BCL2L11 Is Associated With Kawasaki Disease in Intravenous Immunoglobulin Responder Patients
2018; Wolters Kluwer; Volume: 11; Issue: 2 Linguagem: Inglês
10.1161/circgen.117.002020
ISSN2574-8300
AutoresYoung-Chang Kwon, Jae-Jung Kim, Sin Weon Yun, Jeong Jin Yu, Kyung Lim Yoon, Kyung‐Yil Lee, Hong Ryang Kil, Gi Beom Kim, Myung-Ki Han, Min Seob Song, Hye Won Lee, Kee Soo Ha, Sejung Sohn, Young Mi Hong, Gi Young Jang, Jong‐Keuk Lee,
Tópico(s)Inflammasome and immune disorders
ResumoHomeCirculation: Genomic and Precision MedicineVol. 11, No. 2BCL2L11 Is Associated With Kawasaki Disease in Intravenous Immunoglobulin Responder Patients Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBBCL2L11 Is Associated With Kawasaki Disease in Intravenous Immunoglobulin Responder Patients Young-Chang Kwon, PhD, Jae-Jung Kim, PhD, Sin Weon Yun, MD, PhD, Jeong Jin Yu, 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, Kee Soo Ha, MD, PhD, Sejung Sohn, MD, PhD, Young Mi Hong, MD, PhD, Gi Young Jang, MD, PhD and Jong-Keuk Lee, PhDon behalf of the Korean Kawasaki Disease Genetics Consortium Young-Chang KwonYoung-Chang Kwon From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Jae-Jung KimJae-Jung Kim From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Sin Weon YunSin Weon Yun From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Jeong Jin YuJeong Jin Yu From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Kyung Lim YoonKyung Lim Yoon From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Kyung-Yil LeeKyung-Yil Lee From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Hong-Ryang KilHong-Ryang Kil From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Gi Beom KimGi Beom Kim From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Myung-Ki HanMyung-Ki Han From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Min Seob SongMin Seob Song From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Hyoung Doo LeeHyoung Doo Lee From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Kee Soo HaKee Soo Ha From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Sejung SohnSejung Sohn From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Young Mi HongYoung Mi Hong From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) , Gi Young JangGi Young Jang From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) and Jong-Keuk LeeJong-Keuk Lee From the Asan Institute for Life Sciences (Y.-C.K., J.-J.K., J.-K.L) and Department of Pediatrics, Asan Medical Center (J.J.Y.), University of Ulsan College of Medicine, Seoul, Korea; Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea (S.W.Y.); Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea (K.L.Y.); Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea (K.-Y.L.); Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea (H.-R.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea (G.B.K.); Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea (M.-K.H.); Department of Pediatrics, Inje University Paik Hospital, Busan, Korea (M.S.S.); Department of Pediatrics, Pusan National University Hospital, Busan, Korea (H.D.L.); Department of Pediatrics, Korea University Hospital, Seoul, Korea (K.S.H., G.Y.J.); and Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea (S.S., Y.M.H.) and on behalf of the Korean Kawasaki Disease Genetics Consortium Originally published16 Feb 2018https://doi.org/10.1161/CIRCGEN.117.002020Circulation: Genomic and Precision Medicine. 2018;11:e002020Kawasaki disease (KD) is a self-limited systemic vasculitis of an unknown pathogenesis mainly affecting children <5 years old. KD is a clinically heterogeneous disease; its diagnosis is based on common clinical symptoms, and there is no specific diagnostic test for it. Complete KD is diagnosed when subjects have at least 5 of the following 6 principal clinical signs: fever persisting for ≥5 days, bilateral conjunctival congestion, changes to the lips and oral cavity, polymorphous exanthema, changes to peripheral extremities, and acute nonpurulent cervical lymphadenopathy.The standard treatment for KD is high-dose intravenous immunoglobulin (IVIG), manufactured from normal human immunoglobulin purified from the full plasma of a thousand healthy donors; it reduces the duration of fever and the incidence of coronary artery abnormalities. The anti-inflammatory effects of IVIG are manifested in a wide range of pathological conditions, including immune thrombocytopenia, systemic lupus erythrematosus, Guillain–Barré syndrome, and others. Despite IVIG therapy, however, ≈15% of patients with KD have persistent or recurrent fever with a high risk for coronary artery lesions. In our KD patients data, we also observed significant differences in clinical variables between IVIG