尾内 善広

＜Key Points＞(1)川崎病は多因子遺伝性疾患であり、罹患感受性と罹患した際の重症化に遺伝的要因が関与している。(2)ゲノムワイド研究の成果により複数人種で関連が確かな罹患感受性遺伝子が複数見出されている。(3)川崎病と遺伝に関する多施設共同研究「川崎病遺伝コンソーシアム」が発足し、将来にわたって活用可能な形でのDNA試料や診療情報の収集が始まっている(http://raise.umin.jp/jkdgc/)。(著者抄録)

川崎病は主として乳幼児を冒す全身性の血管炎症候群であり、発見から40年以上経った現在でも原因が明らかではない。疫学的な特徴から遺伝的要因の関与が疑われており、近年のゲノムワイド研究から川崎病の罹患感受性に関連する一塩基多型(SNP)が複数同定され、これまで知られていなかった成人期の自己免疫性疾患と共通性があることや、関連遺伝子の機能から、川崎病の臨床上重要な課題であるγグロブリン大量静注療法に対する不応の背景にCa2+/NFAT経路の活性化が存在する可能性が浮上し、重症川崎病の治療法の開発にも結びつきつつある。(著者抄録)

Single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC, rs28493229) and caspase-3 (CASP3, rs113420705) are associated with susceptibility to KD in Japanese and Taiwanese populations. This study was conducted to investigate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) resistance and coronary artery lesion (CAL) in Taiwanese population. A total of 340 KD patients were subjected to assess by the identification of 2-locus genes model. A combinatorial association between ITPKC (rs28493229) and CASP3 (rs113420705) was found in CAL formation (P = 0.0227, OR: 3.06). KD patients with high-risk genotype had a trend of overrepresentation in IVIG resistance compared with individual SNPs. Our findings suggest the existence of genetic factors affecting patients' risk for CAL formation and IVIG responsiveness in a Taiwanese population.

Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705 formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg-1 (n=70) or 1 g kg-1 daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg-1), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients' responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation. © 2013 Macmillan Publishers Limited All rights reserved.

Background: Kawasaki disease (KD) is an acute systemic vasculitis occurring in medium-sized arteries, especially coronary arteries. Patients with KD who fail to respond to standard therapy with intravenous immunoglobulin (IVIG) face a higher risk of developing coronary artery lesions. Cyclosporin A (CsA) is one treatment option for IVIG-resistant KD. However, the mechanism of its suppression of inflammation in patients with KD remains unknown. Methods and results: We analyzed time-line profiles of multiple inflammatory cytokines in sera of 19 patients treated with CsA (4 mg/kg/day, p.o., 14 days) after additional IVIG. Trough concentration of CsA in blood was maintained between 60 and 200 ng/ml. We examined serum samples before, on day 7, and at the end (day 14) of CsA treatment. Assays were conducted using a Milliplex kit (R). Fourteen patients responded to CsA and became afebrile within 5 days (Responders), although five patients were regarded as Non-responders. Serum transitional levels of IL-6 (p < 0.001), sIL-2R (p < 0.001), sTNFRII (p < 0.001), and G-CSF (p < 0.001) reflect disease severity. In Non-responders, average levels of IL-6 at day 7 (43.5 vs. 13.8 pg/ml, p < 0.001) and average levels of sIL-2R at day 14 (21.3 vs. 3.31 pg/ml, p = 0.014) were significantly higher than those in Responders. Conclusion: CsA treatment effectively reduced the persisting serum inflammatory cytokines in most of the IVIG-resistant KD patients. Soluble IL-2R suppression implies a mechanism explaining the effects of CsA. (C) 2012 Elsevier Ltd. All rights reserved.

