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1.  Comparison of Methods to Account for Relatedness in Genome-Wide Association Studies with Family-Based Data 
PLoS Genetics  2014;10(7):e1004445.
Approaches based on linear mixed models (LMMs) have recently gained popularity for modelling population substructure and relatedness in genome-wide association studies. In the last few years, a bewildering variety of different LMM methods/software packages have been developed, but it is not always clear how (or indeed whether) any newly-proposed method differs from previously-proposed implementations. Here we compare the performance of several LMM approaches (and software implementations, including EMMAX, GenABEL, FaST-LMM, Mendel, GEMMA and MMM) via their application to a genome-wide association study of visceral leishmaniasis in 348 Brazilian families comprising 3626 individuals (1972 genotyped). The implementations differ in precise details of methodology implemented and through various user-chosen options such as the method and number of SNPs used to estimate the kinship (relatedness) matrix. We investigate sensitivity to these choices and the success (or otherwise) of the approaches in controlling the overall genome-wide error-rate for both real and simulated phenotypes. We compare the LMM results to those obtained using traditional family-based association tests (based on transmission of alleles within pedigrees) and to alternative approaches implemented in the software packages MQLS, ROADTRIPS and MASTOR. We find strong concordance between the results from different LMM approaches, and all are successful in controlling the genome-wide error rate (except for some approaches when applied naively to longitudinal data with many repeated measures). We also find high correlation between LMMs and alternative approaches (apart from transmission-based approaches when applied to SNPs with small or non-existent effects). We conclude that LMM approaches perform well in comparison to competing approaches. Given their strong concordance, in most applications, the choice of precise LMM implementation cannot be based on power/type I error considerations but must instead be based on considerations such as speed and ease-of-use.
Author Summary
Recently, statistical approaches known as linear mixed models (LMMs) have become popular for analysing data from genome-wide association studies. In the last few years, a bewildering variety of different LMM methods/software packages have been developed, but it has not always been clear how (or indeed whether) any newly-proposed method differs from previously-proposed implementations. Here we compare the performance of several different LMM approaches (and software implementations) via their application to a genome-wide association study of visceral leishmaniasis in 348 Brazilian families comprising 3626 individuals. We also compare the LMM results to those obtained using alternative analysis methods. Overall, we find strong concordance between the results from the different LMM approaches and high correlation between the results from LMMs and most alternative approaches. We conclude that LMM approaches perform well in comparison to competing approaches and, in most applications, the precise LMM implementation will not be too important, and can be chosen on the basis of speed or convenience.
doi:10.1371/journal.pgen.1004445
PMCID: PMC4102448  PMID: 25033443
2.  A multinational study of mental disorders, marriage, and divorce 
Acta psychiatrica Scandinavica  2011;124(6):474-486.
Objective
Estimate predictive associations of mental disorders with marriage and divorce in a cross-national sample.
Method
Population surveys of mental disorders included assessment of age at first marriage in 19 countries (n = 46 128) and age at first divorce in a subset of 12 countries (n = 30 729). Associations between mental disorders and subsequent marriage and divorce were estimated in discrete time survival models.
Results
Fourteen of 18 premarital mental disorders are associated with lower likelihood of ever marrying (odds ratios ranging from 0.6 to 0.9), but these associations vary across ages of marriage. Associations between premarital mental disorders and marriage are generally null for early marriage (age 17 or younger), but negative associations come to predominate at later ages. All 18 mental disorders are positively associated with divorce (odds ratios ranging from 1.2 to 1.8). Three disorders, specific phobia, major depression, and alcohol abuse, are associated with the largest population attributable risk proportions for both marriage and divorce.
Conclusion
This evidence adds to research demonstrating adverse effects of mental disorders on life course altering events across a diverse range of socioeconomic and cultural settings. These effects should be included in considerations of public health investments in preventing and treating mental disorders.
doi:10.1111/j.1600-0447.2011.01712.x
PMCID: PMC4011132  PMID: 21534936
mental disorders; marriage; divorce
3.  Notch1 induced brain tumor models the sonic hedgehog subgroup of human medulloblastoma 
Cancer research  2013;73(17):5381-5390.
