High Producing Tumor Necrosis Factor Alpha Gene Alleles in Protection against Severe Manifestations of Dengue

Dengue virus (DENV) infection usually presents with mild self-limiting dengue fever (DF). Few however, would present with the more severe form of the disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). In the present study, the association between IL-12B, IL-10 and TNF-α gene polymorphisms and dengue severity was investigated. Methods: A case-control study was performed on a total of 120 unrelated controls, 86 DF patients and 196 DHF/DSS patients. The polymorphisms in IL-12B, IL-10 and TNF-α genes were genotyped using PCR-RFLP and PCR-sequencing methods. Results: A protective association of TNF-α -308A allele and -308GA genotype against DHF/DSS was observed, while TNF-α -238A allele and -238GA genotype were associated with DHF/DSS. A combination of TNF-α -308GA+AA genotype and IL-10 non-GCC haplotypes, IL-12B pro homozygotes (pro1/pro1, pro2/pro2) and IL-12B 3''UTR AC were significantly correlated with protective effects against DHF/DSS. An association between the cytokine gene polymorphisms and protection against the clinical features of severe dengue including thrombocytopenia and increased liver enzymes was observed in this study. Conclusion: The overall findings of the study support the correlation of high-producer TNF-α genotypes combined with low-producer IL-10 haplotypes and IL-12B genotypes in reduced risk of DHF/DSS.     

Polymorphisms of the TAP 1 and 2 gene may influence clinical outcome of primary dengue viral infection

Antigen peptides are actively transported across the endoplasmic reticulum by the transporters associated with antigen presentation (TAP). TAP genes polymorphism could influence the selection process that determines which antigen peptides play a role in the pathogenesis of dengue infection. The aim of this study was to investigate the association of TAP genes polymorphism in diverse pathogenesis of dengue infection. This study included 197 dengue-infected patients who were further categorized into 64, 23 and 11 primary dengue fever (DF), dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) cases, respectively and 26, 52, and 21 secondary DF, DHF and DSS cases, respectively as per WHO grading system. TAP1 and 2 gene polymorphisms were performed by the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Analysis of TAP1 gene polymorphism demonstrated decreased frequency of Ile/Ile genotype at TAP1(333) in primary DHF cases (39.1%) when compared with primary DF (64.1%, P < 0.034, OR = 0.611). The genotype frequency of Val/Val at TAP2(379) locus was significantly decreased among primary DHF (43.5%) in comparison to primary DF (71.9%, P = 0.015, OR = 0.605). Significant low proportion of primary DSS were found to have TAP1(637) Asp/Asp genotypes (54.5%) when compared with primary DF (70.3%, P = 0.043). Asp/Asp genotype at TAP1(637) was found to reduce the risk by 0.643 times for primary DSS. There was no significant difference in the genotypes studied between primary and secondary infection and also within secondary dengue infection in all three clinical groups. This report on TAP gene polymorphisms in dengue suggested that among the primary-infected individuals, homozygous patterns for Ile at TAP1(333) Val at TAP2(379) loci and Asp at TAP1(637) were found to be a protective factor against development of DHF and DSS, respectively.     

Association of FCGR2A p.R131H and CCL2 c.-2518 A > G gene variants with thrombocytopenia in patients with dengue virus infection

FCGR2A and CCL2 gene variants are important in dengue pathogenesis and were investigated in 122 dengue patients (DENs) [89 dengue fever (DF) and 33 dengue hemorrhagic fever (DHF)] and 107 healthy controls (HCs) to find out their association with severity of dengue. Genotype frequencies of FCGR2A p.R131H and CCL2 c.-2518 A > G polymorphisms were not different between DF, DHF and HC. Significantly higher frequency of R/R genotype of FCGR2A p.R131H was observed in DEN cases with thrombocytopenia (TP) while the G/G genotype of CCL2 c.-2518 A > G was observed only in DEN cases with TP (p < 0.005). These results suggest that FCGR2A and CCL2 gene variants were associated with the risk of TP in dengue infections.     