全ゲノムを対象とした人類遺伝学的手法により、inositol 1,4,5-trisphosphate 3-kinase C(ITPKC)とCaspase-3(CASP3)の2遺伝子が川崎病の発症関連遺伝子であることを明らかにした。さらに全ゲノム関連解析(GWAS)ではITPKC、CASP3の既報遺伝子領域に加え、ゲノムワイド解析の有意水準を満たす4つの新たな関連領域が確認できた。さらに、各遺伝子多型の相互作用、大量免疫グロブリン静注(IVIG)反応性および冠動脈合併症(CAL)発生との関連を詳細に検討した。ITPKCとCASP3両遺伝子のリスクアレルを一つ以上有するとIVIG抵抗性リスクが有意に高まることが示唆された。同様の関連の傾向がCALのリスクについても認めた。重症化予測スコアリングシステムの改善につながる可能性が示唆された。

Objective To describe the clinical course and outcome of 10 patients with Kawasaki disease (KD) treated with a calcineurin inhibitor after failing to respond to multiple therapies. Study design Demographic and clinical data were prospectively collected using standardized case report forms. T-cell phenotypes were determined by flow cytometry, and KD risk alleles in ITPKC (rs28493229), CASP3 (rs72689236), and FCGR2A (rs1801274) were genotyped. Results Intravenous followed by oral therapy with cyclosporine (CSA) or oral tacrolimus was well tolerated and resulted in defervescence and resolution of inflammation in all 10 patients. There were no serious adverse events, and a standardized treatment protocol was developed based on our experiences with this patient population. Analysis of T-cell phenotype by flow cytometry in 2 subjects showed a decrease in circulating activated CD8(+) and CD4(+) T effector memory cells after treatment with CSA. However, suppression of regulatory T-cells was not seen, suggesting targeting of specific, proinflammatory T-cell compartments by CSA. Conclusion Treatment of refractory KD with a calcineurin inhibitor appears to be a safe and effective approach that achieves rapid control of inflammation associated with clinical improvement. (J Pediatr 2012;161:506-12).

免疫グロブリン大量静注療法不応川崎病(KD)に対するシクロスポリンA(CsA)療法時の血中カリウム濃度について検討した。CsA療法を施行したKD症例11例を対象とした。投与直前には、経口摂取不良によると考えられる低カリウム血症を認める症例が存在した。CsA投与開始後3〜7日に血清カリウム濃度の上昇傾向を認め、2例で血清カリウム値が高カリウム血症の定義を満たした。2例ともに心電図変化、不整脈などの有害事象は認めず、CsAの投与量の変更や中止は行わずに経過した。6例において、血漿カリウム値より血清カリウム値が高値を示し、偽性高カリウム血症の定義を満たした。血清カリウム濃度、血漿カリウム濃度の差と、CsA血中濃度(トラフ値)、白血球数、血小板数、CRP値の回帰分析で、血小板数と弱い相関関係を認めた。全例において、CsA投与の前後でeGFR値は基準値内で、有意差を認めなかった。

Kawasaki disease (KD) is a leading cause of acquired heart disease in children in developed countries. Although it has been thought that symptoms of KD are related to hyperactivation of the immune system triggered by infection with some microorganisms, the etiological agent still remains unknown. In this situation, genetic factors underlying the disease pathogenesis, which have been suggested by epidemiological findings, are expected to be clues to the enigma. Recently, susceptibility genes for KD have been identified in succession by studies with a genome-wide approach. Recent advances in genetic studies for KD will be presented. (Circ J 2012; 76: 1581-1586)

We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22-23 (rs2254546, P = 8.2 x 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 x 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 x 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 x 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease.

