Browsing by Author "Hathairad Hananantachai"

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    Absence of association between the allele coding methionine at position 29 in the N-terminal domain of ICAM-1 (ICAM-1Kilifi) and severe malaria in the northwest of Thailand
    (2001-10-08) Jun Ohashi; Izumi Naka; Jintana Patarapotikul; Hathairad Hananantachai; Sornchai Looareesuwan; Katsushi Tokunaga; University of Tokyo; Mahidol University
    Intercellular adhesion molecule 1 (ICAM-1) is known to be the endothelial receptor for Plasmodium falciparum-infected erythrocytes. Associations of the variant allele coding methionine at position 29 in the N-terminal domain of ICAM-1, ICAM-1Kilifi, with severe malaria have been investigated in African populations, and the results of these investigations have varied widely. In this study, we investigated a possible association between the ICAM-1Kilifi and severe malaria in adult malaria patients living in northwest Thailand. The frequencies of the ICAM-1Kilifi among patients with mild malaria, with non-cerebral severe malaria, and with cerebral malaria were 1.7%, 2.7%, and 2.3%, respectively. This variant showed neither positive nor negative association with severe malaria in Thailand.
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    Absence of association between the Fcγ receptor IIIA-176F\ V polymorphism and the severity of malaria in Thai
    (2002-10-01) Kazuya Omi; Jun Ohashi; Jintana Patarapotikul; Hathairad Hananantachai; Izumi Naka; Sornchai Looareesuwan; Katsushi Tokunaga; Mahidol University; University of Tokyo
    Human Fcγ receptor (FcγR) genes form a clustered gene family, which consists of Fcγ RIIA, IIB, IIC, IIIA, and IIIB genes, on chromosome 1q23. We previously reported that the Fcγ RIIA-131H/H genotype in combination with the FcγRIIIB-NA2 allele is associated with susceptibility to cerebral malaria, and that such an association can be caused by linkage disequilibrium (LD) between these polymorphisms and the primary associated gene(s) in this region. FcγRIIIA is known to exhibit the genetic polymorphism FcγRIIIA-176F/V coded for different affinity to IgG1 and IgG3. In this study, we examined a possible association between FcγRIIIA-176F/V polymorphism and severity of malaria in 462 adult Thai patients with Plasmodium falciparum malaria. The frequencies of FcγRIIIA-176V among patients with mild malaria, with non-cerebral severe malaria, and with cerebral malaria were 32.7%, 29.9%, and 36.3%, respectively. This polymorphism showed neither positive nor negative association with the severity of malaria. Thus, we concluded that the association of FcγRIIA-131H/R and FcγRIIIB-NA1/NA2 polymorphisms with cerebral malaria in Thailand is not due to the LD caused by FcγRIIIA-176F/V.
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    Association of ADAMTS13 polymorphism with cerebral malaria
    (2011-12-15) Sirima Kraisin; Izumi Naka; Jintana Patarapotikul; Duangdao Nantakomol; Pornlada Nuchnoi; Hathairad Hananantachai; Naoyuki Tsuchiya; Jun Ohashi; University of Tsukuba; Chulalongkorn University; Mahidol University
    Background: Cerebral malaria is one of the most severe manifestations of Plasmodium falciparum malaria. The sequestration of parasitized red blood cells (PRBCs) to brain microvascular endothelium has been shown to contribute to the pathophysiology of cerebral malaria. Recent studies reported increased levels of von Willebrand factor (VWF) and reduced activity of VWF-cleaving protease, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), in patients with cerebral malaria. Methods. Association of six single nucleotide polymorphisms (SNPs) of the ADAMTS13 gene with cerebral malaria was examined in 708 Thai patients with P. falciparum malaria. Results: Among six SNPs, the derived allele of a SNP located in intron 28, rs4962153-A, was significantly associated with protection against cerebral malaria when 115 cerebral malaria patients were compared with 367 mild malaria patients (Fisher's exact P-value = 0.0057; OR = 0.27; 95% CI = 0.096-0.76). Significant association was also detected between 115 cerebral malaria and 593 non-cerebral malaria (226 non-cerebral severe malaria and 367 mild malaria) patients (Fisher's exact P-value = 0.012; OR = 0.30; 95% CI = 0.11-0.83). Conclusions: Excessive adhesion of PRBCs to the platelet-decorated ultra-large VWF (ULVWF) appears to enhance the sequestration of PRBCs to cerebral microvascular endothelium. The genetic association observed in the present study implies that the regulation of platelet-decorated ULVWF strings by ADAMTS13 may play a role in the development of cerebral malaria. © 2011 Kraisin et al; licensee BioMed Central Ltd.