While activation of the Notch pathway is observed in many human cancers, it is unknown whether elevated Notch1 expression is sufficient to initiate tumorigenesis in most tissues. To test the oncogenic potential of Notch1 in solid tumors, we expressed an activated form of NOTCH1 (N1ICD) in the developing mouse brain. N1ICD;hGFAP-cre mice were viable but developed severe ataxia and seizures, and died by weaning age. Analysis of transgenic embryonic brains revealed that N1ICD expression induced p53-dependent apoptosis. When apoptosis was blocked by genetic deletion of p53, 30~40% of N1ICD;GFAP-cre;p53+/− and N1ICD;GFAP-cre;p53−/− mice developed spontaneous medulloblastomas. Interestingly, Notch1-induced medulloblastomas most closely resembled the sonic hedgehog (SHH) subgroup of human medulloblastoma at the molecular level. Surprisingly, N1ICD-induced tumors do not maintain high levels of the Notch pathway gene expression, except for Notch2, demonstrating that initiating oncogenic events may not be decipherable by analyzing growing tumors in some cases. In summary, this study demonstrates that Notch1 has an oncogenic potential in the brain when combined with other oncogenic hits, such as p53 loss, and provides a novel mouse model of medulloblastoma.
doi:10.1158/0008-5472.CAN-13-0033
PMCID: PMC3766480  PMID: 23852537
4.  Human rhinovirus C: Age, season, and lower respiratory illness over the past 3 decades 
Background
Human rhinoviruses (HRVs) cause common colds, and the recently discovered HRV-C is increasingly associated with lower respiratory illness among populations such as children and asthmatic patients.
Objective
To determine how HRV-C is associated with respiratory illness and to evaluate changes in prevalence and species over 2 decades.
Methods
A prospective study of children younger than 5 years was performed at the Vanderbilt Vaccine Clinic over a 21-year period. Nasal-wash specimens from children presenting with upper or lower respiratory illness at acute care visits were tested for HRV and HRV-positives genotyped. Demographic and clinical features were compared between children with or without HRV, and with different HRV species.
Results
HRV was detected in 190 of 527 (36%) specimens from a population of 2009 children from 1982 through 2003. Of these, 36% were HRV-C. Age (P = .039) and month of illness (P <.001) were associated with HRV infection and HRV species. HRV-C was significantly associated with lower respiratory illness, compared with HRV-A (P = .014). HRV-A and HRV-C prevalence fluctuated throughout the 21-year period; HRV-C was more prevalent during winter (P = .058).
Conclusions
HRV-C is not a new virus but has been significantly associated with childhood lower respiratory illness in this population for several decades. Temporal changes in virus prevalence occur, and season may predict virus species. Our findings have implications for diagnostic, preventive, and treatment strategies due to the variation in disease season and severity based on species of HRV infection.
doi:10.1016/j.jaci.2012.09.033
PMCID: PMC3748586  PMID: 23146382
Rhinovirus; HRV-C; children; season; lower respiratory illness
5.  Cytokine Responses to Novel Antigens in a Peri-Urban Population in Brazil Exposed to Leishmania infantum chagasi 
Visceral leishmaniasis (VL) is fatal if untreated, and there are no vaccines for this disease. High levels of CD4-derived interferon-γ (IFN-γ) in the presence of low levels of interleukin-10 (IL-10) predicts vaccine success. Tumor necrosis factor-α (TNF-α) is also important in this process. We characterized human immune responses in three groups exposed to Leishmania infantum chagasi in Brazil: 1) drug-cured VL patients (recovered VL); 2) asymptomatic persons with positive Leishmania-specific delayed-type hypersensitivity skin reactions (DTH+); and 3) DTH-negative household contacts. Magnitude of DTH correlated with crude Leishmania antigen–driven IFN-γ, TNF-α, and IL-5, but not IL-10. DTH+ persons showed equivalent levels of IFN-γ, but higher levels of IL-10, to tryparedoxin peroxidase and Leishmania homolog of receptor for activated C kinase compared with recovered VL patients. The IFN-γ:IL-10 and TNF-α:IL-10 ratios were higher in recovered VL patients than in DTH+ persons. Seven of 11 novel candidates (R71, L37, N52, L302.06, M18, J41, and M22) elicited cytokine responses (36–71% of responders) in recovered VL patients and DTH+ persons. This result confirmed their putative status as cross-species vaccine/immunotherapeutic candidates.