Kawasaki disease (KD) is a systemic vasculitis syndrome predominantly affecting infants younger than 5 years. We have been trying to identify susceptibility genes for KD by a genome-wide approach. A linkage study of affected sib pairs and subsequent association studies using single nucleotide polymorphisms (SNPs) identified SNPs in ITPKC at 19q13.2 and CASP3 at 4q35 which confer risk for KD in the Japanese and Caucasian children. Recently we performed a genome-wide association study (GWAS) and identified 3 additional susceptibility loci for KD (FAM167A-BLK, HLAclassII and CD40). Associations of the SNPs in FAM167A-BLK and CD40 gene regions were also seen in a GWAS independently performed by a Taiwanese research group. A functional SNP of FCGR2A gene was associated with KD in a GWAS for European KD patients and we replicated the finding in our Japanese samples. Interestingly variations in FAM167A-BLK, CD40 and FCGR2A regions have been associated with several autoimmune diseases of adulthood. We believe further investigation of these loci will foster better understanding of the pathogenesis and pathophysiology of the disease.<br>

Kawasaki disease (KD) is a systemic vasculitis associated with cardiovascular symptom. A previous study in the European descent has indicated that genetic variants of the transforming growth factor-beta (TGF-beta) pathway are involved in the KD susceptibility and clinical status. This study was conducted to investigate if polymorphisms in TGF-beta signaling pathway are associated with KD susceptibility, and the coronary artery lesion formation. A total of 950 subjects (381 KD patients and 569 controls) were investigated to identify 12 single-nucleotide polymorphisms in the TGF-beta signaling pathway (rs2796817, rs10482751, rs2027567, rs12029576, rs11466480, rs4776338, rs12901071, rs7162912, rs1438386, rs6494633, rs12910698 and rs4776339) by using TaqMan Allelic Discrimination assay. Our results indicated that rs1438386 in the SMAD3 is significantly associated with the susceptibility of KD. Additionally, both haplotypes of TGF beta 2 and SMAD3 were also associated with the risk of KD. This study showed that genetic polymorphisms in TGF-beta signaling pathway are associated with KD susceptibility, but not coronary artery lesions formation, or intravenous immunoglobulin treatment response in the Taiwanese population. Journal of Human Genetics (2011) 56, 840-845; doi:10.1038/jhg.2011.113; published online 20 October 2011

Background: There are still no definite treatments for refractory Kawasaki disease (KD). In this pilot study, we evaluated the use of cyclosporin A (CyA) treatment in patients with refractory KD. Methods: We prospectively collected clinical data of CyA treatment (4-8 mg/kg/d, oral administration) for refractory KD patients using the same protocol among several hospitals. Refractory KD is defined as the persistence or recurrence of fever (37.5 degrees C or more of an axillary temperature) at the end of the second intravenous immunoglobulin (2 g/kg) following the initial one. Results: Subjects were enrolled out of 329 KD patients who were admitted to our 8 hospitals between January 2008 and June 2010. Among a total of 28 patients of refractory KD treated with CyA, 18 (64.3%) responded promptly to be afebrile within 3 days and had decreased C-reactive protein levels, the other 4 became afebrile within 4 to 5 days. However, 6 patients (21.4%) failed to become afebrile within 5 days after the start of CyA and/or high fever returned after becoming afebrile within 5 days. Although hyperkalemia developed in 9 patients at 3 to 7 days after the start of CyA treatment, there were no serious adverse effects such as arrhythmias. Four patients (1.2%), 2 before and the other 2 after the start of CyA treatment, developed coronary arterial lesions. Conclusion: CyA treatment is considered safe and well tolerated, and a promising option for patients with refractory KD. Further investigations will be needed to clarify optimal dose, safety, and timing of CyA treatment.

川崎病は1歳前後の乳幼児に多い血管炎症候群である.何らかの感染が契機となって発症すると考えられているが,初めての報告から40年以上が経過した現在においてもその原因は解明されていない.その一方で川崎病には家族内集積性や,東北アジア系に多いという罹患率の明らかな人種差など,遺伝的要因の関与を示唆する疫学データが知られている.近年genome-wide解析により川崎病の罹患関連遺伝子ITPKCおよびCASP3が同定され,また大規模な国際共同研究による新たな罹患関連遺伝子同定の試みも進行中である.複数の罹患関連遺伝子の知見を病因や病態の解明に結びつけていくこと,またIVIG治療への抵抗性や冠動脈病変発生リスクに関連する遺伝子などの同定を通じ,臨床に役立てていくことが今後の課題である.(著者抄録)