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    Association of low density lipoprotein receptor related protein 5 genetic variation, a133v and BMD in thai menopausal women
    (2014) Anong Kitjaroentham; อนงค์ กิจเจริญธรรม; Hathairad Hananantachai; หทัยรัชต หาญอนันตชัย; Benjaluck Phonrat; Sangchai Preutthipan; Rungsunn Tungtrongchitr; รังสรรค์ ตั้งตรงจิตร; Mahidol University. Faculty of Tropical Medicine. Department of Tropical Nutrition and Food Science; Mahidol University. Faculty of Tropical Medicine. Department of Social and Environmental Medicine; Mahidol University. Faculty of Tropical Medicine. Department of Clinical Medicine
    Postmenopausal osteoporosis and bone mass are influenced by multiple factors including genetics. Low density lipoprotein receptor related protein 5 (LRP5), a co-receptor of Wnt signaling, is an important regulator of bone development and maintenance. The presence of a LRP5 single nucleotide polymorphism (SNP), A1330V, was determined by PCR-RFLP method in 332 Thai menopausal women. AA genotype subjects had lower radial BMD (p value = 0.015). Furthermore, women with low BMI (≤ 25) had higher risk of radial BMD osteoporosis (Odd’s ratio = 7.41, p value = 0.007) but aging (50 years) and A1330V SNP had no effect. In conclusion, LRP5 A1330V SNP may contribute to osteoporosis susceptibility in Thai menopausal women.
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    Association of PECAM1/CD31 polymorphisms with cerebral malaria
    (2016-01-01) Jun Ohashi; Izumi Naka; Hathairad Hananantachai; Jintana Patarapotikul; University of Tokyo; University of Tsukuba; Mahidol University
    © E-Century Publishing Corporation. All rights reserved. Platelet/endothelial cell adhesion molecule-1 (PECAM1/CD31), a receptor recognized by P. falciparum-infected red blood cells (iRBCs), on the vascular endothelium has been implicated in mediating cytoadherence in patients with P. falciparum malaria. To examine associations of PECAM1 polymorphisms with cerebral malaria, 11 tag single nucleotide polymorphisms (SNPs) of PECAM1 were analysed for 312 Thai patients with P. falciparum malaria (109 with cerebral malaria and 203 with mild malaria). The rs1122800-C allele was significantly associated with protection from cerebral malaria (P = 0.017), and the rs9912957-A significantly increased the risk for cerebral malaria (P = 0.0065) in malaria patients. Fine-scale mapping using genotyped and imputed SNPs and linkage disequilibrium (LD) analysis revealed that rs1122800 and rs9912957 were located in two distinct LD blocks and were independently associated with cerebral malaria. The rs1122800-C allele was significantly associated with lower expression level of PECAM1 in EBV-transformed lymphoblastoid cell lines (P = 0.045). The present results suggest that PECAM1-mediated cytoadherence of iRBCs to brain endothelium plays a crucial role in the pathogenesis of cerebral malaria.
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    Association of the endothelial protein C receptor (PROCR) rs867186-G allele with protection from severe malaria
    (2014-03-17) Izumi Naka; Jintana Patarapotikul; Hathairad Hananantachai; Hiroo Imai; Jun Ohashi; University of Tsukuba; Mahidol University; Kyoto University
    Background: Cytoadhesion of Plasmodium falciparum-infected erythrocytes to endothelial cells in microvessels is a remarkable characteristic of severe malaria. The endothelial protein C receptor (EPCR), encoded by the endothelial protein C receptor gene (PROCR), has recently been identified as an endothelial receptor for specific P. falciparum erythrocyte membrane protein 1 (PfEMP1) subtypes containing domain cassettes (DCs) 8 and 13. The PROCR rs867186-G allele (serine-to-glycine substitution at position 219 of EPCR; 219Gly) has been shown to be associated with higher levels of plasma soluble EPCR (sEPCR). In this study, the association of PROCR rs867186 with severe malaria is examined in Thai population. Methods. A total of 707 Thai patients with P. falciparum malaria (341 with severe malaria and 336 with mild malaria) were genotyped for rs867186. To assess the association of PROCR rs867186 with severe malaria, three models (dominant, recessive and allelic) were evaluated. The rates of non-synonymous and synonymous substitutions were estimated for the coding sequence of the PROCR gene. Results: The rs867186-GG genotype was significantly associated with protection from severe malaria (P-value = 0.026; odds ratio = 0.33; 95% confidence interval = 0.12-0.90). Evolutionary analysis provided no evidence of strong positive selection acting on the PROCR gene. Conclusion: The rs867186-GG genotype showed significant association with protection from severe malaria. The present results suggest that PfEMP1-EPCR interaction, which can mediate cytoadhesion and/or reduce cytoprotective and anti-inflammatory effects, is crucial to the pathogenesis of severe malaria. © 2014 Naka et al.; licensee BioMed Central Ltd.
