HLA-B*54:01 Is Associated With Susceptibility to Kawasaki Disease
2019; Wolters Kluwer; Volume: 12; Issue: 1 Linguagem: Inglês
10.1161/circgen.118.002365
ISSN2574-8300
AutoresYoung-Chang Kwon, Bo Kyung Sim, Jeong Jin Yu, Sin Weon Yun, Kyung Lim Yoon, Kyung‐Yil Lee, Hong Ryang Kil, Gi Beom Kim, Myung-Ki Han, Min Seob Song, Hye Won Lee, Gi Young Jang, Young Mi Hong, O.‐J. Kwon, Heung‐Bum Oh, Jong‐Keuk Lee, In Sook Park, Soo‐Jong Hong, Kwi-Joo Kim, Sejung Sohn, Kee Soo Ha, Hyo‐Kyoung Nam, Jung-Hye Byeon, Jung-Woo Rhim, Dong Soo Kim, Lee Jae-Moo, Jong-Duk Kim,
Tópico(s)Mechanical Circulatory Support Devices
ResumoHomeCirculation: Genomic and Precision MedicineVol. 12, No. 1HLA-B*54:01 Is Associated With Susceptibility to Kawasaki Disease Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBHLA-B*54:01 Is Associated With Susceptibility to Kawasaki Disease Young-Chang Kwon, PhD, Bo Kyung Sim, BS, Jeong Jin Yu, MD, PhD, Sin Weon Yun, MD, PhD, Kyung Lim Yoon, MD, PhD, Kyung-Yil Lee, MD, PhD, Hong-Ryang Kil, MD, PhD, Gi Beom Kim, MD, PhD, Myung-Ki Han, MD, Min Seob Song, MD, PhD, Hyoung Doo Lee, MD, PhD, Gi Young Jang, MD, PhD, Young Mi Hong, MD, PhD, Oh-Joong Kwon, PhD, Heung-Bum Oh, MD, PhD, Jong-Keuk Lee, PhD and on behalf of the Korean Kawasaki Disease Genetics Consortium Young-Chang KwonYoung-Chang Kwon Asan Institute for Life Sciences (Y.-C.K., B.K.S., J.-K.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. , Bo Kyung SimBo Kyung Sim Asan Institute for Life Sciences (Y.-C.K., B.K.S., J.-K.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. , Jeong Jin YuJeong Jin Yu Department of Pediatrics (J.J.Y.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. , Sin Weon YunSin Weon Yun Department of Pediatrics, Chung-Ang University Hospital, Seoul (S.W.Y.). , Kyung Lim YoonKyung Lim Yoon Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul (K.L.Y.). , Kyung-Yil LeeKyung-Yil Lee Department of Pediatrics, Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon (K.-Y.L.). , Hong-Ryang KilHong-Ryang Kil Department of Pediatrics, Chungnam National University Hospital, Daejeon (H.-R.K.). , Gi Beom KimGi Beom Kim Department of Pediatrics, Seoul National University Children's Hospital, Seoul (G.B.K.). , Myung-Ki HanMyung-Ki Han Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung (M.-K.H.). , Min Seob SongMin Seob Song Department of Pediatrics, Inje University Paik Hospital, Busan (M.S.S.). , Hyoung Doo LeeHyoung Doo Lee Department of Pediatrics, Pusan National University Hospital, Busan (H.D.L.). , Gi Young JangGi Young Jang Department of Pediatrics, Korea University Hospital, Seoul (G.Y.J.). , Young Mi HongYoung Mi Hong Department of Pediatrics, Ewha Womans University Hospital, Seoul (Y.M.H.). , Oh-Joong KwonOh-Joong Kwon Biowithus Life Science Institute, Seoul (O.-J.K.). , Heung-Bum OhHeung-Bum Oh Department of Laboratory Medicine (H.-B.O.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. , Jong-Keuk LeeJong-Keuk Lee Jong-Keuk Lee, PhD, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul 05505, Korea. Email E-mail Address: [email protected] Asan Institute for Life Sciences (Y.-C.K., B.K.S., J.-K.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. and on behalf of the Korean Kawasaki Disease Genetics Consortium and Korean Kawasaki Disease Genetics Consortium: the following authors also participated in this work as members of the Korean Kawasaki Disease Genetics Consortium who contributed to sample and data collection Originally published15 Jan 2019https://doi.org/10.1161/CIRCGEN.118.002365Circulation: Genomic and Precision Medicine. 