Myocardial infarction (MI) occurs as the result of complex interactions of multiple genetic and environmental factors. By conducting a genome wide association study in a Japanese population using 210 785 single nucleotide polymorphism (SNP) markers, we identified a novel susceptible locus for MI on chromosome 5p15.3. An SNP (rs11748327) in this locus showed significant association in several independent cohorts (combined P = 5.3 x 10(-13), odds ratio = 0.80, comparison of allele frequency). Association study using tag SNPs in the same linkage disequilibrium block revealed that two additional SNPs (rs490556 and rs521660) conferred risk of MI. These findings indicate that the SNPs on chromosome 5p15.3 are novel protective genetic factors against MI. Journal of Human Genetics (2011) 56, 47-51; doi:10.1038/jhg.2010.141; published online 25 November 2010

Aneurysms of the vascular wall represent a final common pathway for a number of inflammatory processes, including atherosclerosis and idiopathic vasculitis syndromes. Kawasaki disease (KD) is an acute, self-limited vasculitis in children and the leading cause of acquired coronary artery aneurysms. We sought to identify shared molecular mechanisms of aneurysm formation by genotyping eight polymorphisms in matrix metalloproteinase (MMP)-1, 3, 7, 12 and 13 in the gene cluster on Chr.11q22, whose gene products have been implicated in aneurysm formation or are known to have elastase activity. We genotyped 482 US-UK KD patients (aneurysm+: n=111, aneurysm : n=371) and tested our findings in an independent cohort of 200 Japanese KD patients (aneurysm+: n=58, aneurysm-: n=142). Analysis of the five MMP genes identified modest trends in allele and genotype frequencies for MMP-3 rs3025058 (-/T) and haplotypes containing MMP-3 rs3025058 (-/T) and MMP-12 rs2276109 (A/G) (nominal P=2 to 4x10(-5)) that conferred increased risk of aneurysm formation in US-UK subjects. This finding was validated in Japanese subjects and suggests the importance of this locus in aneurysm formation in children with KD. The region encompassing these risk haplotypes is a prime candidate for resequencing to look for rare genetic variation that may influence aneurysm formation. Journal of Human Genetics (2010) 55, 779-784; doi:10.1038/jhg.2010.109; published online 9 September 2010

Kawasaki disease (KD; OMIM 611775) is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene (CASP3) that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5&apos; untranslated region of CASP3 (rs72689236; P = 4.2 x 10(-8) in the Japanese and P = 3.7 x 10(-3) in the European Americans) abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggest that altered CASP3 expression in immune effecter cells influences susceptibility to KD.

Background: The etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown. Methodology/Principal Findings: We used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., or. four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR) = 2.25, p = 0.004 and OR = 6.26, p = 0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR = 0.21, p = 0.026) and CAL development (OR = 0.44, p = 0.071). Conclusions/Significance: The CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG.

川崎病(Kawasaki disease)は乳幼児に好発する原因不明の急性熱性疾患である.症例の多くは自然軽快するが,無治療で経過した川崎病患児の約20〜25%に冠動脈瘤や拡張に代表される冠動脈病変が生じ先進国における小児の後天性心疾患の最大の原因となっている.川崎病は東アジア,特に日本人に多く発症すること,同胞間の再発危険率が高いことなどから遺伝的要因が原因の一端を担っていると考えられ,その解明に向けた研究が国内外で進んでいる.我々は罹患同胞対解析と連鎖不平衡マッピングを組み合わせたゲノムワイドアプローチによりinositol 1,4,5-trisphosphate 3-kinase-C(ITPKC)が人種間に共通した川崎病の感受性遺伝子であることを発見した.ITPKCがT細胞内におけるNFATを介したサイトカイン産生に抑制的に働くこと,イントロン1に位置する機能的多型によりITPKC産物が減少するメカニズムも判り,川崎病の病態にCa2+/NFAT経路が重要であることが示唆された.Ca2+/NFAT経路を抑制するシクロスポリンA(CsA)やFK506がエヴィデンスに基づく川崎病の治療薬となる可能性を検討中である.今後はさらに検討の幅を広げ,さらなる感受性遺伝子の同定を通じ川崎病の臨床へ貢献したいと考えている.(著者抄録)