responders (n=832) and nonresponders (n=147), where the latter group showed more severe inflammation and poorer clinical outcomes, including a longer duration of fever days (median 6.0 versus 8.0 days; P=8.99×10–16), higher C-reactive protein levels (median 6.6 versus 10.9 mg/L; P=2.02×10–8), and a higher ratio of coronary artery lesions (23.6% versus 39.5%; P=3.35×10–5). Despite the clinical differences between responders and nonreponders, the genetic risk factors determining treatment responsiveness have not been studied.To identify the IVIG response-specific genetic variants associated with KD, we initially performed an IVIG response-stratified genome-wide association study, using our previous data from 296 cases (196 IVIG responders and 100 IVIG nonresponders) and 1000 control subjects genotyped with the Illumina Omni1-Quad BeadChip as described in our previous study.1 For replication study, we selected 40 IVIG response-specific candidate single nucleotide polymorphisms (SNPs) considering their P values (P 0.30 in another subgroup) and their immune-related functions and tested them in an independent sample set consisting of 697 patients with KD (650 IVIG responders and 47 IVIG nonresponders) and 3553 control subjects. Genotyping for the replication study in the additional 697 patients with KD was performed using the Fluidigm SNPType assay platform (Fluidigm Corp, San Francisco, CA). This process identified an intronic SNP (rs3789065) in the BCL2L11 gene that showed a significant association with KD in IVIG responders (odds ratio=1.42; P=8.94×10–11) but not in nonresponders (odds ratio=1.06; P=0.654; Table). This suggests that BCL2L11 may play a role as a KD susceptibility gene in responders. By power calculation using CaTs program (http://csg.sph.umich.edu/abecasis/CaTS/), we found that our study has 85.4%, 74.3%, and 0.3% power to detect an odds ratio=1.38 with risk allele frequency=0.447, prevalence=0.001947 (194.7/100 000),2 and genome-wide significance level (P=5×10–8) in all KD samples, IVIG responders, and IVIG nonresponders, respectively. These data indicate that the role of BCL2L11 gene in IVIG nonresponders is still not clear because of small sample size. Although BCL2L11 is significantly associated with KD in IVIG responders, the genotype of the BCL2L11 risk allele did not show any significant effect on the clinical variables of patients with KD (data not shown).Table. IVIG Response-Specific KD Susceptibility of Intronic SNP rs3789065 (Risk Allele: C) in the BCL2L11 GeneSubgroupCollectionn (Case/Controls)RAF (Case/Control)Allelic ModelAdditive Model (Sex as Covariate)OR (95% CI)PValueOR (95% CI)PValueIVIG respondersGWAS196/10000.536/0.4261.55 (1.25–1.93)6.85×10–5*1.57 (1.26–1.95)5.80×10–5*Replication650/35530.535/0.4531.39 (1.23–1.56)8.12×10–8*1.38 (1.22–1.56)2.22×10–7*Combined846/45530.535/0.4471.42 (1.28–1.58)4.37×10–11*1.42 (1.28–1.58)8.94×10–11*IVIG nonrespondersGWAS100/10000.440/0.4261.06 (0.79–1.42)0.7111.06 (0.79–1.42)0.680Replication47/35530.500/0.4531.21 (0.80–1.82)0.3701.21 (0.80–1.83)0.370Combined147/45530.459/0.4471.05 (0.83–1.32)0.6941.06 (0.84–1.33)0.654All KDGWAS296/10000.503/0.4261.36 (1.13–1.64)9.34×10–4*1.38 (1.14–1.66)7.29×10–4*Replication697/35530.532/0.4531.37 (1.22–1.54)8.04×10–8*1.37 (1.21–1.54)2.29×10–7*Combined993/45530.524/0.4471.36 (1.23–1.50)8.31×10–10*1.38 (1.25–1.52)1.06×10–10*Association analysis was performed using the PLINK (http://pngu.mgh.harvard.edu/~purcell/plink/) for allelic model and additive model with sex as covariate. GWAS indicates genome wide association studies; IVIG, intravenous immunoglobulins; KD, Kawasaki disease; OR, odds ratio; RAF, risk allele frequency; and SNP, single nucleotide polymorphism.*Significant P values (P<0.05).BCL2L11 (Bcl-2-like protein 11), a member of proapoptotic BH3-only protein in the Bcl-2 family that encodes the Bcl-2 interacting protein, is highly expressed in the immune system, including in bone marrow, and lymph nodes (http://www.proteinatlas.org/ENSG00000153094-BCL2L11/tissue). In murine models, the loss of BCL2L11 can lead to the survival of autoreactive B cells and T cells that are likely to contribute to the development of autoimmune disease.3 This indicates that BCL2L11 plays a critical role in regulating the homeostasis of lymphocytes. Interestingly, it has been previously reported that the KD-associated intronic SNP (rs3789065) in BCL2L11 is associated with serum concentrations of inflammation-associated complement component 3 peptide (HWESASXX),4 and a risk allele (C allele) of a KD-associated SNP (rs3789065) showed significantly reduced expression of the BCL2L11 gene in human peripheral blood monocytes (P=4.23×10–20).5 These data suggest that the allele-specific reduced