2019;12:e002365Kawasaki disease (KD) is an acute systemic vasculitis that is a leading cause of acquired heart disease in children. The pathogenesis of KD remains unknown. It is likely that KD is caused by abnormal immune responses to unknown trigger(s) in genetically susceptible children.1 The HLA (human leukocyte antigen) genes, known as the most polymorphic gene in vertebrate animals, encode the protein on the cell-surface antigen-presenting proteins that is involved in the regulation of the immune system. The roles of HLA genes have been investigated in several immune-mediated vascular diseases, including Behcet disease, KD, and Wegener granulomatosis. A recent genome-wide association study demonstrated the significant association of HLA class II region (HLA-DQB2-DOB) with KD in a Japanese population.2 Our previous genome-wide association study conducted in a Korean population demonstrated a significant association with KD of the HLA class I locus that contains the HLA-B and HLA-C genes.3 These studies suggest that either HLA class I or class II may be associated with KD and play a role in KD pathogenesis. However, a specific HLA gene and HLA allele associated with KD has not been identified.To identify HLA gene association with KD in Korean children, in this study, we performed a high-resolution sequence-based typing (SBT) for exon 2 of the HLA-DRB1 gene, exon 2 to 3 of the HLA-DQB1 gene, and exon 2 to 4 of the HLA-A, HLA-B, HLA-C, and HLA-DPB1 genes using the AVITA SBT Kit (Biowithus, Seoul, Korea), and all sequenced data from the SBT assays were further analyzed for variants, including nonsynonymous single-nucleotide polymorphisms, amino acids, and HLA alleles at 4-digit resolution based on the IMGT (International Immunogenetics project)/HLA database release 3.27.0 (January 2017; https://www.ebi.ac.uk/ipd/imgt/hla/). To examine the associations between 6 classical HLA genes and KD, we initially performed SBT in 160 patients with KD and 278 control subjects for a discovery stage. Among the 6 HLA genes, the most significant association with KD was observed in HLA-B gene, with the highest P of 1.35×10−4 at the level of nonsynonymous single-nucleotide polymorphism and amino acid polymorphism (data not shown). To validate the association between HLA-B gene and KD, an additional 618 cases of KD were genotyped by SBT for the HLA-B gene and compared with in-house control data of HLA-B (n=14 364), which were genotyped using same kit and deposited at Asan Medical Center (correlation coefficient between 2 control data used in discovery and validation stage, r=0.98). A very significant association of HLA-B was also observed in the replication study with the highest P of 1.10×10−5 at the level of nonsynonymous single-nucleotide polymorphism and amino acid polymorphism (data not shown). In the combined analysis, including 778 cases of KD and 14 642 controls, HLA-B*54:01 allele is significantly associated with KD, exceeding a significance threshold Bonferroni corrected for 87 observed HLA-B alleles (odds ratio, 1.45; P=8.25×10−5; Bonferroni-corrected P [Pc]=7.18×10−3; Table).Table. Association of HLA-B With Susceptibility to KDVariantDiscovery Stage (160 Cases vs 278 Controls)Validation Stage (618 Cases vs 14 364 Controls)Combined Stage (778 Cases vs 14 642 Controls)Allele Count, %ORP ValueAllele Count, %ORP ValueAllele Count, %ORP ValuePc Value*EffectCaseControlCaseControlCaseControlAlleleHLA-B*13:0210 (3.1)21 (3.8)0.820.61526 (2.1)944 (3.3)0.630.02136 (2.3)965 (3.3)0.700.033NSProtectiveHLA-B*15:274 (1.3)1 (0.2)7.030.0625 (0.4)73 (0.3)1.590.3109 (0.6)74 (0.3)2.300.016NSRiskHLA-B*27:042 (0.6)1 (0.2)3.490.3036 (0.5)62 (0.2)2.260.0518 (0.5)63 (0.2)2.400.016NSRiskHLA-B*27:052 (0.6)19 (3.4)0.180.01023 (1.9)821 (2.9)0.640.03825 (1.6)840 (2.9)0.550.003NSProtectiveHLA-B*44:022 (0.6)8 (1.4)0.430.34110 (0.8)418 (1.5)0.550.06112 (0.8)426 (1.5)0.530.026NSProtectiveHLA-B*44:0320 (6.3)51 (9.2)0.660.12782 (6.6)2534 (8.8)0.730.008102 (6.6)2585 (8.8)0.720.002NSProtectiveHLA-B*46:0118 (5.6)30 (5.4)1.050.88674 (6.0)1322 (4.6)1.320.02492 (5.9)1352 (4.6)1.300.018NSRiskHLA-B*52:0115 (4.7)28 (5.0)0.930.81846 (3.7)809 (2.8)1.330.06161 (3.9)837 (2.9)1.390.015NSRiskHLA-B*54:0126 (8.1)35 (6.3)1.320.306105 (8.5)1713 (6.0)1.462.61×10−4131 (8.4)1748 (6.0)1.458.25×10−5†7.18×10−3†RiskHLA-B*56:041 (0.3)0 (0.0)NA0.3651 (0.1)1 (0.0)23.30.0812 (0.1)1 (0.0)37.70.007NSRiskAmino acid polymorphism (amino acid position: minor amino acid)91: