Annie Chamberland

Association of common polymorphisms in the fractalkine receptor (CX3CR1) with obesity.

The inflammatory component in obesity is now well established. The CX3CR1 gene encodes the fractalkine (CX3CL1) receptor and has two coding single‐nucleotide polymorphisms, V249I and T280M, linked to a lower risk of other inflammatory diseases such as coronary artery disease (CAD) and asthma. To determine whether CX3CR1 is associated with obesity, we genotyped the V249I and T280M polymorphisms of the CX3CR1 gene in subjects with a BMI ≥30 kg/m2 and nonobese controls with a BMI <30 kg/m2. Binary logistic regression analyses revealed that the 280MM genotype was associated with obesity (P = 0.022). A gender‐specific one‐way ANOVA was also conducted to investigate mean BMI and waist circumference differences between genotypes of each polymorphism. For both polymorphisms independently, women carrying two copies of the minor allele had significant higher mean waist circumference than those carrying only one copy of the minor allele (MM > TM, P = 0.031; II > VI, P = 0.013) or those who were homozygous for the major allele (MM > TT, P = 0.005; II > VV, P = 0.006). We also observed significant higher mean waist circumference in men carrying one copy of the minor allele when compared to those who were homozygous for the major allele for the T280M polymorphism (TM > TT, P = 0.029). This study suggests that CX3CR1, a biomarker of obesity in this sample, constitutes a potential target for further investigation of the role of inflammation in the expression of obesity‐related phenotypes.

Low prevalence of detectable HIV plasma viremia in patients treated with antiretroviral therapy in Burkina Faso and Mali.

Background:Sub-Saharan Africa has seen dramatic increases in the numbers of people treated with antiretroviral therapy (ART). Although standard ART regimens are now universally applied, viral load measurement is not currently part of standard monitoring protocols in sub-Saharan Africa. Methods:We describe the prevalence of inadequate virological response (IVR) to ART (viral load ≥ 500 copies/mL) and identify factors associated with this outcome in 606 HIV-positive patients treated for at least 6 months. Recruitment took place in 7 hospitals and community-based sites in Bamako and Ouagadougou, and information was collected using medical charts and interviews. Results:The overall prevalence of IVR in treatment-naive patients was 12.3% and 24.4% for pretreated patients. There were no differences in rates of IVR according to ART delivery sites and time on treatment. Patients living farther away [odds ratio (OR) = 2.48; 95% confidence interval (CI) 1.40 to 4.39], those on protease inhibitor or nucleoside reverse transcriptase inhibitor regimens (OR = 3.23; 95% CI 1.79 to 5.82) and those reporting treatment interruptions (OR = 2.36; 95% CI 1.35 to 4.15), had increased odds of IVR. Immune suppression (OR = 3.32, 95% CI 1.94 to 5.70) and poor self-rated health (OR = 2.00; 95% CI 1.17 to 3.41) were also associated with IVR. Conclusions:Sufficient expertise and dedication exist in public hospital and community-based programs to achieve rates of treatment success comparable to better-resourced settings.

Profiling of differentially expressed genes using suppression subtractive hybridization in an equine model of chronic asthma.

Background Gene expression analyses are used to investigate signaling pathways involved in diseases. In asthma, they have been primarily derived from the analysis of bronchial biopsies harvested from mild to moderate asthmatic subjects and controls. Due to ethical considerations, there is currently limited information on the transcriptome profile of the peripheral lung tissues in asthma. Objective To identify genes contributing to chronic inflammation and remodeling in the peripheral lung tissue of horses with heaves, a naturally occurring asthma-like condition. Methods Eleven adult horses (6 heaves-affected and 5 controls) were studied while horses with heaves were in clinical remission (Pasture), and during disease exacerbation induced by a 30-day natural antigen challenge during stabling (Challenge). Large peripheral lung biopsies were obtained by thoracoscopy at both time points. Using suppression subtractive hybridization (SSH), lung cDNAs of controls (Pasture and Challenge) and asymptomatic heaves-affected horses (Pasture) were subtracted from cDNAs of horses with heaves in clinical exacerbation (Challenge). The differential expression of selected genes of interest was confirmed using quantitative PCR assay. Results Horses with heaves, but not controls, developed airway obstruction when challenged. Nine hundred and fifty cDNA clones isolated from the subtracted library were screened by dot blot array and 224 of those showing the most marked expression differences were sequenced. The gene expression pattern was confirmed by quantitative PCR in 15 of 22 selected genes. Novel genes and genes with an already defined function in asthma were identified in the subtracted cDNA library. Genes of particular interest associated with asthmatic airway inflammation and remodeling included those related to PPP3CB/NFAT, RhoA, and LTB4/GPR44 signaling pathways. Conclusions Pathways representing new possible targets for anti-inflammatory and anti-remodeling therapies for asthma were identified. The findings of genes previously associated with asthma validate this equine model for gene expression studies.