Significance of Transporter Associated with Antigen Processing 2 (<Emphasis Type="Italic">TAP2</Emphasis>) Gene Polymorphisms in Susceptibility to Dengue Viral Infection

Background and Aims The polymorphic transporter associated with antigen processing (TAP)1 and TAP2 genes encode subunits of the transporter that delivers peptides to the human leukocyte antigen class I molecules. Because the polymorphism of the TAP genes has been shown to affect peptide transport, it has been suggested that TAP genes are potential regulators of the immune response. We recently reported that TAP1 gene polymorphism is associated with severe dengue infection. This study was carried out to elucidate whether TAP2 polymorphisms are involved in diverse pathogenesis of dengue infection. Materials and Methods This study included 100 controls and 197 dengue-infected patients who were further categorized into 90 dengue fever (DF) cases, 75 dengue hemorrhagic fever cases (DHF), and 32 dengue shock syndrome (DSS) cases as per WHO grading system. TAP2 gene polymorphisms were determined by amplification refraction mutation system-polymerase chain reaction. Results The frequency of isoleucine at TAP2 379 (34.5%) was increased among DHF in comparison to controls (21%, P = 0.014). DHF cases were more likely to be heterozygous at TAP2 379 (50.7%) than controls [24%, odds ratio (OR) = 2.11, P = 0.001]. Significantly high proportion of DHF was found to have TAP2 665 threonine/alanine (THR/ALA) genotypes (30.7%) when compared with DF (13.3%, OR = 2.3, P = 0.006) cases. There was no difference in the genotypes studied between DSS and controls or DF or DHF. Conclusion This first report on TAP 2 gene polymorphism in dengue suggested that heterozygous pattern at TAP2 379 locus confers susceptibility to DHF, and TAP2 665 THR/ALA genotype was found to be a risk factor for development of DHF.     

Genetic ancestry and income are associated with dengue hemorrhagic fever in a highly admixed population

To test whether African ancestry is protective for severe dengue, we genotyped 49 hospitalized cases of dengue hemorrhagic fever (DHF) as well as 293 neighborhood cases of dengue fever and 294 asymptomatic controls in Salvador, Bahia, Brazil. Ancestry-informative markers and 282 unlinked SNPs not associated with the clinical presentation of dengue were used to estimate ancestry. After controlling for income, both self-defined Afro-Brazilian ethnicity and African ancestry were protective for DHF (P=0.02, OR=0.28 and P=0.02, OR=0.13, respectively). Income or an index of income indicators, however, was also independently associated with the diagnosis of DHF.     

Immunopathogenesis of dengue hemorrhagic fever and shock syndrome: role of TAP and HPA gene polymorphism

Clinical outcomes of dengue infection such as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) could be attributed to host genetic factors. The transporters associated with antigen processing (TAP) genes are polymorphic genes located in the human leukocyte antigen (HLA) class II region and are essentially involved in class I antigen presentation. Therefore, these genes might grant susceptibility to severe dengue infection. Hence, the aim of the study was to type the TAP1 gene (using amplification refraction mutation system [ARMS] polymerase chain reaction [PCR]) and HPA1 and HPA2 gene polymorphism (by PCR–sequence specific primers) in different clinical spectrums of dengue infection. The study included 100 controls and 91 DF, 75 DHF, and 32 DSS patients. The results revealed that the frequencies of valine at TAP1 333 and HPA 1b at HPA1 were increased among DHF and DSS, respectively, in comparison to controls (p <0.05). The frequency of genotype TAP1 333 ILE/VAL (61.3%) was significantly higher in DHF compared with control (37%, p = 0.005) or DF (38.9%, p = 0.007) patients. A significantly greater proportion of DHF patients demonstrated HPA1a/1a and HPA 2a/2b genotypes than DF patients. DSS patients were more likely to be heterozygous at HPA1 than DHF (OR = 4.75, p = 0.003). A positive correlation existed between TAP1 333 and HPA1 in DHF (p = 0.017, r = 0.229). This first report on TAP and HPA gene polymorphism in dengue suggested that the heterozygous pattern at the TAP1 333 locus and HPA1a/1a and HPA2a/2b genotypes confer susceptibility to DHF and the HPA1a/1b genotype was determined to be a genetic risk factor for DSS.     