Tyr89 (27.8)114 (20.5)1.490.014313 (25.3)5796 (20.2)1.341.10×10−5402 (25.8)5910 (20.2)1.387.24×10−8†7.38×10−6†Risk104: Thr43 (13.4)127 (22.8)0.527.02×10−4204 (16.5)6102 (21.2)0.736.32×10−5247 (15.9)6229 (21.3)0.703.50×10−7†3.57×10−5†Protective329: Ala121 (37.8)237 (42.6)0.810.146484 (39.2)12840 (44.7)0.801.27×10−4605 (38.9)13077 (44.7)0.797.16×10−6†7.30×10−4†ProtectiveHaplotype of amino acid position 91 (rs1071816), 104 (rs1131223), and 329 (rs1051488)‡Tyr-Asn-Thr62 (19.4)84 (15.1)1.350.124241 (19.5)4275 (14.7)1.391.07×10−5303 (19.5)4359 (14.7)1.381.03×10−6†1.64×10−5†RiskSer-Thr-Ala33 (10.3)102 (18.3)0.510.002145 (11.7)4830 (16.6)0.663.13×10−6178 (11.4)4932 (16.6)0.642.86×10−8†4.57×10−7†ProtectiveThis table shows the KD-associated HLA-B alleles and haplotypes with P <0.05 in the combined stage. These statistical values are for the allelic model. ORs and P value were calculated using χ2 test or Fisher exact test in case of allele count <5. Ala indicates alanine; KD, Kawasaki disease; NS, not significant; OR, odds ratio; Pc, Bonferroni-corrected P value; Thr, threonine; and Tyr, tyrosine.*Pc represents adjusted P value from Bonferroni correction with a total number of HLA-B alleles (n=87), amino acid residues (n=102), or haplotypes (n=16).†Significant Pc value.‡Haplotypes of HLA-B are grouped based on the amino acid residues present at positions 91, 104, and 329 within HLA-B.To identify the functional amino acid residues in HLA-B gene associated with KD, we analyzed individual amino acid polymorphisms for KD association using the combined data set. To determine amino acid residues contributing independently to KD susceptibility, a forward stepwise conditional analysis was performed in 23 amino acid positions that were significantly associated with KD after Bonferroni correction (Pc<4.90×10−4). Amino acid positions 91, 104, and 329 in HLA-B gene were independently associated with susceptibility to KD, with the highest P at amino acid position 91 (rs1071816, p.Tyr91Cys/Phe/Ser; odds ratio, 1.38; P=7.24×10−8; Pc=7.38×10−6; Table). In addition, a forward stepwise conditional analysis found that 2 haplotypes of amino acid positions 91, 104, and 329 were independently associated with KD. The haplotype of tyrosine at 91, asparagine at 104, and threonine at 329 (Tyr-Asn-Thr) in HLA-B was significantly associated with increased susceptibility to KD (odds ratio, 1.38; P=1.03×10−6; Pc=1.64×10−5), whereas the haplotype of Ser-Thr-Ala protected against KD (odds ratio, 0.64; P=2.86×10−8; Pc=4.57×10−7; Table).Our data indicate that the development of KD may also be involved in HLA class I and CD8+ (cluster of differentiation 8) T cell-mediated pathogenesis. However, the association of HLA-B with KD was not as strong as the previously known KD susceptibility genes BLK and BCL2L11, which are mainly associated with B-cell immunity.3,4 This result suggests that HLA-B may play a role in subgroup(s) of KD patients, particularly in cases triggering HLA class I and CD8+ T cell-mediated immune response.In conclusion, HLA-B*54:01 allele and 3 amino acid positions (91, 104, and 329) in the HLA-B gene were associated with KD. These studies suggest the interesting possibility that HLA-B molecules may play a crucial role in the pathogenesis of KD.This study was approved by our Institutional Review Board at Asan Medical Center (institutional review board No. 2014-0823), and informed consent was obtained from the parents of the patients with KD. The data and analytic methods will be made available to other researchers on reasonable request.AppendixKorean Kawasaki Disease Genetics Consortium: the following authors also participated in this work as members of the Korean Kawasaki Disease Genetics Consortium who contributed to sample and data collection: In-Sook Park, Soo-Jong Hong, Kwi-Joo Kim (Department of Pediatrics, Asan Medical Center, Seoul, Korea); Sejung Sohn (Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea); Kee Soo Ha, Hyo-Kyoung Nam, Jung-Hye Byeon (Department of Pediatrics, Korea