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    CD36 polymorphism is associated with protection from cerebral malaria
    (2003-02-01) Kazuya Omi; Jun Ohashi; Jintana Patarapotikul; Hathairad Hananantachai; Izumi Naka; Sornchai Looareesuwan; Katsushi Tokunaga; University of Tokyo; Mahidol University
    The human protein CD36 is a major receptor for Plasmodium falciparum-infected erythrocytes and contributes to the pathology of P. falciparum malaria. We performed variation screening of the CD36 gene and examined the possible association between CD36 polymorphisms and the severity of malaria in 475 adult Thai patients with P. falciparum malaria. Accordingly, we identified nine CD36 polymorphisms with a high-frequency (>15%) minor allele. Of these, the frequencies of the - 14T→C allele in the upstream promoter region and the - 53G→T allele in the downstream promoter region were significantly decreased in patients with cerebral malaria compared to those with mild malaria (P = .016 for - 14T→C and P = .050 for - 53G→T). The analysis of linkage disequilibrium (LD) between the nine common polymorphisms revealed that there are two blocks with strong LD in the CD36 gene and that the - 14T→C and - 53G→T polymorphisms are within the upstream block of 35 kb from the upstream promoter to exon 8. Further association testing after the second variation screening in the upstream block indicated that the in3(TG)12(i.e., 12 TG repeats in intron 3) allele is most strongly associated with the reduction in the risk of cerebral malaria (odds ratio 0.59; 95% confidence interval 0.40-0.87; P = .0069). We found, by reverse-transcriptase PCR amplification, that in3(TG)12is involved in the nonproduction of the variant CD36 transcript that lacks exons 4 and 5. Since exon 5 of the gene is known to encode the ligand-binding domain for P. falciparum-infected erythrocytes, in3(TG)12itself or a primary variant on the haplotype with in3(TG)12may be responsible for protection from cerebral malaria in Thailand. Results of the present study suggest that LD mapping has potential for detecting a disease-associated variant on the basis of haplotype blocks.
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    Comparative study of heavy metal and pathogenic bacterial contamination in sludge and manure in biogas and non-biogas swine farms
    (2011-06-01) Phitsanu Tulayakul; Alongkot Boonsoongnern; Suwicha Kasemsuwan; Srisamai Wiriyarampa; Juree Pankumnoed; Suwanna Tippayaluck; Hathairad Hananantachai; Ratchaneekorn Mingkhwan; Ramnaree Netvichian; Sutha Khaodhiar; Kasetsart University; Mahidol University; Chulalongkorn University
    The objective of this study is to determine and compare the heavy metal (Zn, Cu, Cd, Pb) and bacterial (E. coli, coliform and Salmonella spp.) contamination between swine farms utilizing biogas and non-biogas systems in the central part of Thailand. Results showed that average levels of E. coli, coliform, BOD, COD, Zn, Cu and Pb in sludge from the post-biogas pond were higher than the standard limits. Moreover, the levels of E. coli, coliform, Cd and Pb were also higher than the standard limits for dry manure. The levels of E. coli, coliform and BOD on biogas farms were lower than on non-biogas farms. Following isolation of Salmonella spp., it was found that Salmonella serovars Rissen was the most abundant at 18.46% (12/65), followed by Anatum 12.31% (8/65), and Kedougou 9.23% (6/65). The pathogenic strains of Salmonella serovars Paratyphi B var. java and Typhimurium were present in equal amounts at 4.62% (3/65) in samples from all swine farms. This study revealed that significant reduction in E. coli and coliform levels in sludge from covered lagoon biogas systems on swine farms. The presence of Salmonella as well as Cd and Pb, in significant amount in dry manure, suggests that there is a high probability of environmental contamination if it is used for agricultural purposes. Thus, careful waste and manure disposal from swine farms and the regular monitoring of wastewater is strongly recommended to ensure the safety of humans, other animals and the environment. © 2011 The Research Centre for Eco-Environmental Sciences, Chinese Academy of Sciences.