川崎病にはその背景に遺伝的要因が存在することが指摘されており、感受性遺伝子同定の試みが成果を上げつつある。筆者らはゲノムワイドアプローチによりITPKC遺伝子上の一塩基多型(SNP)が人種を超えて川崎病の罹患感受性や冠動脈病変リスク等と関連することを見出した。SNPのリスクアレルによるITPKCの発現低下がITPKCのT細胞活性化抑制因子としての作用を減弱させることが川崎病の罹患や重症化の背景となっていると考えられる。今後さらに遺伝的要因の研究が進めば川崎病の病因や人種差の謎が解明され、遺伝子型にもとづくオーダーメイド医療にも道が開けると期待される。(著者抄録)

川崎病は乳幼児期に好発する全身の血管炎症候群であり、先進国の小児後天性心疾患の最大の原因となっている。高熱・発疹を主徴とした臨床像から何らかの感染の関与が疑われるが、発見から40年以上が経過した現在においても原因は不明である。疫学データから遺伝的素因の存在が疑われており、罹患感受性や罹患した際の合併症リスクと関連した遺伝子多型が存在すると考えられている。川崎病のゲノム研究は候補遺伝子を中心として比較的小規模なサンプルにより行われてきたが、近年ゲノムワイドな探索も行われるようになり、成果が報告されつつある。(著者抄録)

Kawasaki disease (KD) is a leading cause of acquired cardiac disease of children in the developed countries. The pathogen that triggers this perplexing disease is still unknown after 40 y from the first description. Epidemiologic findings have made us believe that there are considerable genetic components in the etiology and some candidate genetic variations, which confer susceptibility to KD or risk for coronary artery lesions have been identified. However, most of them remain to be definitively confirmed by replication studies with large cohorts. In this article, I review the candidate gene association studies to date. I also introduce our recent findings in genome-wide approach, which revealed the importance of Ca(2+)/nuclear factor of activated T-cells pathway in the pathogenesis of KD. (Pediatr Res 65: 46R-54R, 2009)

Myocardial infarction is a common disease and among the leading causes of death in the world. We previously reported association of variants in LGALS2, encoding galectin-2, with myocardial infarction susceptibility in a case-control association study in a Japanese population(1). Here we identify BRAP (BRCA1-associated protein) as a galectin-2-binding protein. We report an association of SNPs in BRAP with myocardial infarction risk in a large Japanese cohort (P = 3.0 x 10(-18), OR = 1.48, 2,475 cases and 2,778 controls), with replication in additional Japanese and Taiwanese cohorts (P = 4.4 x 10(-6), 862 cases and 1,113 controls and P = 4.7 x 10(-3), 349 cases and 994 controls, respectively). BRAP expression was observed in smooth muscle cells (SMCs) and macrophages in human atherosclerotic lesions. BRAP knockdown by siRNA using cultured coronary endothelial cells suppressed activation of NF-kappa B, a central mediator of inflammation.

