hashino, K., Maeno, Y. et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 94, 1379–1385 (1996).

  3. 3

    Newburger, J. W., Takahashi, M., Burns, J. C., Beiser, A. S., Chung, K. J., Duffy, C. E. et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N. Engl. J. Med. 315, 341–347 (1986).

  4. 4

    Durongpisitkul, K., Gururaj, V. J., Park, J. M. & Martin, C. F. The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics 96, 1057–1061 (1995).

  5. 5

    Newburger, J. W. & Fulton, D. R. Kawasaki disease. Curr. Opin. Pediatr. 16, 508–514 (2004).

  6. 6

    Lee, K. Y., Han, J. W. & Lee, J. S. Kawasaki disease may be a hyperimmune reaction of genetically-susceptible children to variants of normal environmental flora. Med. Hypotheses 69, 642–651 (2007).

  7. 7

    Makino, N., Nakamura, Y., Yashiro, M., Ae, R., Tsuboi, S., Aoyama, Y. et al. Descriptive epidemiology of Kawasaki disease in Japan, 2011-2012: from the results of the 22nd nationwide survey. J. Epidemiol. 25, 239–245 (2015).

  8. 8

    Kim, G. B., Park, S., Eun, L. Y., Han, J. W., Lee, S. Y., Yoon, K. L. et al. Epidemiology and clinical features of Kawasaki disease in South Korea, 2012-2014. Pediatr. Infect. Dis. J. 36, 482–485 (2017).

  9. 9

    Okubo, Y., Nochioka, K., Sakakibara, H., Testa, M. & Sundel, R. P. National survey of pediatric hospitalizations due to Kawasaki disease and coronary artery aneurysms in the USA. Clin. Rheumatol. 36, 413–419 (2017).

  10. 10

    Holman, R. C., Curns, A. T., Belay, E. D., Steiner, C. A., Effler, P. V., Yorita, K. L. et al. Kawasaki syndrome in Hawaii. Pediatr. Infect. Dis. J. 24, 429–433 (2005).

  11. 11

    Fujita, Y., Nakamura, Y., Sakata, K., Hara, N., Kobayashi, M., Nagai, M. et al. Kawasaki disease in families. Pediatrics 84, 666–669 (1989).

  12. 12

    Harada, F., Sada, M., Kamiya, T., Yanase, Y., Kawasaki, T. & Sasazuki, T. Genetic analysis of Kawasaki syndrome. Am. J. Hum. Genet. 39, 537–539 (1986).

  13. 13

    Uehara, R., Yashiro, M., Nakamura, Y. & Yanagawa, H. Kawasaki disease in parents and children. Acta Paediatr. 92, 694–697 (2003).

  14. 14

    Onouchi, Y., Gunji, T., Burns, J. C., Shimizu, C., Newburger, J. W., Yashiro, M. et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat. Genet. 40, 35–42 (2008).

  15. 15

    Onouchi, Y., Ozaki, K., Burns, J. C., Shimizu, C., Hamada, H., Honda, T. et al. Common variants in CASP3 confer susceptibility to Kawasaki disease. Hum. Mol. Genet. 19, 2898–2906 (2010).

  16. 16

    Khor, C. C., Davila, S., Breunis, W. B., Lee, Y. C., Shimizu, C., Wright, V. J. et al. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat. Genet. 43, 1241–1246 (2011).

  17. 17

    Onouchi, Y., Ozaki, K., Burns, J. C., Shimizu, C., Terai, M., Hamada, H. et al. A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat. Genet. 44, 517–521 (2012).

  18. 18

    Lee, Y. C., Kuo, H. C., Chang, J. S., Chang, L. Y., Huang, L. M., Chen, M. R. et al. Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis. Nat. Genet. 44, 522–525 (2012).

  19. 19

    Newburger, J. W., Takahashi, M., Gerber, M. A., Gewitz, M. H., Tani, L. Y. & Burns, J. C. et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young American Heart Association. Circulation 110, 2747–2771 (2004).

  20. 20

    McCrindle, B. W., Rowley, A. H., Newburger, J. W., Burns, J. C., Bolger, A. F., Gewitz, M. et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation 135, e927–e999 (2017).

  21. 21

    Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

  22. 22

    International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), Harley, J. B. International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), Alarcón-Riquelme, M. E. International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), Criswell, L. A. International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), Jacob, C. O. International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), Kimberly, R. P. et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).

  23. 23

    Deng, Y., Zhao, J., Sakurai, D., Sestak, A. L., Osadchiy, V., Langefeld, C. D. et al. Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. Ann. Rheum. Dis. 75, 2007–2013 (2016).

  24. 24

    Graham, R. R., Cotsapas, C., Davies, L., Hackett, R., Lessard, C. J., Leon, J. M. et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat. Genet. 40, 1059–1061 (2008).

  25. 25

    Hom, G., Graham, R. R., Modrek, B., Taylor, K. E., Ortmann, W., Garnier, S. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).

  26. 26

    Han, J. W., Zheng, H. F., Cui, Y., Sun, L. D., Ye, D. Q., Hu, Z. et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234–1237 (2009).

  27. 27

    Okada, T., Wu, D., Trynka, G., Raj, T., Terao, C., Ikari, K. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).