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    Critical factors on chemical properties and heavy metals in water for livestock farms in Thailand
    (2013-01-01) Teeraporn Makaroon; Suwicha Kasemsuwan; Nattavut Ratanavanichrojn; Hathairad Hananantachai; Rachaneekorn Mingkhwan; Sutha Khaodhiar; Phitsanu Tulayakul; Faculty of Veterinary Medicine; Kasetsart University; Mahidol University; Chulalongkorn University
    This study aimed to investigate chemical quality of animal drinking used in livestock farms in Thailand. Samples and information from 68 pig farms, 35 chicken farms and 9 duckling farms were collected during March to August 2011. Water quality data were analyzed and compared with standard levels using the Mann-Whitney U and Wilcoxon Signed Rank Tests. Results revealed that median chemical values of water for livestock were generally within standard levels, except manganese and iron, which were detected in surfacewater with median values of 0.183 and 0.506 ppm, respectively, and are both higher than standard limits for drinking water. Median pH value in groundwater was 6.85, which was significantly (p < 0.05) lower than pH value (7.23) in surfacewater, and median level of hardness was 169.5 ppm in groundwater, which was significantly higher than that of surface water. Logistic regression was performed to identify a common source of water chemical contaminants and revealed that farms located outside the western region of Thailand and using surfacewater for their livestock were at risk of the high manganese levels in the water. Moreover, analyzed data from Department of Groundwater Resources of Thailand demonstrated high amount of hardness, manganese and iron in groundwater of Thailand, correlated with our findings. Thus, farms using surface or underground water should be aware of high level of manganese, iron and hardness.
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    Diversifying selection on the thrombospondin-related adhesive protein (TRAP) gene of plasmodium falciparum in Thailand
    (2014-02-28) Jun Ohashi; Yuji Suzuki; Izumi Naka; Hathairad Hananantachai; Jintana Patarapotikul; University of Tsukuba; Mahidol University
    Sporozoites of Plasmodium falciparum are transmitted to human hosts by Anopheles mosquitoes. Thrombospondin-related adhesive protein (TRAP) is expressed in sporozoites and plays a crucial role in sporozoite gliding and invasion of human hepatocytes. A previous study showed that the TRAP gene has been subjected to balancing selection in the Gambian P. falciparum population. To further study the molecular evolution of the TRAP gene in Plasmodium falciparum, we investigated TRAP polymorphisms in P. falciparum isolates from Suan Phueng District in Ratchaburi Province, Thailand. The analysis of the entire TRAP coding sequences in 32 isolates identified a total of 39 single nucleotide polymorphisms (SNPs), which comprised 37 nonsynonymous and two synonymous SNPs. McDonald-Kreitman test showed that the ratio of the number of nonsynonymous to synonymous polymorphic sites within P. falciparum was significantly higher than that of the number of nonsynonymous to synonymous fixed sites between P. falciparum and P. reichenowi. Furthermore, the rate of nonsynonymous substitution was significantly higher than that of synonymous substitution within Thai P. falciparum. These results indicate that the TRAP gene has been subject to diversifying selection in the Thai P. falciparum population as well as the Gambian P. falciparum population. Comparison of our P. falciparum isolates with those from another region of Thailand (Tak province, Thailand) revealed that TRAP was highly differentiated between geographically close regions. This rapid diversification seems to reflect strong recent positive selection on TRAP. Our results suggest that the TRAP molecule is a major target of the human immune response to pre-erythrocytic stages of P. falciparum. © 2014 Ohashi et al. This.