doi:10.4269/ajtmh.2012.12-0180
PMCID: PMC3516316  PMID: 22826477
6.  Common variants in the HLA-DRB1-HLA-DQA1 Class II region are associated with susceptibility to visceral leishmaniasis 
Nature genetics  2013;45(2):208-213.
To identify susceptibility loci for visceral leishmaniasis we undertook genome-wide association studies in two populations; 989 cases and 1089 controls from India, and 357 cases in 308 Brazilian families (1970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, resulting in Pcombined=2.76×10−17 and OR(95%CI)=1.41(1.30-1.52) across the three cohorts at rs9271858. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.
doi:10.1038/ng.2518
PMCID: PMC3664012  PMID: 23291585
7.  Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil 
Infection, Genetics and Evolution  2012;12(5):1102-1110.
Leishmania braziliensis causes cutaneous (CL) and mucosal (ML) leishmaniasis. In the mouse, Fli1 was identified as a gene influencing enhanced wound healing and resistance to CL caused by L. major. Polymorphism at FLI1 is associated with CL caused by L. braziliensis in humans, with an inverse association observed for ML disease. Here we extend the analysis to look at other wound healing genes, including CTGF, TGFB1, TGFBR1/2, SMADS 2/3/4/7 and FLII, all functionally linked along with FLI1 in the TGF beta pathway. Haplotype tagging single nucleotide polymorphisms (tag-SNPs) were genotyped using Taqman technology in 325 nuclear families (652 CL cases; 126 ML cases) from Brazil. Robust case-pseudocontrol (CPC) conditional logistic regression analysis showed associations between CL and SNPs at CTGF (SNP rs6918698; CC genotype; OR 1.67; 95%CI 1.10–2.54; P=0.016), TGFBR2 (rs1962859; OR 1.50; 95%CI 1.12–1.99; P=0.005), SMAD2 (rs1792658; OR 1.57; 95%CI 1.04–2.38; P=0.03), SMAD7 (rs4464148; AA genotype; OR 2.80; 95%CI 1.00–7.87; P=0.05) and FLII (rs2071242; OR 1.60; 95%CI 1.14–2.24; P=0.005), and between ML and SNPs at SMAD3 (rs1465841; OR 2.15; 95%CI 1.13–4.07; P=0.018) and SMAD7 (rs2337107; TT genotype; OR 3.70; 95%CI 1.27–10.7; P=0.016). Stepwise logistic regression analysis showed that all SNPs associated with CL at FLI1, CTGF, TGFBR2, and FLII showed independent effects from each other, but SNPs at SMAD2 and SMAD7 did not add independent effects to SNPs from other genes. These results suggest that TGFβ signalling via SMAD2 is important in directing events that contribute to CL, whereas signalling via SMAD3 is important in ML. Both are modulated by the inhibitory SMAD7 that acts upstream of SMAD2 and SMAD3 in this signalling pathway. Along with the published FLI1 association, these data further contribute to the hypothesis that wound healing processes are important determinants of pathology associated with cutaneous forms of leishmaniasis.
doi:10.1016/j.meegid.2012.03.017
PMCID: PMC3372530  PMID: 22554650
leishmaniasis; wound healing; TGFB pathway; CTGF; SMADs; FLII; FLI1
8.  Multiple Processes Underlie Benzodiazepine-Mediated Increases in the Consumption of Accepted and Avoided Stimuli 
Chemical Senses  2012;37(5):431-444.
