ヒトゲノム多様性研究室

熱帯感染症とヒトの遺伝的適応


感染症にかかりにくいヒト、感染症にかかった場合に、重症化するヒトとしないヒトがいます。遺伝的な違いにより、体内で作られる酵素やタンパク質の機能・量に差が生じ、感染症感受性・重症化に影響を与えている可能性があります。
マラリア

マラリアは熱帯・亜熱帯地域に生息するハマダラ蚊属の蚊の吸血によって媒介する感染症で、熱帯熱マラリア・四日熱マラリア・三日熱マラリア・卵型マラリアの4種類があります。その中でも熱帯熱マラリアは症状が重く、重症化すると死亡することもまれではありません。
2011年の世界マラリア・レポートによると、2010年のマラリア患者数は約2億1600万人、マラリアによる死亡者数は65万人と推定されています。死亡者の大部分はサハラ以南のアフリカに住む5歳以下の子供です。2010年には、99の国と地域にマラリア感染が確認されており、アフリカのみならず、東南アジア諸国・南アジア・オセアニア・中南米でも多くの感染がみられます。
私たちは、タイ北西部に居住するタイ人マラリア患者を対象として、脳性マラリアなどのマラリア重症化に対する感受性または抵抗性を示す遺伝子多型の検出とその進化学的解析を行っています。また、マラリア患者(ホスト)とその患者に感染している熱帯熱マラリア原虫(病原体)を対象に、マラリア感染の成立・維持の過程において、直接的に作用しあうヒト側分子と原虫側分子をコードする遺伝子を解析して、ヒトと原虫の遺伝子多型間の相互作用や、多型や遺伝子に作用する正の自然選択の検出を試みています。


デング熱

デングウイルスの感染によって引き起こされるデング熱は、ネッタイシマカ・ヒトスジシマカの吸血によって媒介する感染症です。デング熱は媒介者であるネッタイシマカの生息域と感染地域がほぼ一致しており、全世界で年間約1億人がデング熱を発症し、約25万人がデング出血熱を発症していると考えられています。アジアを中心に熱帯・亜熱帯地域が主な感染地域ですが、昨今の地球温暖化により媒介蚊の生息範囲の拡大が懸念されています。

デング熱は軽症ですみますが、デング出血熱という重篤な病型をとると、ショック症状で死亡することもあります。デングウイルスにはI〜IV型の4つのタイプがあり、異なるタイプのウイルスに感染する2度目の感染が、デング出血熱を発症するリスクの1つであることが知られています。しかし、2度目の感染でも重症化しない個体がほとんどであり、重症化の原因についてはよく理解されていません。
私たちは、タイに居住するデング熱・デング出血熱の患者(15歳以下の子供)を対象として、感染したウイルスのタイプや年齢を調整した上で、デング出血熱に対する感受性または抵抗性を示すヒト遺伝子多型の検出を目指しています。


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  本研究に関する文献


Kamori D, Hasan Z, Ohashi J, Kawana-Tachikawa A, Gatanaga H, Oka S, Ueno T (2017) Identification of two unique naturallyoccurring Vpr sequence polymorphisms associated with clinical parameters in HIV-1 chronic infection. Journal of MedicalVirology 89: 123-129.


Dang TN, Naka I, Sa-Ngasang A, Anantapreecha S, Wichukchinda N, Sawanpanyalert P, Patarapotikul P, Tsuchiya N, Ohashi J(2016) Association of BAK1 single nucleotide polymorphism with a risk for dengue hemorrhagic fever. BMC Medical Genetics17: 43.


Ohashi J, Naka I, Hananantachai H, Patarapotikul J (2016) Association of PECAM1/CD31 polymorphisms with cerebral malaria.International Journal of Molecular Epidemiology and Genetics 7: 87?94.


Mita T, Culleton R, Takahashi N, Nakamura M, Tsukahara T, Hunja C, Win Z, Htike W, Marma A, Dysoley L, Ndounga M,Dzodzomenyo M, Akhwale W, Kobayashi J, Uemura H, Kaneko A, Hombhanje F, Ferreira M, Endo H, Ohashi J (2016) Littlepolymorphism at the K13 propeller locus in worldwide Plasmodium falciparum populations prior to the introduction ofartemisinin combination therapies. Antimicrobial Agents and Chemotherapy 60: 3340-3347.


Yasukochi Y, Naka I, Hananantachai H, Patarapotikul J, Ohashi J (2015) Genetic evidence for contribution of  human dispersal to the genetic diversity of EBA-175 in Plasmodium falciparum. Malaria Journal, in press


Dang TN, Naka I, Sa-Ngasang A, Anantapreecha S, Chanama S, Wichukchinda N, Sawanpanyalert P, Patarapotikul P,TsuchiyaN, Ohashi J (2014) A replication study confirms the association of GWAS-identified SNPs at MICB and PLCE1 in Thai  patients  with dengue shock syndrome. BMC Medical Genetics 15: 58.


Naka I, Patarapotikul J, Hananantachai H, Imai H, Ohashi J*(2014)  Association of the endothelial protein C receptor (PROCR)rs867186-G allele with protection from severe malaria. Malaria Journal 13:105  doi:10.1186/1475-2875-13-105.