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    Evolution of Fseg/Cseg dimorphism in region III of the Plasmodium falciparum eba-175 gene
    (2017-04-01) Yoshiki Yasukochi; Izumi Naka; Jintana Patarapotikul; Hathairad Hananantachai; Jun Ohashi; Mie University; University of Tokyo; Mahidol University
    © 2017 Elsevier B.V. The 175-kDa erythrocyte binding antigen (EBA-175) of the malaria parasite Plasmodium falciparum is important for its invasion into human erythrocytes. The primary structure of eba-175 is divided into seven regions, namely I to VII. Region III contains highly divergent dimorphic segments, termed Fseg and Cseg. The allele frequencies of segmental dimorphism within a P. falciparum population have been extensively examined; however, the molecular evolution of segmental dimorphism is not well understood. A comprehensive comparison of nucleotide sequences among 32 P. falciparum eba-175 alleles identified in our previous study, two Plasmodium reichenowi, and one P. gaboni orthologous alleles obtained from the GenBank database was conducted to uncover the origin and evolutionary processes of segmental dimorphism in P. falciparum eba-175. In the eba-175 nucleotide sequence derived from a P. reichenowi CDC strain, both Fseg and Cseg were found in region III, which implies that the original eba-175 gene had both segments, and deletions of F- and C-segments generated Cseg and Fseg alleles, respectively. We also confirmed the presence of allele with Fseg and Cseg in another P. reichenowi strain (SY57), by re-mapping short reads obtained from the GenBank database. On the other hand, the segmental sequence of eba-175 ortholog in P. gaboni was quite diverged from those of the other species, suggesting that the original eba-175 dimorphism of P. falciparum can be traced back to the stem linage of P. falciparum and P. reichenowi. Our findings suggest that Fseg and Cseg alleles are derived from a single eba-175 allele containing both segments in the ancestral population of P. falciparum and P. reichenowi, and that the allelic dimorphism of eba-175 was shaped by the independent emergence of similar dimorphic lineage in different species that has never been observed in any evolutionary mode of allelic dimorphism at other loci in malaria genomes.
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    Extended linkage disequilibrium surrounding the hemoglobin E variant due to malarial selection
    (2004-01-01) Jun Ohashi; Izumi Naka; Jintana Patarapotikul; Hathairad Hananantachai; Gary Brittenham; Sornchai Looareesuwan; Andrew G. Clark; Katsushi Tokunaga; University of Tokyo; Cornell University; Mahidol University; Columbia University, College of Physicians and Surgeons
    The hemoglobin E variant (HbE;β26Glu→Lys) is concentrated in parts of Southeast Asia where malaria is endemic, and HbE carrier status has been shown to confer some protection against Plasmodium falciparum malaria. To examine the effect of natural selection on the pattern of linkage disequilibrium (LD) and to infer the evolutionary history of the HbE variant, we analyzed biallelic markers surrounding the HbE variant in a Thai population. Pairwise LD analysis of HbE and 43 surrounding biallelic markers revealed LD of HbE extending beyond 100 kb, whereas no LD was observed between non-HbE variants and the same markers. The inferred haplotype network suggests a single origin of the HbE variant in the Thai population. Forward-in-time computer simulations under a variety of selection models indicate that the HbE variant arose 1,240-4,440 years ago. These results support the conjecture that the HbE mutation occurred recently, and the allele frequency has increased rapidly. Our study provides another clear demonstration that a high-resolution LD map across the human genome can detect recent variants that have been subjected to positive selection.
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    Fcγ receptor IIA and IIIB polymorphisms are associated with susceptibility to cerebral malaria
    (2002-12-01) Kazuya Omi; Jun Ohashi; Jintana Patarapotikul; Hathairad Hananantachai; Izumi Naka; Sornchai Looareesuwan; Katsushi Tokunaga; University of Tokyo; Mahidol University
    Human FcγRIIA and FcγRIIIB exhibit genetic polymorphisms, FcγRIIA-131H/R and FcγRIIIB-NA1/NA2, coding for different capacities for IgG binding and phagocytosis. Recently, FcγRIIA-131R was reported to be associated with protection against high-density Plasmodium falciparum infection in Kenya. Furthermore, FcγRIIIB-NA1/NA2 polymorphism was shown to influence FcγRIIA function in an allele-specific manner. In this study, we examined a possible association of FcγRIIA-131H/R and FcγRIIIB-NA1/NA2 polymorphisms with malaria severity in 107 cerebral malaria patients, 157 non-cerebral severe malaria patients, and 202 mild malaria controls living in northwest Thailand. This study reveals that, with the FcγRIIIB-NA2 allele, the FcγRIIA-131H/H genotype is associated with susceptibility to cerebral malaria (OR 1.85, 95% CI 1.14-3.01; P=0.012), although these polymorphisms are not individually involved in the disease severity. Our results suggest that FcγRIIA-131H/R and FcγRIIIB-NA1/NA2 polymorphisms have an interactive effect on host defense against malaria infection. © 2002 Elsevier Science Ireland Ltd. All rights reserved.