Profile of killer cell immunoglobulin‐like receptor and its human leucocyte antigen ligands in dengue‐infected patients from Western India

Killer cell immunoglobulin‐like receptors (KIRs) regulate the activation of natural killer cells (NKs). Qualitative and quantitative differences in the type and the number of KIRs expressed on NK cells affect its activation which would influence the outcome of the disease. In this study, 114 hospitalized cases of dengue [82 dengue fever (DF) and 32 dengue haemorrhagic fever (DHF) cases] and 104 healthy controls (HC) without no known history of hospitalization for dengue‐like illness were investigated for their KIR gene profile to find out the association of KIR genes with dengue disease severity. KIR gene profile was investigated using duplex sequence‐specific priming polymerase chain reaction‐based typing system. The results revealed a higher frequency of KIR3DL1 gene [P = 0.0225; odds ratio (OR) 4.1 95% confidence interval (CI) 1.1–14.8] and lower frequency of KIR3DS1/3DS1 genotype [P = 0.0225; OR 0.24 95% CI (0.068–0.88)] in DF cases compared to HC. Immunoglobulin‐like receptor gene frequencies were not different between DHF and DF or HC. The results suggest that KIR3DL1/KIR3DS1 locus might be associated with the risk of developing DF.     

Association of vitamin D receptor gene polymorphisms with clinical outcomes of dengue virus infection

Vitamin D is known to affect pathogenesis of dengue through modulation of immune responses. Vitamin D exerts its effects through vitamin D receptor (VDR). The functioning of VDR is affected by the gene polymorphisms in the coding (rs2228570) and 3′untranslated region (UTR) (rs1544410, rs7975232 and rs731236). In the present study, VDR gene polymorphisms were investigated in 112 dengue infected patients (83 dengue fever (DF) and 29 dengue hemorrhagic fever cases (DHF)) and 105 apparently healthy controls (HCs) using polymerase chain reaction based restriction fragment length polymorphisms methods. HCs had no documented evidence of symptomatic dengue. Results revealed significantly lower frequency of ‘C’ allele of rs7975232 in all dengue patients (DEN) as compared to HCs [(P corrected (Pc) = 0.014, Odds ratio (OR) 0.51]. The frequency of C/C genotype of rs7975232 was significantly lower in DEN and DF cases compared to HCs (DEN vs. HCs: Pc = 0.0184, OR 0.24; DF cases vs. HCs: Pc = 0.028, OR 0.21). The frequency of T allele of rs2228570 in a dominant mode was significantly higher in DHF cases as compared to DF cases (P = 0.034 OR 2.58). A significantly lower frequency of the haplotype G-C-T (Pc = 0.0135) and higher frequency of the haplotype G-A-T (Pc = 0.000085) was observed in DEN and DF cases as compared to HCs. The results suggest that the 3′UTR haplotypes of VDR gene are differentially associated with risk of symptomatic dengue requiring hospitalization. The ‘T’ allele of rs2228570 polymorphism in a dominant mode of inheritance is associated with DHF.     

Association of HLA-DRB1 and TNF genotypes with dengue hemorrhagic fever

Genes coding for human leukocyte antigen (HLA) class II molecules and tumor necrosis factor (TNF)-α are polymorphic and have been shown to influence susceptibility to infectious diseases. In the present study, HLA-DRB1, -DQB1 and TNF gene polymorphisms were investigated in 114 dengue patients (DEN) [85 dengue fever (DF) cases and 29 dengue hemorrhagic fever (DHF) cases] and 110 healthy controls (HCs) using PCR based methods. The frequencies of HLA-DRB1^∗07 allele [DF vs. DHF, P = 0.0034, Pc = 0.044, OR 3.79] and HLA-DRB1^∗07/^∗15 genotype [DF vs. DHF, P = 0.00071, Pc = 0.038, OR 10.41] were significantly higher in DHF cases as compared to HCs and DF cases. Higher frequency of rs1800629 ‘G/A’ genotype was observed in DHF cases as compared to DF cases. The frequency of rs1799964 ‘C/C’ genotype of the TNF gene was found to be significantly higher in all patient groups compared to HCs [HCs vs. DEN, P = 0.0054, Pc = 0.0162, OR 3.57; HCs vs. DF, P = 0.036, OR 2.89; HCs vs. DHF, P = 0.0088, Pc = 0.0240, OR 5.11]. Presence of combination of HLA-DRB1^∗07/^∗15 with either rs1799964 ‘C/C’ genotype or rs1800629 ‘G/A’ genotype or both was present in 17.2% of DHF cases and 1.2% in HCs while this combination was not observed in DF cases. The results suggest that HLA-DRB1^∗07/^∗15 genotype in combination with TNF polymorphisms influence progression to DHF.     