A COMPARISON OF TWO SETS OF MICROARRAY EXPERIMENTS TO DEFINE ALLERGIC ASTHMA EXPRESSION PATTERN

Allergic asthma is a complex trait. Several approaches have been used to identify biomarkers involved in this disease. This study aimed at demonstrating the relevance and validity of microarrays in the definition of allergic asthma expression pattern. The authors compared the transcript expressions of bronchial biopsy of 2 different microarray experiments done 2 years apart, both including nonallergic healthy and allergic asthmatic subjects (n = 4 in each experiment). U95Av2 and U133A GeneChips detected respectively 89 and 40 differentially expressed genes. Fifty-five percent of the U133A genes were previously identified with the U95Av2 arrays. The immune signaling molecules and the proteolytic enzymes were the most preserved categories between the 2 experiments, because 3/4 of the genes identified by the U133A were also significant in the U95Av2 study for both categories. These results demonstrate the relevance of microarray experiments using bronchial tissues in allergic asthma. The comparison of these GeneChip studies suggests that earlier microarray results are as relevant as actual ones to target new genes of interest, particularly in function categories linked to the studied disease. Moreover, it demonstrates that microarrays are a valuable technology to target novel allergic asthma pathways as well as biomarkers.

Genetic variation in immune signaling genes differentially expressed in asthmatic lung tissues

BACKGROUND Eight genes in the immune signaling pathway shown to be differentially expressed in asthmatic lung biopsy specimens in a previous microarray experiment were selected as candidate genes for asthma susceptibility. OBJECTIVE We sought to perform an association study with these genes and asthma-related phenotypes in 3 independent Canadian familial asthma collections and 1 Australian asthma case-control study. METHODS Tagging single nucleotide polymorphisms were selected by using the HapMap public database (r(2) > 0.8; minor allele frequency >0.10) and genotyped with the Illumina platform. Family-based association and trend tests for asthma, atopy, airway hyperresponsiveness, and allergic asthma phenotypes were done in each sample, correcting for multiple testing. RESULTS Uncorrected associations with polymorphisms within 7 genes were detected with 1 or more of the phenotypes in 1 or more of the 4 populations (.001 <P < .05). After correction, the 15-lipoxygenase (15-LO) associations with airway hyperresponsiveness and allergic asthma remained significant in 2 Canadian samples (corrected P = .022 and .049, respectively), and the association of the CD14 antigen with asthma remained significant in 1 Canadian sample (corrected P = .042). In both cases a protective effect of the minor alleles was observed. CONCLUSION Expression profiling studies are a useful way to identify candidate genes for asthma because this approach has led to the first report of an association with 15-LO in 2 independent populations. Because 15-LO is involved in anti-inflammatory processes, further functional and clinical investigation of the role of this biologic pathway in asthma is warranted.

Favorable Interactions between Enfuvirtide and 1-β-d-2,6-Diaminopurine Dioxolane In Vitro

ABSTRACT We evaluated the in vitro anti-human immunodeficiency virus type 1 (HIV-1) interactions between 1- β-d-2,6-diaminopurine dioxolane (DAPD) and enfuvirtide (T-20) against clinical isolates sensitive and resistant to reverse transcriptase and protease inhibitors. Interactions between T-20 and DAPD were synergistic to nearly additive, with combination index values ranging from 0.53 to 1.06 at 95% inhibitory concentrations. These studies suggest that a combination of T-20 and DAPD might be useful in the treatment of antiretroviral drug-experienced patients.