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    A functional polymorphism in the IL1B gene promoter, IL1B -31C>T, is not associated with cerebral malaria in Thailand
    (2005-08-14) Jun Ohashi; Izumi Naka; Akihiro Doi; Jintana Patarapotikul; Hathairad Hananantachai; Noppadon Tangpukdee; Sornchai Looareesuwan; Katsushi Tokunaga; University of Tokyo; Mahidol University
    Background: IL-1β and IL-1RA levels are higher in the serum of cerebral malaria patients than in patients with mild malaria. Recently, the level of IL1B expression was reported to be influenced by a polymorphism in the promoter of IL1, IL1B -31C>T. Methods: To examine whether polymorphisms in IL1B and IL1RA influence the susceptibility to cerebral malaria, IL1B -31C>T, IL1B 3953C>T, and IL1RA variable number of tandem repeat (VNTR) were analysed in 312 Thai patients with malaria (109 cerebral malaria and 203 mild malaria patients). Results: In this population, IL1B -31C>T and IL1RA VNTRwere detected, while IL1B 3953C>T (i.e., IL1B 3953T) was not observed in the polymorphism screening for 32 patients. Further analyses for IL1B -31C>T and IL1RA VNTR in 110 cerebral malaria and 206 mild malaria patients showed no significant association of these polymorphisms with cerebral malaria. Conclusion: The present results suggest that IL1B -31C>T and IL1RA VNTR polymorphisms do not play a crucial role in susceptibility or resistance to cerebral malaria. © 2005 Ohashi et al; licensee BioMed Central Ltd.
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    A functional polymorphism in the IL1B gene promoter, IL1B -31C>T, is not associated with cerebral malaria in Thailand.
    (2005-08-14) Ohashi, Jun; Naka, Izumi; Doi, Akihiro; Jintana Patarapotikul; จินตนา ภัทรโพธิกุล; Hathairad Hananantachai; Noppadon Tangpukdee; นพดล ตั้งภักดี; Sornchai Looareesuwan; ศรชัย หลูอารีย์สุวรรณ; Tokunaga, Katsushi; Mahidol University. Faculty of Tropical Medicine
    IL-1beta and IL-1RA levels are higher in the serum of cerebral malaria patients than in patients with mild malaria. Recently, the level of IL1B expression was reported to be influenced by a polymorphism in the promoter of IL1, IL1B -31C>T. METHODS: To examine whether polymorphisms in IL1B and IL1RA influence the susceptibility to cerebral malaria, IL1B -31C>T, IL1B 3953C>T, and IL1RA variable number of tandem repeat (VNTR) were analysed in 312 Thai patients with malaria (109 cerebral malaria and 203 mild malaria patients). RESULTS: In this population, IL1B -31C>T and IL1RA VNTR were detected, while IL1B 3953C>T (i.e., IL1B 3953T) was not observed in the polymorphism screening for 32 patients. Further analyses for IL1B -31C>T and IL1RA VNTR in 110 cerebral malaria and 206 mild malaria patients showed no significant association of these polymorphisms with cerebral malaria. CONCLUSION: The present results suggest that IL1B -31C>T and IL1RA VNTR polymorphisms do not play a crucial role in susceptibility or resistance to cerebral malaria.