Mannose-binding lectin gene (MBL2) polymorphisms related to the mannose-binding lectin low levels are associated to dengue disease severity

Dengue is the main arbovirosis in the tropical and subtropical areas of the world. The majority of infected individuals present an asymptomatic outcome while others progress to dengue fever (DF) or dengue haemorrhagic fever (DHF). Dengue infection evolution to severe outcomes is in part, related to innate immunity response. The MBL2 gene encodes for a pathogen recognition pattern molecule, the mannose-binding lectin (MBL). Variant alleles at promoter and structural regions of the MBL2 are related to serum MBL levels and function. Due to the important inflammatory modulation role of MBL, MBL2 polymorphisms could influence dengue progression. Therefore, this study investigated associations of MBL2 polymorphisms and serum MBL levels in patients with dengue. Genotyping of promoter and structural regions of MBL2 was performed by real-time PCR using Taqman® probes in 161 patients presenting DF or DHF outcome. For the serum MBL determination a commercial ELISA kit was used. The variant OO genotype and O allele were associated with DHF (p = 0.008 and p = 0.009 respectively). Haplotypes correlated to MBL low levels were associated with DHF (p = 0.04). Our results support the hypothesis that patients carrying genotypes or haplotypes of low production of MBL would be more susceptible to DHF.     

Association of MICA and MICB alleles with symptomatic dengue infection

Dengue viruses (DV) are one of the most important arthropod-borne viral diseases in the developing world. DV can cause syndromes that are either self-limiting or severe. Allelic variants of human leukocyte antigen (HLA) genes have been demonstrated to be associated with disease susceptibility. Here we report the association of nonclassical HLA class I MICA–MICB genes with disease outcome during DV infection. A sequencing-based typing method and genotyping of MICA and MICB in a well-characterized group of Cuban individuals with dengue hemorrhagic fever (DHF), dengue fever (DF), or asymptomatic dengue infection (ADI) was performed. Statistical analysis revealed a tendency for MICA*008 and MICB*008 to associate with susceptibility to illness when symptomatic versus asymptomatic cases (odds ratio [OR] = 2.1, p_v = 0.03, and OR = 10.4, p = 0.0096, respectively) were compared. Surprisingly, a stronger association of both allelic forms was observed for the DF patients compared with the ADI group (MICA*008, OR = 5.2, p = 0.0001; and MICB*008, OR = 13.2, p = 0.0025) rather than the severe cases. Major histocompatibility class I-related gene-related natural killer cells and/or γδ and αβ T-cell activation might regulate the development of symptomatic DF and DHF.     

Kinetics of dengue virus-specific serum immunoglobulin classes and subclasses correlate with clinical outcome of infection.

The kinetics of dengue virus (DEN)-specific serum immunoglobulin classes (immunoglobulin M [IgM] and IgA) and subclasses (IgG1 to IgG4) were studied in patients suffering from dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). Serum samples from non-DEN febrile patients were included as controls. IgM, IgG1, and IgG3 serum antibodies were the predominant immunoglobulins throughout the course of illness in all three patient groups. In contrast, IgA antibodies were significantly higher in the acute phase in DSS patients compared to those in DF patients (P < 0.05). The levels of IgG1 differed significantly between patients with DF and those with DHF and DSS (P < 0.05). A significant difference was also found in IgG3 levels between DF patients and DHF patients (P < 0.05) but not between DF patients and DSS patients. Finally, levels of IgG4 antibodies differed significantly between DF patients and DSS patients (P < 0.05). Collectively, these data show that increased levels of DEN-specific IgA, IgG1, and IgG4 serum antibodies are risk markers for the development of DHF and DSS and that their measurement may provide valuable guidance for early therapeutic intervention.     