Association Study between Candidate Genes and Obesity-Related Phenotypes Using a Sample of Lumberjacks

Introduction: Complex traits such as obesity are modulated by genetic and environmental factors and lead to varied clinical presentations.The aim of this study was to investigate associations between candidate genes and obesity-related phenotypes using a sample of 252 lumberjacks issued from a founder population and sharing a common and circumscribed environment. Methods: Thirty-seven variants in 18 genes were genotyped. The restriction fragment length polymorphism method and the template-directed dye-terminator incorporation assay with fluorescence polarization detection were employed for the genotyping assays. Multivariate logistic regression models were built in order to calculate the relative odds of exhibiting obesity-related phenotypes associated with the presence of the studied polymorphism. Among them, 21 single nucleotide polymorphisms were tested for associations with obesity phenotypes. Results: Significant associations were found between carriers of the minor alleles of APOE-ε2, FABP2-A54T, UCP1-L229M, LPL-HindIII, LPL-S447X and LPL-T1973C, patients bearing a combination of LPL-D9N, LPL-N291S and LPL-P207L and obesity-related phenotypes. Conclusion: The present results suggest that a particular population such as lumberjacks, sharing the same environment, could help target genes involved in complex traits.

Gonorrhea, Chlamydia and HIV incidence among female sex workers in Cotonou, Benin: A longitudinal study

Female sex workers (FSWs) continue to carry a heavy burden of sexually transmitted infections (STI). For prevention purposes, there is a need to identify most-at-risk subgroups among them. The objective of this longitudinal cohort study conducted at Dispensaire IST, Cotonou, Benin, was to assess Neisseria gonorrhoeae (NG) / Chlamydia trachomatis (CT) incidence and determinants; and HIV incidence among FSWs in presence of STI/HIV risk reduction activities. Overall, 319 adult FSWs were followed quarterly from September 2008 to March 2012. NG/CT were detected from endocervical swabs by Amplified DNA Assays employing Strand displacement amplification technology. HIV testing was done on capillary blood using two consecutive rapid diagnostic tests. Anderson-Gill proportional hazard models (HR) were used to determine factors independently associated with NG/CT incidence. The majority of FSWs were HIV-negative (188, 58.9%). There were 6 HIV seroconversions among these 188 HIV-negative women. HIV incidence (95% Confidence interval, CI) was 1.41 (0.28–2.54) seroconversions per 100 person-years at risk (PYAR): 6 events / 425.1 PYAR. Sixty-two out of 319 women experienced 83 new episodes of NG/CT for an overall incidence rate (95% CI) of 10.8 (8.17–13.88) events / 100 PYAR. From month-24 onwards, HIV-positive women (treated: HR (95%CI): 4.2 (1.60–10.77); untreated: HR (95%CI): 4.2 (1.59–11.49) were more likely to acquire NG/CT compared to HIV-negative FSWs. Longer duration in sex work (>2 years: HR; 95%CI: 0.4 (0.22–0.72)) was protective against NG/CT. Refusal by clients (55.8%) was the main reason for non-condom use. Enrolling women from one clinic (Dispensaire IST) may have impaired generalizability of the findings. New NG/CT/HIV infections were observed among FSWs notwithstanding ongoing prevention interventions. To eliminate HIV transmission among FSWs, STI/HIV control programs need to promote women’s empowerment and address vulnerability to infection of HIV-positive FSWs.

HIV-1 envelope sequence-based diversity measures for identifying recent infections

Identifying recent HIV-1 infections is crucial for monitoring HIV-1 incidence and optimizing public health prevention efforts. To identify recent HIV-1 infections, we evaluated and compared the performance of 4 sequence-based diversity measures including percent diversity, percent complexity, Shannon entropy and number of haplotypes targeting 13 genetic segments within the env gene of HIV-1. A total of 597 diagnostic samples obtained in 2013 and 2015 from recently and chronically HIV-1 infected individuals were selected. From the selected samples, 249 (134 from recent versus 115 from chronic infections) env coding regions, including V1-C5 of gp120 and the gp41 ectodomain of HIV-1, were successfully amplified and sequenced by next generation sequencing (NGS) using the Illumina MiSeq platform. The ability of the four sequence-based diversity measures to correctly identify recent HIV infections was evaluated using the frequency distribution curves, median and interquartile range and area under the curve (AUC) of the receiver operating characteristic (ROC). Comparing the median and interquartile range and evaluating the frequency distribution curves associated with the 4 sequence-based diversity measures, we observed that the percent diversity, number of haplotypes and Shannon entropy demonstrated significant potential to discriminate recent from chronic infections (p<0.0001). Using the AUC of ROC analysis, only the Shannon entropy measure within three HIV-1 env segments could accurately identify recent infections at a satisfactory level. The env segments were gp120 C2_1 (AUC = 0.806), gp120 C2_3 (AUC = 0.805) and gp120 V3 (AUC = 0.812). Our results clearly indicate that the Shannon entropy measure represents a useful tool for predicting HIV-1 infection recency.