gene expression of BCL2L11 results in high susceptibility in IVIG responders.In conclusion, we have identified an intronic SNP (rs3789065) in BCL2L11 which is significantly associated with KD at the genome-wide significance level in IVIG responders but not in nonresponders. These findings provide new insights into KD susceptibility in patients with KD with IVIG responsiveness.Young-Chang Kwon, PhDJae-Jung Kim, PhDSin Weon Yun, MD, PhDJeong Jin Yu, MD, PhDKyung Lim Yoon, MD, PhDKyung-Yil Lee, MD, PhDHong-Ryang Kil, MD, PhDGi Beom Kim, MD, PhDMyung-Ki Han, MDMin Seob Song, MD, PhDHyoung Doo Lee, MD, PhDKee Soo Ha, MD, PhDSejung Sohn, MD, PhDYoung Mi Hong, MD, PhD*Gi Young Jang, MD, PhD*Jong-Keuk Lee, PhD*on behalf of the Korean Kawasaki Disease Genetics ConsortiumAcknowledgmentsWe thank all of our patients and their families for participating in this study. The following authors also participated in this work as members of the Korean Kawasaki Disease Genetics Consortium: In-Sook Park, Soo-Jong Hong, Kwi-Joo Kim (Department of Pediatrics, Asan Medical Center, Seoul, Korea); Hyo-Kyoung Nam, Jung-Hye Byeon (Department of Pediatrics, Korea University Hospital, Seoul, Korea); Jung-Woo Rhim (Department of Pediatrics, The 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); and Jae-Moo Lee and Jong-Duk Kim (Seoul Clinical Laboratories, Seoul, Korea).Sources of FundingThis work was supported by a grant from the Ministry of Health and Welfare of the Republic of Korea (HI15C1575).DisclosuresNone.Footnotes*Drs Hong, Jang, and J.-K. Lee contributed equally to this work.Circ Genom Precis Med is available at http://circgenetics.ahajournals.org.Correspondence to: Jong-Keuk Lee, PhD, Asan Institute for Life Sciences, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul 05505, Korea. E-mail [email protected]References1. Kim JJ, Yun SW, Yu JJ, Yoon KL, Lee KY, Kil HR, 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.2017.87.CrossrefMedlineGoogle Scholar2. Kim GB, Park S, Eun LY, Han JW, Lee SY, Yoon KL, et al. Epidemiology and clinical features of Kawasaki disease in South Korea, 2012-2014.Pediatr Infect Dis J. 2017; 36:482–485. doi: 10.1097/INF.0000000000001474.CrossrefMedlineGoogle Scholar3. Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Köntgen F, et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.Science. 1999; 286:1735–1738.CrossrefMedlineGoogle Scholar4. Suhre K, Shin SY, Petersen AK, Mohney RP, Meredith D, Wägele B, et al; CARDIoGRAM. Human metabolic individuality in biomedical and pharmaceutical research.Nature. 2011; 477:54–60. doi: 10.1038/nature10354.CrossrefMedlineGoogle Scholar5. Zeller T, Wild P, Szymczak S, Rotival M, Schillert A, Castagne R, et al. Genetics and beyond–the transcriptome of human monocytes and disease susceptibility.PLoS One. 2010; 5:e10693. doi: 10.1371/journal.pone.0010693.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Mateo P and Flores-Suárez L (2021) Vasculitis, Medicine - Programa de Formación Médica Continuada Acreditado, 10.1016/j.med.2021.05.007, 13:34, (1943-1953), Online publication date: 1-May-2021. Kwon Y, Sim B, Yu J, Yun S, Yoon K, Lee K, Kil H, Kim G, Han M, Song M, Lee H, Jang G, Hong Y, Kwon O, Oh H, Lee J, Park I, Hong S, Kim K, Sohn S, Ha K, Nam H, Byeon J, Rhim J, Kim D, Lee J and Kim J (2019) HLA-B*54:01 Is Associated With Susceptibility to Kawasaki Disease, Circulation: Genomic and Precision Medicine, 12:1, Online publication date: 1-Jan-2019. Demirkaya E, Arici Z, Romano M, Berard R and Aksentijevich I (2019) Current State of Precision Medicine in Primary Systemic Vasculitides, Frontiers in Immunology, 10.3389/fimmu.2019.02813, 10 Acosta-Herrera M, González-Gay M, Martín J and Márquez A (2019) Leveraging Genetic Findings for Precision Medicine in Vasculitis, Frontiers in Immunology, 10.3389/fimmu.2019.01796, 10 Kim J, Kim H, Yu J, Yun S, Lee K, Yoon K, Kil H, Kim G, Han M, Song M, Lee H, Jun H, Ha K, Hong Y, Jang G and Lee J (2021) IgA Levels Are Associated with Coronary Artery Lesions in Kawasaki Disease, Korean Circulation Journal, 10.4070/kcj.2020.0345, 51:3, (267) Lee J (2021) Hygiene Hypothesis as the Etiology of Kawasaki Disease: Dysregulation of Early B Cell Development, International Journal of Molecular Sciences, 10.3390/ijms222212334, 22:22, (12334) February 2018Vol 11, Issue 2 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.117.002020PMID: 29453247 Originally publishedFebruary 16, 2018 Keywordsgenome wide association studyimmunoglobulins, intravenousmucocutaneous lymph node syndromepolymorphism, single nucleotidePDF download Advertisement SubjectsCoronary Artery DiseaseGenetic, Association StudiesInflammationPediatricsPrecision Medicine
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