Naka I, Patarapotikul J, Hananantachai H, Ohashi J* (2014) Lack of Association between BSG Polymorphisms and Cerebral  Malaria. Japanese Journal of Infectious Diseases 67(6):432-5.


Honma H, Hirai M, Nakamura S, Hakimi H, Kawazu S, Palacpac NMQ, Hisaeda H, Matsuoka H, Kawai S, Endo H,YasunagaT,Ohashi J, Mita T, Horii T, Furusawa M, Tanabe K (2014)  Generation of rodent malaria parasites with a high mutation rate by  destructing proof reading activity of DNA polymerase δ. DNA Research (4):439-46.


Ohashi J*, Suzuki Y, Naka I, Hananantachai H, Patarapotikul J (2014)  Diversifying selection on the thrombospondin-related  adhesive protein (TRAP) gene of Plasmodium falciparum in Thailand. PLoS ONE 9: e90522.


Sa-Ngasang A, Ohashi J, Naka I, Anantapreecha S, Sawanpanyalert P, Patarapotikul J (2014) Association of IL1B -31C/T and  IL1RA variable number of an 86-bp tandem repeat with Dengue Shock Syndrome in Thailand. The Journal of Infectious  Diseases 210(1):138-145.


Mita T, Ohashi J, Nakamura M, Endo H, Tanabe K (2014) Ordered accumulation of mutations conferring resistance tosulfadoxine-pyrimethamine in the Plasmodium falciparum parasite. The Journal of Infectious Diseases209: 130-139.


Hirayasu K*, Ohashi J, Kashiwase K, Hananantachai H, Naka I, Ogawa A, Takanashi M, Satake M, Nakajima K, Arase H,Tokunaga K, Patarapotikul J, Yabe T* (2012) Significant association of KIR2DL3-HLA-C1 combination with cerebral malaria  and implications for co-evolution of KIR and HLA. PLoS Pathogens 8: e1002565.


Kraisin S, Naka I, Patarapotikul J, Nantakomol D, Nuchnoi P, Hananantachai H, Tsuchiya N, Ohashi J* (2011) Association of  ADAMTS13 polymorphism with cerebral malaria. Malaria Journal 10: 366.


Mita T*, Venkatesan M, Ohashi J, Culleton R, Takahashi N, Tsukahara T, Ndounga M, Dysoley L, Endo H, Hombhanje F,Ferreira MU, Plowe CV, Tanabe K (2011) Limited geographical origin and global spread of sulfadoxine-resistant dhps alleles inPlasmodium falciparum populations. The Journal of Infectious Diseases 204: 1980-1988.


Naka I, Patarapotikul J, Tokunaga K, Hananantachai H, Tsuchiya N, Ohashi J* (2009) A replication study of the associationbetween the IL12B promoter allele CTCTAA and susceptibility to cerebral malaria in Thai population. Malaria Journal 8: 290.


Naka I, Nishida N, Patarapotikul J, Nuchnoi P, Tokunaga K, Hananantachai H, Tsuchiya N, Ohashi J* (2009) Identification of a  haplotype block in the 5q31 cytokine gene cluster associated with the susceptibility to severe malaria. Malaria Journal 8: 232.


Noranate N, Prugnolle F, Jouin H, Tall A, Marrama L, Sokhna C, Ekala MT, Guillotte M, Bischoff E, Bouchier C,Patarapotikul J,Ohashi J, Trape JF, Rogier C, Mercereau-Puijalon O* (2009) Population diversity and antibody selective pressure to  Plasmodium falciparum MSP1 block2 locus in an African malaria-endemic setting. BMC Microbiology 9: 219.


Naka I, Patarapotikul J, Hananantachai H, Tokunaga K, Tsuchiya N, Ohashi J* (2009) IFNGR1 polymorphisms in Thai malariapatients. Infection, Genetics and Evolution 9: 1406-1409.


Teeranaipong P, Ohashi J*, Patarapotikul J, Kimura R, Nuchnoi P, Hananantachai H, Naka I, Putaporntip C, Jongwutiwes S,Tokunaga K (2008) A Functional SNP in the CR1 Promoter Region Contributes to Protection against Cerebral Malaria.TheJournal of Infectious Diseases 198: 1880-1891.


Nuchnoi P, Ohashi J*, Naka I, Nacapunchai D, Tokunaga K, Nishida N, Patarapotikul J (2008) Linkage DisequilibriumStructure of the 5q31-33 Region in a Thai Population. Journal of Human Genetics 53: 850-856.


Naka I, Ohashi J*, Nuchnoi P, Hananantachai H, Looareesuwan S, Tokunaga K ,Patarapotikul J (2008) Lack ofassociation ofthe HbE variant with protection from cerebral malaria in Thailand. Biochemical Genetics 46: 708-711.


Nuchnoi P, Ohashi J*, Kimura R, Hananantachai H, Naka I, Krudsood S, Looareesuwan S, Tokunaga K, Patarapotikul J (2008)Significant association between TIM1 promoter polymorphisms and protection against cerebral malaria inThailand. Annals ofHuman Genetics72: 327-336.


