Effects of the killer immunoglobulin-like receptor (KIR) polymorphisms on HIV acquisition: A meta-analysis.

BACKGROUND: Genetic involvement of Killer Immunoglobulin-like Receptor (KIR) polymorphisms and Human Immunodeficiency Virus (HIV)-exposed seronegative (HESN) compared to HIV-infected (HIVI) individuals has been reported. However, inconsistency of the outcomes reduces precision of the estimates. A meta-analysis was applied to obtain more precise estimates of association. METHODS: A multi-database literature search yielded thirteen case-control studies. Risks were expressed as odds ratios (ORs) and 95% confidence intervals (CIs) with significance set at a two-tailed P-value of ≤ 0.05. We used two levels of analyses: (1) gene content that included 13 KIR polymorphisms (2DL1-3, 2DL5A, 2DL5B, 2DS1-3, 2DS4F, 2DS4D, 2DS5, 3DL1 and 3DS1); and (2) 3DL1/S1 genotypes. Subgroup analysis was ethnicity-based (Caucasians, Asians and Africans). Outlier treatment was applied to heterogeneous effects which dichotomized the outcomes into pre-outlier (PRO) and post-outlier (PSO). Multiple comparisons were addressed with the Bonferroni correction. RESULTS: We generated 52 and 18 comparisons from gene content and genotype analyses, respectively. Of the 70 comparisons, 13 yielded significant outcomes, two (indicating reduced risk) of which survived the Bonferroni correction (Pc). These protective effects pointed to the Caucasian subgroup in 2DL3 (OR 0.19, 95% CI 0.09, 0.40, Pc < 10-3) and 3DS1S1 (OR 0.37, 95% CI 0.24, 0.56, Pc < 10-3). These two PSO outcomes yielded effects of increased magnitude and precision, as well as raised significance and deemed robust by sensitivity analysis. Of the two, the 2DL3 effect was improved with a test of interaction (Pc interaction < 10-4). CONCLUSION: Multiple meta-analytical treatments presented strong evidence of the protective effect (up to 81%) of the KIR polymorphisms (2DL3 and 3DS1S1) among Caucasians. The Asian and African outcomes were inconclusive due to the low number of studies.

Associations of DC-SIGN (CD209) promoter -336G/A polymorphism (rs4804803) with dengue infection: A systematic review and meta-analysis.

BACKGROUND AND AIM: Dengue virus entry into a host is associated with a cell surface protein, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin). A common CD209-336G/A (rs4804803) polymorphism in DC-SIGN may affect severity of dengue virus infection (DEN) and incidence of dengue fever (DF) or the more severe dengue hemorrhagic fever (DHF). However, the reported associations of these two outcomes and CD-209 have been inconsistent, which prompted a meta-analysis to obtain more precise estimates. METHODS: A literature search yielded seven case-control studies. We calculated pooled odds ratios (OR) and 95% confidence intervals using standard genetic models. Outlier treatment examined sources of potential heterogeneity. Subgroup analysis was performed for ethnicity and age. RESULTS: All significant outcomes for association indicating reduced risk were pegged at P=0.007-0.05. In the homozygous and recessive models, these were observed in the overall analysis (OR 0.52-0.55), and subgroups of South/Central Americans (OR 0.30-0.32) and school-age children (OR 0.44) in the DHF analysis as well as the codominant model among Asians in DF (OR 0.59). These significant outcomes are strengthened by their non-heterogeneity (P>0.10) and robustness of the effects. Most pooled effects in DF and DEN were variable. CONCLUSIONS: The DC-SIGN -336G/A polymorphism significantly affects DHF and DF incidence with the effect more pronounced in certain analyzed patient subgroups.

Associations of tumor necrosis factor-α-308 polymorphism with dengue infection: A systematic review and meta-analysis.

Inconsistency of reported associations between the tumor necrosis factor-alpha-308 (TNFα-308) polymorphism (rs1800629) and dengue virus infection prompted a meta-analysis, to obtain more precise estimates. A literature search yielded 14 case-control studies. We calculated pooled odds ratios (OR) and 95% confidence intervals in three groups according to severity, dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue (DEN) using standard genetic models. Pooled ORs were subjected to modifier treatment where re-analysis was confined to Hardy-Weinberg compliant (HWC) studies. Heterogeneity of outcomes warranted examining their sources with outlier treatment. In subgroup analysis, we compared Asian and South/Central American (SCA)/Brazilian effects. Overall pooled outcomes yielded no significant effects (OR 0.66-1.44, P=0.08-0.96). In the dominant-codominant model, pooled effects were heterogeneous (I2=47%-71%) which was lost/reduced (I2=0%-43%) when outlier treatment was applied. This also yielded significant associations (OR 0.68-0.77, P=0.02-0.05). Our results are best seen in the Asian subgroup, which in itself already yielded significant effects in DEN (OR 0.62-0.67, P=0.01-0.02). These reduced risk findings were significant from the tests of interaction (P=0.001-0.02) which highlights the protective effects of TNFα-308 among Asians. TNFα-308 effects on dengue are based on significance and non-heterogeneity of the post-outlier outcomes in the dominant and codominant models. Here, pooled effects may also be ethnic specific, where Asians are protected but not SCA. Both modified and Asian effects are up to 38% protective.

Characterization of a novel two-component system response regulator involved in biofilm formation and a low-iron response of Burkholderia pseudomallei.

Two-component systems (TCSs) regulate an adaptive response to environmental conditions, leading to changes in bacterial cellular processes. In this study, we identified a novel TCS response regulator gene, designated as bfmR (biofilm formation-associated regulator) that regulates biofilm formation by Burkholderia pseudomallei (Bp). An insertion mutant of the Bp bfmR gene resulted in a significant decrease in expression of fimbriae chaperone-usher assembly genes (BPSL2O28 and BPSL22 7), leading to suppression of assembly of fimbriae on the cell surface and reduced biofilm formation. The defective phenotypes of the mutant strain were restored by introducing a complementing plasmid having an intact bfmR gene. Using RT-PCR analyses, we found that bfmR gene expression was upregulated under low-iron growth conditions. In addition, the bfmR mutant strain showed retarded growth in low-iron medium and in phagocytic cells compared to the wild-type strain. These results indicate that bfmR is a novel positive regulator for controlling assembly of fimbriae and biofilm formation, and is upregulated under low-iron conditions.

Comparison of stress adaptation and survival rate between Burkholderia pseudomallei with mutant and wild type bfmR.

Burkholderia pseudomallei (Bp) is highly adaptable to a wide range of environmental changes for survival and pathogenesis. However, the underlying mechanisms of such adaptability are still unclear. Two-component system (TCS) is a common signal transduction used by bacteria in response to environmental changes. A gene designated as bfmR (locus tag of BPSL2024) has been proposed to encode a response regulator, a member of the TCS, and was studied by mutagenesis and comparison of its phenotypic changes compared with those of the wild type. The growth rates of the mutant Bp at temperatures of 37 degrees-39 degrees C and pH 5-8 were significantly lower than the wild type strain (p < 0.05), especially at 39 degrees C (p = 0.01) and pH 7 (p = 0.01). The survival rate of the mice infected with the mutant strain is not significantly different from mice infected with wild type strain. The defective phenotypes were recovered in the complemented strain. These results indicated that bfmR is involved in adaptation of Bp to thermal- and pH-induced stress conditions.