Background and aims: A number of genome-wide association studies have been performed as a robust means of identifying susceptibility loci for Crohn's disease (CD). The loci detected after the completion of the HapMap project are quite concordant among these studies, suggesting that the results are reliable. Recently, the Wellcome Trust Case Control Consortium (WTCCC) reported the primary scanning of 17 000 individuals for seven diseases, including CD, and a subsequent study has validated these susceptible genetic variants in independent UK sample sets. The purpose of this study was to study the possible association of the variants reported by the WTCCC with CD in a Japanese population. Patients and methods: A total of 484 patients with CD and 470 healthy controls were examined. Seventeen genetic variants at eight newly identified loci, including IRGM, NKX2-3 and PTPN2, were genotyped using the TaqMan assay or the invader assay. Results: A positive association signal presumably common to different ethnic groups for rs10883365 was detected in the upstream region of NKX2-3 (p = 0.019 under the genotypic model, p = 0.0065 under the allelic model, p = 0.019 under the recessive model, p = 0.036 under the dominant model). In addition to rs10883365, marginal associations for two single nucleotide polymorphisms (SNPs) were detected in the Japanese population; rs6887695 near IL12B and rs10761659 on 10q21. Further genotype-phenotype analysis found a significant association between rs6887695 and patients with pure ileal CD. Conclusions: The results indicate that the three loci are possible candidates for conferring susceptibility to CD in people of different ethnicities.

Kawasaki disease (KD) is an acute systemic vasculitis syndrome, which primarily affects in children under the age of 5 years. In 20-25% of cases, if untreated, coronary artery lesions develop, making KD the leading cause of acquired heart disease in children in both Japan and the United States. Since 1970, 19 nationwide surveys of KD in Japan have been conducted every 2 years and the data are stored in a database. Even though the etiology of KD remains unknown, despite enthusiastic research spanning more than 40 years, we have learnt a great deal about KD from this enormous database. These 19 epidemiologic studies indicate a strong genetic influence on the disease susceptibility, prompting us and other researchers to identify the responsible genes for KD by applying either the candidate gene approach or the genome-wide approach. We have employed a genome-wide linkage study using affected sibling pair data of KD in Japan and have identified several susceptibility loci. Further analysis focusing on a region of chromosome 19, where one of the linked loci was detected, identified a predisposing gene, which codes inositol 1,4,5-trisphosphate 3-kinase C (ITPKC). In this review, we summarize the cumulative knowledge regarding KD, and then outline our hypothesis of the role ITPKC plays in KD susceptibility and our trial that aims toward the implementation of personalized medicine for KD.

川崎富作博士による川崎病の発見からすでに40年以上が経過し,精力的な研究が続けられて来たにもかかわらず,原因となる病原体は不明であり,治療抵抗群への対応など多くの課題が残されている.一方,疫学調査により,遺伝要因が大きいことが明らかになってきた.最近,我々は人類遺伝学的手法により,ITPKC遺伝子が,川崎病への易罹患性に関与している感受性遺伝子であることを明らかにした.原因となる遺伝子多型が,冠動脈瘤の発生および治療抵抗性に関与している可能性も示唆された.また,これまで不明であったITPKCの役割の1つがT細胞活性化の抑制であることが明らかとなった.遺伝要因の本態が明らかになることで,遺伝子型に基づいた初期治療の選択という個別化医療の可能性が開けた.(著者抄録)

川崎富作博士が川崎病を新しい疾患として発表したのが1967年であるので、すでに40年が経過している。この間、2年ごとの全国的な疫学的調査により多くの知見が集積されてきた。基本的には自然治癒する疾患であるが、冠動脈瘤という重大な合併症がある。急性期治療としてアスピリン内服とγグロブリン療法が効果的であり、冠動脈瘤の発生も抑制するが、治療抵抗例もみられる。また、40年間にわたる精力的な研究にもかかわらず、原因となる病原体はいぜん不明のままである。一方、疫学的調査により、遺伝要因の大きいことが明らかになってきた。最近、著者らは人類遺伝学的手法により、川崎病への易罹患性に関与している感受性遺伝子のひとつを明らかにした。原因となる遺伝子多型が冠動脈瘤の発生および治療抵抗性に関与している可能性が示唆された。この知見を遺伝子型に基づいた初期治療の選択という個別化医療に応用できる可能性が開けた。(著者抄録)