Naka I, Ohashi J*, Patarapotikul J, Hananantachai H, Wilairatana P, Looareesuwan S, Tokunaga K (2007) The genotypes ofGYPA and GYPB carrying the MNSs antigens are not associated with cerebral malaria. Journal of Human Genetics 52: 476-479.


Hananantachai H, Patarapotikul J, Ohashi J*, Naka I, Krudsood S, Looareesuwan S, Tokunaga K (2007) Significant association between TNF-α (TNF) promoter allele (-1031C, -863C, and -857C) and cerebral malaria in Thailand. TissueAntigens 69: 277-280.


Dechkum N, Hananantachai H, Patarapotikul J*, Ohashi J, Krudsood S, Looareesuwan S, Tokunaga K (2006) Monocyte Chemoattractant Protein 1 (MCP-1) Gene Polymorphism Is Not Associated with Severe and Cerebral Malaria in Thailand.Japanese Journal of Infectious Diseases 59: 239-244.


Jalloh A*, van Thien H, Ferreira MU, Ohashi J, Matsuoka H, Kanbe T, Kikuchi A, Kawamoto F (2006) Sequence Variationin theT-Cell Epitopes of the Plasmodium falciparum Circumsporozoite Protein among Field Isolates Is Temporally Stable:a 5-YearLongitudinal Study in Southern Vietnam. Journal of Clinical Microbiology 44: 1229-1235.


Ohashi J*, Naka I, Patarapotikul J, Hananantachai H, Tangpukdee N, Looareesuwan S, Tokunaga K (2005) A functional polymorphism in the IL1B gene promoter, IL1B -31C>T, is not associated with cerebral malaria in Thailand. Malaria Journal 4:38.


Ohashi J*, Naka I, Patarapotikul J, Hananantachai H, Brittenham G, Looareesuwan S, Clark AG, Tokunaga K (2005)Stronglinkage disequilibrium of a HbE variant with the (AT)9(T)5 repeat in the BP1 binding site upstream of the beta-globingene in Thai population. Journal of Human Genetics 50: 7-11.


Hananantachai H, Patarapotikul J, Ohashi J*, Naka I, Looareesuwan S, Tokunaga K (2005) Polymorphisms of HLA-B and HLA-DRB1 genes in Thai malaria patients. Japanese Journal of Infectious Diseases 58: 25-28.


Ohashi J*, Naka I, Patarapotikul J, Hananantachai H, Brittenham G, Looareesuwan S, Clark AG, Tokunaga K (2004) Extendedlinkage disequilibrium surrounding the hemoglobin E variant due to malarial selection. American Journal of HumanGenetics74: 1198-1208.


Ohashi J*, Naka I, Patarapotikul J, Hananantachai H, Looareesuwan S, Tokunaga K (2003) A single nucleotide substitutionfrom C to T at position -1055 in the IL-13 promoter is associated with protection from severe malaria in Thailand. Genes andImmunity 4: 528-531.


Naka I, Ohashi J*, Patarapotikul J, Hananantachai H, Looareesuwan S, Tokunaga K (2003) Genetic variants of ?-globingene inThai malaria patients. Southeast Asian Journal of Tropical Medicine and Public Health 34: 29-31.


Omi K, Ohashi J*, Patarapotikul J, Hananantachai H, Naka I, Looareesuwan S, Tokunaga K (2003) CD36 polymorphismisassociated with protection from cerebral malaria. American Journal of Human Genetics 72: 364-374.


Omi K, Ohashi J*, Patarapotikul J, Hananantachai H, Naka I, Looareesuwan S, Tokunaga K (2002) Absence of Associationbetween the Fc? receptor IIIA-176F/V Polymorphism and the Severity of Malaria in Thai. Japanese Journal of InfectiousDiseases 55: 167-169.


Omi K, Ohashi J*, Patarapotikul J, Hananantachai H, Naka I, Looareesuwan S, Tokunaga K (2002) Fcg receptor IIA and IIIBpolymorphisms are associated with susceptibility to cerebral malaria. Parasitology International 51: 361-366.


Ohashi J*, Naka I, Patarapotikul J, Hananantachai H, Looareesuwan S, Tokunaga K (2002) Significant association of longerforms of CCTTT microsatellite repeat in inducible nitric oxide synthase (iNOS) promoter with severe malaria in Thailand. TheJournal of Infectious Diseases 186: 578-581.


Ohashi J*, Naka I, Patarapotikul J, Hananantachai H, Looareesuwan S, Tokunaga K (2001) Absence of association betweenthe allele coding methionine at position 29 in the N-terminal domain of ICAM-1 (ICAM-1Kilifi) and severe malariain thenorthwest of Thailand. Japanese Journal of Infectious Diseases 54: 114-116.


Hananantachai H, Patarapotikul J, Looareesuwan S, Ohashi J*, Naka I, Tokunaga K (2001) Lack of association of -308A/GTNFA promoter and 196R/M TNFR2 polymorphisms with disease severity in Thai adult malaria patients. American Journal ofMedical Genetics 102: 391-392.