University Hospital, Seoul, Korea); JungWoo Rhim (Department of Pediatrics, Catholic University of Korea, St. Mary's Hospital, Daejeon, Korea); Dong Soo Kim (Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Korea); Jae-Moo Lee, Jong-Duk Kim (Seoul Clinical Laboratories, Seoul, Korea).AcknowledgmentsWe thank all of our patients and their families for participating in this study.Sources of FundingThis research was supported by a grant from the National Research Foundation of Korea funded by the Ministry of Education (NRF-2015R1D1A1A01057371) and a grant from the Ministry of Health and Welfare of the Republic of Korea (HI15C1575).DisclosuresNone.Footnotes*Dr Kwon and B.K. Sim contributed equally to this work as first authors.†A list of all participants in the Korean Kawasaki Disease Genetics Consortium is given in the Appendix.https://www.ahajournals.org/journal/circgenJong-Keuk Lee, PhD, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul 05505, Korea. Email [email protected]comReferences1. Burgner D, Harnden A. Kawasaki disease: what is the epidemiology telling us about the etiology?Int J Infect Dis. 2005; 9:185–194. doi: 10.1016/j.ijid.2005.03.002CrossrefMedlineGoogle Scholar2. Onouchi Y, et al; Japan Kawasaki Disease Genome Consortium; US Kawasaki Disease Genetics Consortium. A genome-wide association study identifies three new risk loci for Kawasaki disease.Nat Genet. 2012; 44:517–521. doi: 10.1038/ng.2220CrossrefMedlineGoogle Scholar3. Kim JJ, et al; Korean Kawasaki Disease Genetics Consortium. A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease.J Hum Genet. 2017; 62:1023–1029. doi: 10.1038/jhg.2017.87CrossrefMedlineGoogle Scholar4. Kwon YC, et al; Korean Kawasaki Disease Genetics Consortium. BCL2L11 is associated with Kawasaki disease in intravenous immunoglobulin responder patients.Circ Genom Precis Med. 2018; 11:e002020. doi: 10.1161/CIRCGEN.117.002020LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Shahbaz F, Martins R, Umair A, Ukrani R, Jabeen K, Sohail M and Khan E (2022) A Review of Coronaviruses Associated With Kawasaki Disease: Possible Implications for Pathogenesis of the Multisystem Inflammatory Syndrome Associated With COVID-19, Clinical Medicine Insights: Pediatrics, 10.1177/11795565221075319, 16, (117955652210753), Online publication date: 1-Jan-2022. Faridah I, Perwitasari D and Chang W (2022) Genetic Study of Kawasaki Disease Kawasaki Disease, 10.1007/978-981-19-2944-1_11, (103-116), . Gorelik M (2021) Learning about Kawasaki disease from COVID-19 and the Multisystem Inflammatory Syndrome in Children, Current Opinion in Pediatrics, 10.1097/MOP.0000000000001047, 33:6, (603-609), Online publication date: 1-Dec-2021. McMurray J, May J, Cunningham M and Jones O (2020) Multisystem Inflammatory Syndrome in Children (MIS-C), a Post-viral Myocarditis and Systemic Vasculitis—A Critical Review of Its Pathogenesis and Treatment, Frontiers in Pediatrics, 10.3389/fped.2020.626182, 8 Jang Y, Kim T, Moon J, Yang T, Kim K, Park B, Lim J, Jun J, Lee S, Jung K, Park K, Jung K, Chu K and Lee S (2020) HLAs associated with perampanel-induced psychiatric adverse effects in a Korean population, Scientific Reports, 10.1038/s41598-020-70601-1, 10:1, Online publication date: 1-Dec-2020. Shimizu C, Kim J, Eleftherohorinou H, Wright V, Hoang L, Tremoulet A, Franco A, Hibberd M, Takahashi A, Kubo M, Ito K, Tanaka T, Onouchi Y, Coin L, Levin M, Burns J and Shike H (2019) HLA-C variants associated with amino acid substitutions in the peptide binding groove influence susceptibility to Kawasaki disease, Human Immunology, 10.1016/j.humimm.2019.04.020, 80:9, (731-738), Online publication date: 1-Sep-2019. January 2019Vol 12, Issue 1 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.118.002365PMID: 31017802 Originally publishedJanuary 15, 2019 Keywordspolymorphism, single nucleotidemucocutaneous lymph node syndromehumansHLA-B antigenschildPDF download Advertisement SubjectsGenetic, Association Studies
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