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    A functional single-nucleotide polymorphism in the CR1 promoter region contributes to protection against cerebral malaria
    (2008-12-15) Phairote Teeranaipong; Jun Ohashi; Jintana Patarapotikul; Ryosuke Kimura; Pornlada Nuchnoi; Hathairad Hananantachai; Izumi Naka; Chaturong Putaporntip; Somchai Jongwutiwes; Katsushi Tokunaga; University of Tokyo; Tokai University School of Medicine; Mahidol University; Chulalongkorn University; Naresuan University; University of Tsukuba
    Background. Although the level of erythrocyte complement receptor type 1 (E-CR1) expression in patients with malaria has been extensively studied, whether the level of expression of E-CR1 is associated with severe malaria remains controversial. The present study examined a possible association of polymorphisms in the CR1 gene with the severity of malaria, and it evaluated the influence of the associated polymorphism on expression of E-CR1. Methods. Seventeen single-nucleotide polymorphisms in CR1 were genotyped in 477 Thai patients who had Plasmodium falciparum malaria (203 had mild malaria, 165 had noncerebral severe malaria, and 109 had cerebral malaria). The E-CR1 expression level was measured by flow cytometry in 24 healthy Thai subjects. Results. The T allele of the reference single-nucleotide polymorphism rs9429942 in the CR1 promoter region was strongly associated with protection against cerebral malaria (2.2% of patients with mild malaria vs. 7.8% of patients with cerebral malaria; P = .0009; Bonferroni-adjusted Pc= .0306). The E-CR1 expression level was significantly higher in individuals with the TT genotype of rs9429942 than in individuals with the TC genotype of rs9429942 (P = .0282). Conclusions. We identified a CR1 promoter allele, associated with higher E-CR1 expression, that conferred protection against cerebral malaria. Previous studies have shown that the rate of clearance of immune complexes (ICs) from the circulation is related to the E-CR1 level. These results lead to the hypothesis that the clearance of ICs regulated by E-CR1 therefore plays a crucial role in the pathogenesis of cerebral malaria. © 2008 by the Infectious Diseases Society of America. All rights reserved.
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    Generation and characterization of cross neutralizing human monoclonal antibody against 4 serotypes of dengue virus without enhancing activity
    (2017-01-01) Subenya Injampa; Nataya Muenngern; Chonlatip Pipattanaboon; Surachet Benjathummarak; Khwanchit Boonha; Hathairad Hananantachai; Waranya Wongwit; Pongrama Ramasoota; Pannamthip Pitaksajjakul; Mahidol University
    © 2017 Injampa et al. Background. Dengue disease is a leading cause of illness and death in the tropics and subtropics. Most severe cases occur among patients secondarily infected with a different dengue virus (DENV) serotype compared with that from the first infection, resulting in antibody-dependent enhancement activity (ADE). Our previous study generated the neutralizing human monoclonal antibody, D23-1B3B9 (B3B9), targeting the first domain II of E protein, which showed strong neutralizing activity (NT) against all four DENV serotypes. However, at sub-neutralizing concentrations, it showed ADE activity in vitro. Methods. In this study, we constructed a new expression plasmid using the existing IgG heavy chain plasmid as a template for Fc modification at position N297Q bysite-directed mutagenesis. The resulting plasmid was then co-transfected with a light chain plasmid to produce full recombinant IgG (rIgG) in mammalian cells(N297Q-B3B9). This rIgG was characterized for neutralizing and enhancing activity by using different Fc R bearing cells. To produce sufficient quantities of B3B9 rIgG for further characterization, CHO-K1 cells stably secreting N297Q-B3B9 rIgG were then established. Results. The generated N297Q-B3B9 rIgG which targets the conserved N-terminal fusion loop ofDENVenvelope protein showed the same cross-neutralizing activity to all four DENV serotypes as those of wild type rIgG. In both FcγRI- and RII-bearing THP- 1 cells and FcγRII-bearing K562 cells, N297Q-B3B9 rIgG lacked ADE activity against all DENV serotypes at sub-neutralizing concentrations. Fortunately, the N297Q-B3B9rIgG secreted from stable cells showed the same patterns of NT and ADE activities as those of the N297Q-B3B9 rIgG obtained from transient expression against DENV2. Thus, the CHO-K1 stably expressing N297Q-B3B9 HuMAb can be developed as high producer stable cells and used to produce sufficient amounts of antibody for further characterization as a promising dengue therapeutic candidate. Discussion. Human monoclonal antibody, targeted to fusion loop of envelope domainII (EDII), was generated and showed cross-neutralizing activity to 4 serotypes of DENV, but did not cause any viral enhancement activity in vitro. This HuMAb could be further developed as therapeutic candidates. Subjects Biotechnology, Molecular Biology, Virology, Infectious Diseases.