KIR copy number variations in dengue-infected patients from northeastern Thailand

Killer immunoglobulin-like receptors (KIRs) are a family of receptors expressed on Natural killer (NK) cells. The extensive polymorphism of KIR is involved in the immune responses of NK cells and influences dengue infections. We investigated the diversity of KIR copy numbers in dengue-infected patients from northeastern Thailand. Copy numbers of KIRs were determined by quantitative polymerase chain reaction in 137 dengue-infected patients, comprising 63 dengue fever (DF) and 74 dengue hemorrhagic fever (DHF). The distribution of KIRs was observed to be between 0 and 4 copies. The KIR AA genotype with heterozygous KIR2DS4D/WT was the most common in dengue patients, 25.4% DF and 23% DHF. Forty KIR profiles were determined in dengue patients, including 31 usual, 6 expanded, and 3 contracted profiles. Investigation of KIR copy number and dengue severity indicated that two copies of KIR2DL3 combined with HLA-C1C1 associated with an increased risk of DHF (OR 2.32, 95% CI 1.159–4.624, P = 0.016), whereas one copy of KIR2DL2 and KIR2DL3 together with HLA-C1C1 associated with a reduced risk of DHF (OR 0.17, 95% CI 0.058–0.482, P < 0.001). The outcomes of this study will contribute to the understanding of KIR complexity and innate immune responses in dengue infections.     

Elevated serum PAR-1 levels as an emerging biomarker of inflammation to predict the dengue infection severity

The present study was designed to check the serum levels of protease-activated receptor (PAR-1) in patients during different phases of dengue severity. Moreover, a correlation between serum PAR-1 levels and hematological parameters, inflammatory cytokine levels, and liver functional changes was also determined. Based on the World Health Organization criteria, the study population was divided into: nonsevere dengue fever (DF; n = 30), severe dengue hemorrhagic fever (DHF; n = 19), and severe dengue shock syndrome (DSS; n = 11). The platelet count (PLT) and hematocrit (HCT) were analyzed using an automated hematology analyzer and liver function enzymes aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphate (ALP), bilirubin were checked by auto-analyzer using diagnostic kits. Moreover, the levels of inflammatory mediators C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), and PAR-1 were determined using respective ELISA kits. The HCT levels were elevated and platelet count decreased significantly during dengue complications (DHF and DSS) compared to the DF patients, while the levels of liver functional biomarkers AST, ALT, ALP, and bilirubin remained elevated in DHF and DSS groups than in the corresponding DF group. Similarly, the inflammatory cytokine levels of CRP, TNF-α, IL-6, and IL-17 in DHF and DSS subjects were markedly increased when observed against DF subjects. Notably, the PAR-1 levels were significantly elevated in DHF and DSS groups than in the DF group and positively correlated with changes in HCT levels, inflammatory biomarkers, and liver enzymes. Our findings conclude that PAR-1 levels persistently increased with the severity of the dengue infection and are strongly associated with various clinical manifestations. Thus, PAR-1 levels can be used as a diagnostic marker for assessing dengue severity.     

Serum cytokine/chemokine profiles in patients with dengue fever (DF) and dengue hemorrhagic fever (FHD) by using protein array

BackgroundDENV infection can induce different clinical manifestations varying from mild forms to dengue fever (DF) or the severe hemorrhagic fever (DHF). Several factors are involved in the progression from DF to DHF. No marker is available to predict this progression. Such biomarker could allow a suitable medical care at the beginning of the infection, improving patient prognosis.ObjectivesThe aim of this study was to compare the serum expression levels of acute phase proteins in a well-established cohort of dengue fever (DF) and dengue hemorrhagic fever (DHF) patients, in order to individuate a prognostic marker of diseases severity.Study designThe serum levels of 36 cytokines, chemokines and acute phase proteins were determined in DF and DHF patients and compared to healthy volunteers using a multiplex protein array and near-infrared (NIR) fluorescence detection. Serum levels of IL-1ra, IL-23, MIF, sCD40 ligand, IP-10 and GRO-α were also determined by ELISA.ResultsAt the early stages of infection, GRO-α and IP-10 expression levels were different in DF compared to DHF patients. Besides, GRO-α was positively correlated with platelet counts and IP-10 was negatively correlated with total protein levels.ConclusionsThese findings suggest that high levels of GRO-α during acute DENV infection may be associated with a good prognosis, while high levels of IP-10 may be a warning sign of infection severity.     