  28. 28

    Liu, Y., Helms, C., Liao, W., Zaba, L. C., Duan, S., Gardner, J. et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 4, e1000041 (2008).

  29. 29

    Asano, K., Matsushita, T., Umeno, J., Hosono, N., Takahashi, A., Kawaguchi, T. et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat. Genet. 41, 1325–1329 (2009).

  30. 30

    Fellay, J., Ge, D., Shianna, K. V., Colombo, S., Ledergerber, B., Cirulli, E. T. et al. Common genetic variation and the control of HIV-1 in humans. PLoS Genet. 5, e1000791 (2009).

  31. 31

    Limou, S., Le Clerc, S., Coulonges, C., Carpentier, W., Dina, C., Delaneau, O. et al. Genomewide association study of an AIDS-nonprogression cohort emphasizes the role played by HLA genes (ANRS Genomewide Association Study 02). J. Infect. Dis. 199, 419–426 (2009).

  32. 32

    Daly, A. K., Donaldson, P. T., Bhatnagar, P., Shen, Y., Pe'er, I., Floratos, A. et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat. Genet. 41, 816–819 (2009).

  33. 33

    Génin, E., Schumacher, M., Roujeau, J. C., Naldi, L., Liss, Y., Kazma, R. et al. Genome-wide association study of Stevens-Johnson Syndrome and toxic epidermal necrolysis in Europe. Orphanet J. Rare Dis. 6, 52 (2011).

  34. 34

    Tohkin, M., Kaniwa, N., Saito, Y., Sugiyama, E., Kurose, K., Nishikawa, J. et al. A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Pharmacogenomics J. 13, 60–69 (2011).

  35. 35

    Eriksson, N., Tung, J. Y., Kiefer, A. K., Hinds, D. A., Francke, U., Mountain, J. L. et al. Novel associations for hypothyroidism include known autoimmune risk loci. PLoS ONE 7, e34442 (2012).

  36. 36

    Kato, S., Kimura, M., Tsuji, K., Kusakawa, S., Asai, T., Juji, T. et al. HLA antigens in Kawasaki disease. Pediatrics 61, 252–255 (1978).

  37. 37

    Krensky, A. M., Berenberg, W., Shanley, K. & Yunis, E. J. HLA antigens in mucocutaneous lymph node syndrome in New England. Pediatrics 67, 741–743 (1981).

  38. 38

    Oh, J. H., Han, J. W., Lee, S. J., Lee, K. Y., Suh, B. K., Koh, D. K. et al. Polymorphisms of human leukocyte antigen genes in Korean children with Kawasaki disease. Pediatr. Cardiol. 29, 402–408 (2008).

  39. 39

    Shrestha, S., Wiener, H. W., Aissani, B., Shendre, A., Tang, J. & Portman, M. A. Imputation of class I and II HLA loci using high-density SNPs from ImmunoChip and their associations with Kawasaki disease in family-based study. Int. J. Immunogenet. 42, 140–146 (2015).

  40. 40

    Huang, Y., Lee, Y. J., Chen, M. R., Hsu, C. H., Lin, S. P., Sung, T. C. et al. Polymorphism of transmembrane region of MICA gene and Kawasaki disease. Exp. Clin. Immunogenet. 17, 130–137 (2000).

  41. 41

    Inohara, N. & Nuñez, G. NODs: intracellular proteins involved in inflammation and apoptosis. Nat. Rev. Immunol. 3, 371–382 (2003).

  42. 42

    Tschopp, J., Martinon, F. & Burns, K. NALPs: a novel protein family involved in inflammation. Nat. Rev. Mol. Cell Biol. 4, 95–104 (2003).

  43. 43

    Alphonse, M. P., Duong, T. T., Shumitzu, C., Hoang, T. L., McCrindle, B. W., Franco, A. et al. Inositol-triphosphate 3-kinase c mediates inflammasome activation and treatment response in Kawasaki disease. J. Immunol. 197, 3481–3489 (2016).

  44. 44

    Onoyama, S., Ihara, K., Yamaguchi, Y., Ikeda, K., Yamaguchi, K., Yamamura, K. et al. Genetic susceptibility to Kawasaki disease: analysis of pattern recognition receptor genes. Hum. Immunol. 73, 654–660 (2012).

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Acknowledgements

We thank all the patients with Kawasaki disease and their families for participating in this study. This work was supported by a grant from the Ministry of Health & Welfare of the Republic of Korea (HI15C1575) and a grant from the Korea Center for Disease Control and Prevention (2014-ER7402-00).

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Correspondence to Jong-Keuk Lee.

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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, Kyung-Yil Lee5, Ja-Young Hwang5, Jung-Woo Rhim5, Min Seob Song9, Hyoung Doo Lee10, Dong Soo Kim20, Kyung Lim Yoon4, Hong-Ryang Kil6, Gi Beom Kim7, Jae-Moo Lee21 and Jong-Duk Kim21 20Department of Pediatrics, Yonsei University College of Medicine, Severance Children’s Hospital, Seoul, Korea; and 21Seoul Clinical Laboratories, Seoul, Korea

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Kim, J., Yun, S., Yu, J. et al. A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease. J Hum Genet 62, 1023–1029 (2017) doi:10.1038/jhg.2017.87

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