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    Genetic evidence for contribution of human dispersal to the genetic diversity of EBA-175 in Plasmodium falciparum
    (2015-08-01) Yoshiki Yasukochi; Izumi Naka; Jintana Patarapotikul; Hathairad Hananantachai; Jun Ohashi; University of Tokyo; Mahidol University
    © 2015 Yasukochi et al. Background: The 175-kDa erythrocyte binding antigen (EBA-175) of Plasmodium falciparum plays a crucial role in merozoite invasion into human erythrocytes. EBA-175 is believed to have been under diversifying selection; however, there have been no studies investigating the effect of dispersal of humans out of Africa on the genetic variation of EBA-175 in P. falciparum. Methods: The PCR-direct sequencing was performed for a part of the eba-175 gene (regions II and III) using DNA samples obtained from Thai patients infected with P. falciparum. The divergence times for the P. falciparum eba-175 alleles were estimated assuming that P. falciparum/Plasmodium reichenowi divergence occurred 6 million years ago (MYA). To examine the possibility of diversifying selection, nonsynonymous and synonymous substitution rates for Plasmodium species were also estimated. Results: A total of 32 eba-175 alleles were identified from 131 Thai P. falciparum isolates. Their estimated divergence time was 0.13-0.14 MYA, before the exodus of humans from Africa. A phylogenetic tree for a large sequence dataset of P. falciparum eba-175 alleles from across the world showed the presence of a basal Asian-specific cluster for all P. falciparum sequences. A markedly more nonsynonymous substitutions than synonymous substitutions in region II in P. falciparum was also detected, but not within Plasmodium species parasitizing African apes, suggesting that diversifying selection has acted specifically on P. falciparum eba-175. Conclusions: Plasmodium falciparum eba-175 genetic diversity appeared to increase following the exodus of Asian ancestors from Africa. Diversifying selection may have played an important role in the diversification of eba-175 allelic lineages. The present results suggest that the dispersals of humans out of Africa influenced significantly the molecular evolution of P. falciparum EBA-175.
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    The genotypes of GYPA and GYPB carrying the MNSs antigens are not associated with cerebral malaria
    (2007-05-01) Izumi Naka; Jun Ohashi; Jintana Patarapotikul; Hathairad Hananantachai; Polrat Wilairatana; Sornchai Looareesuwan; Katsushi Tokunaga; University of Tokyo; Mahidol University
    Plasmodium falciparum invades erythrocytes via several routes using different red blood cell receptors that include glycophorin A (GYPA) and glycophorin B (GYPB). GYPA has two codominant alleles, i.e., M and N, that correspond to the M and N antigens, which differ by two amino acids (S1L, G5E); the codominant alleles of GYPB, i.e., S and s, correspond to the S and s antigens, which differ by a single amino acid (T29M). If these antigens influence the efficiency of erythrocyte invasion by malaria parasites, the MNSs phenotype may be associated with the severity of malaria. To examine this, the GYPA and GYPB genotypes carrying the MNSs antigens were analyzed in 109 and 203 Thai patients with cerebral malaria and mild malaria, respectively. Neither the genotype nor allele frequencies at each locus were statistically different between the cerebral and mild malaria patients. Thus, we conclude that the MNSs antigens do not reveal the difference in susceptibility to cerebral malaria. © 2007 The Japan Society of Human Genetics and Springer.
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    Identification of a haplotype block in the 5q31 cytokine gene cluster associated with the susceptibility to severe malaria
    (BioMed Central Ltd., 2009) Izumi Naka; Nao Nishida; Jintana Patarapotikul; Pornlada Nuchnoi; Katsushi Tokunaga; Hathairad Hananantachai; Naoyuki Tsuchiya; Jun Ohashi
    Background: It has been previously demonstrated that a single nucleotide polymorphism (SNP) in the IL13 promoter region, IL13 -1055T>C (rs1800925), was associated with susceptibility to severe malaria in Thais. In the present study, fine association mapping for a cytokine gene cluster including IL4, IL5, and IL13 on chromosome 5q31 was conducted using the same malaria subjects to refine the region containing a primary variant or a haplotype susceptible to severe malaria. Methods: A total of 82 SNPs spanning 522 kb of the 5q31 region were analysed in 368 patients with Plasmodium falciparum malaria (203 mild malaria and 165 severe malaria patients). Results: Only rs1881457 located in the promoter region of IL13, which is in linkage disequilibrium with rs1800925 (r2 = 0.73), showed a significant association with severe malaria after adjusting for multiple testing (P = 0.046 by permutation test). This SNP was in a haplotype block spanning 97 kb (from rs2069812 to rs2240032). The detected haplotype block contained the RAD50 gene and the promoter of IL13, but not the other genes. Conclusion: A haplotype block in which a primary polymorphism associated with severe malaria is likely to be encoded was identified in Thai malaria patients