Profile of human leukocyte antigen class I alleles in patients with dengue infection from Western India

Human leukocyte antigen (HLA) class I alleles are known to affect the cytotoxic T lymphocyte responses and influence susceptibility to viral infections. The objective of the present study was to find out whether HLA class I alleles are associated with clinical manifestations of dengue virus infection. The profile of HLA class I alleles were investigated in 224 human subjects [85 dengue fever (DF) cases, 29 dengue hemorrhagic fever (DHF) cases and 110 healthy controls (HCs)] from Western India using PCR based methods. Results revealed significantly higher frequency of HLA-A^∗33 in DF cases compared to HCs [P = 0.032, Odds ratio (OR) 2.12]. The frequency of HLA-A^∗02:11 was higher in DHF cases compared to DF cases. The frequency of HLA-B^∗18 was significantly higher in dengue (DEN) cases [P = 0.047 Pc = 0.846, OR 3.53]. The frequency of HLA-Cw^∗07 allele was significantly higher in DEN cases [DEN vs. HCs: P = 0.0120, Pc = 0.168, OR 2.00]. Significance was observed even when the cases were categorized in to DF and DHF [DF vs. HCs: P = 0.0349, Pc = 0.49, OR 1.87; DHF vs. HCs: P = 0.0399, Pc = 0.56, OR 2.4]. The combined frequency of HLA-Cw^∗07 with HLA-DRB1^∗07/^∗15 genotype was significantly higher in DHF cases as compared to DF and HCs [DHF vs. HCs: P = 0.022, OR 5.31; DHF vs. DF: P = 0.027, OR 5.49]. On the other hand, the frequency of combination of HLA-Cw^∗07 without HLA-DRB1^∗07 was significantly higher in DF cases compared to HCs [DF vs. HCs: P = 0.002, OR 2.42 (1.28–4.55)]. The results suggest that HLA-A^∗∗33 may be associated with DF while HLA-B^∗18 and HLA-Cw^∗07 alleles may be associated with symptomatic dengue requiring hospitalization. In the presence of HLA-DRB1^∗07/^∗15 genotype, HLA-Cw^∗07 is associated with increased risk of developing DHF while in the presence of other HLA-DRB1 alleles, HLA-Cw^∗07 is associated with DF.     

Non classical HLA genes and non-HLA genes in a population of infants at familial risk of atopy

Aim: We investigated on parental history and IgE serum level in 2588 consecutive newborns to individuate babies “at risk” of atopy at birth and we analysed the polymorphisms of class III region to evaluate the association with immunogenetic markers of HLA: C4A, C4B, LTA, RAGE and TNFA genes; we performed TNF and IgE receptor (FCERB1) physiologically related gene polymorphisms. Result: 791 babies/2588 (30.6%) were considered “at risk” for atopy and followed-up: 400 had familial history of atopy (at least one parent or sibling), 256 had IgE > 0.35 kUA/l at birth and during the follow-up and 135 were positive for both conditions.The allele C4B2 was significantly more frequent in the sample of babies at risk (22.1% vs 10%, p < 0.001). Furthermore, the mean value of IgE at birth in babies carrying the allele C4B2 was 2.26 KUA/l versus 0.74 KUA/l in those not carrying this allele (p = 0.01). No significant association emerged for RAGE at the centromeric end of class III region and for LTA, TNFA at the telomeric one. TNFRI, TNFRII and FCERB1 gene polymorphisms also seemed not implicated. Conclusion: Our study confirms that HLA class III region seems involved in familial predisposition to atopy, and C4B gene probably acts as a marker of a more restricted subregion.     

Evidence for association with hepatocellular carcinoma at the PAPSS1 locus on chromosome 4q25 in a family-based study

A region on chromosome 4q25 has recently been highlighted as linked to hepatocellular carcinoma (HCC). In this study, we performed a family-based association analysis with 67 single-nucleotide polymorphisms (SNPs) to map this linkage region in 240 families with HCC, 212 (88.3%) of which were ascertained through hepatitis B virus surface antigen (HBsAg)-positive index cases. Individual SNP analysis with correction for multiple testing identified 10 SNPs in two correlated haplotype blocks, located in or around the 3′-phosphoadenosine 5′-phosphosulfate synthetase-1 (PAPSS1) gene (all P-values: <0.0075). Our linkage data and GIST (Genotype identity-by-descent sharing test) indicate that 6 of these 10 SNPs contributed to the linkage signal. The haplotype block of the strongest association with HCC extended from the intron 5 to the 3′-flanking region of PAPSS1; multiple consecutive three-SNP haplotypes in this region were significant. The most significant haplotype showed odd ratios of 3.41 (95% confidence interval (CI)=1.36–8.53) for homozygous individuals in a case-unaffected sibling analysis. This haplotype also revealed an association with elevated serum α-fetoprotein and with poor survival in familial cases and an independent series of HBsAg-positive cases with small tumor present at the time of hospital admission. These results implicate PAPSS1 as a candidate HCC-susceptibility gene in hepatitis B carriers.     

Dengue hemorrhagic fever – A systemic literature review of current perspectives on pathogenesis,prevention and control

BackgroundDengue is an arboviral disease caused by dengue virus. Symptomatic dengue infection causes a wide range of clinical manifestations, from mild dengue fever (DF) to potentially fatal disease, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). We conducted a literature review to analyze the risks of DHF and current perspectives for DHF prevention and control.MethodsAccording to the PRISMA guidelines, the references were selected from PubMed, Web of Science and Google Scholar database using search strings containing a combination of terms that included dengue hemorrhagic fever, pathogenesis, prevention and control. Quality of references were evaluated by independent reviewers.ResultsDHF was first reported in the Philippines in 1953 and further transmitted to the countries in the region of South-East Asia and Western Pacific. Plasma leakages is the main pathophysiological hallmark that distinguishes DHF from DF. Severe plasma leakage can result in hypovolemic shock. Various factors are thought to impact disease presentation and severity. Virus virulence, preexisting dengue antibodies, immune dysregulation, lipid change and host genetic susceptibility are factors reported to be correlated with the development of DHF. However, the exact reasons and mechanisms that triggers DHF remains controversial. Currently, no specific drugs and licensed vaccines are available to treat dengue disease in any of its clinical presentations.ConclusionThis study concludes that antibody-dependent enhancement, cytokine dysregulation and variation of lipid profiles are correlated with DHF occurrence. Prompt diagnosis, appropriate treatment, active and continuous surveillance of cases and vectors are the essential determinants for dengue prevention and control.     

Impact of population admixture on the distribution of immune response co-stimulatory genes polymorphisms in a Brazilian population

Co-stimulatory molecules are essential in the orchestration of immune response and polymorphisms in their genes are associated with various diseases. However, in the case of variable allele frequencies among continental populations, this variation can lead to biases in genetic studies conducted in admixed populations such as those from Brazil. The aim of this study was to evaluate the influence of genomic ancestry on distributions of co-stimulatory genes polymorphisms in an admixed Brazilian population. A total of 273 individuals from the north of Brazil participated in this study. Nine single nucleotide polymorphisms in 7 genes (CD28, CTLA4, ICOS, CD86, CD40, CD40L and BLYS) were determined by polymerase chain reaction-restriction fragment length polymorphism. We also investigated 48 insertion/deletion ancestry markers to characterize individual African, European and Amerindian ancestry proportions in the samples. The analysis showed that the main contribution was European (43.9%) but also a significant contribution of African (31.6%) and Amerindian (24.5%) ancestry. ICOS, CD40L and CD86 polymorphisms were associated with genomic ancestry. However there were no significant differences in the proportions of ancestry for the other SNPs and haplotypes studied. Our findings reinforce the need to apply AIMs in genetic association studies involving these polymorphisms in the Brazilian population.