Hyperphagia is a reported side effect of anxiolytic benzodiazepines such as chlordiazepoxide (CDP). Prior research has focused primarily on the ingestive responses to sweet or solid foods. We examined CDP effects on licking for normally accepted and avoided taste solutions across a range of concentrations. The effect of CDP (10 mg/kg) versus saline on the licking patterns of water-restricted rats for water and 3 concentrations of sucrose, saccharin, NaCl, monosodium glutamate (MSG), citric acid, and quinine (Q-HCl) solutions was evaluated during 1 h tests. CDP increased meal size for all tastants except citric acid. Analysis of licking microstructure revealed 3 dissociable effects of CDP. CDP affected oromotor coordination as indicated by a uniform increase in the modal interlick interval for all stimuli. CDP increased meal size as indicated by shorter pauses during consumption of water, MSG, and weaker saccharin concentrations, and by fewer long interlick intervals (250–2000 ms) for normally avoided tastants. CDP also increased meal size by increasing burst size, burst duration, and the initial rate of licking for most solutions, suggesting increased hedonic taste evaluation. CDP did not affect variables associated with postingestive feedback such as meal duration or number of bursts, and the results also suggest that CDP did not enhance the perceived taste intensity. We hypothesize that the reduction of pause duration is consistent with an increased motivation to sample the stimulus that synergizes with changes in taste-mediated responsiveness to some but not all stimuli to yield increases in the consumption of both normally accepted and avoided taste stimuli.
doi:10.1093/chemse/bjr125
PMCID: PMC3348171  PMID: 22248457
CDP; chlordiazepoxide; ingestion; licking; microstructure
9.  Influence of maternal asthma on etiology and severity of infant acute respiratory infection 
Background
Respiratory syncytial virus (RSV) and rhinovirus infections are the most common significant infant respiratory illnesses and are associated with increased but differential risks of childhood asthma.
Objective
Determine whether maternal asthma is associated with higher odds of infant respiratory infection with rhinovirus versus RSV and increased infection severity.
Methods
Mother-infant dyads were enrolled 2004–2008 during an infant respiratory infection (104 rhinovirus, 279 RSV). Mothers were classified into mutually exclusive groups (atopic asthma, non-atopic asthma, no asthma). We determined viral etiology by polymerase chain reaction and severity of infant respiratory infection by bronchiolitis severity score. Adjusted relative odds of maternal asthma with viral etiology were calculated using logistic regression. Proportional odds models assessed the association of maternal asthma and infant infection severity.
Results
Infants with a mother with atopic asthma compared to infants whose mothers did not have asthma were more likely to have rhinovirus versus RSV infection (adjusted odds ratio 2.42 [95% CI: 1.19–4.90]). Similarly, among infants with rhinovirus, having a mother with atopic asthma was associated with increased infection severity (adjusted odds ratio 3.10, 95% CI 1.21–7.98). This relationship was not seen among infants with RSV.
Conclusions
Clinically significant rhinovirus infection during infancy was more strongly associated with having a mother with atopic asthma than clinically significant RSV infection. Having a mother with atopic asthma was associated with increased severity of infant rhinovirus, but not RSV infections. Infants with rhinovirus were more likely to have a familial atopic predisposition, which may partly explain subsequent increased asthma risk.
doi:10.1016/j.jaci.2012.01.045
PMCID: PMC3340428  PMID: 22336082
Atopic predisposition; acute respiratory infection; rhinovirus; respiratory syncytial virus; asthma
10.  A Mechanistic Role for Type III IFN-λ1 in Asthma Exacerbations Mediated by Human Rhinoviruses 
Rationale: Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear.
Objectives: To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing.
Methods: We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma.
Measurements and Main Results: HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21–2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-λ1 levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms (P < 0.001). Moreover, after adjusting for IFN-λ1, children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57–2.46; P = 0.66).
Conclusions: Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-λ1 responses mediate exacerbations caused by HRV. Modulation of IFN- λ1 should be studied as a therapeutic target for exacerbations caused by HRV.
doi:10.1164/rccm.201108-1462OC
PMCID: PMC3361761  PMID: 22135341
asthma; interferon-λ; rhinovirus; children; asthma exacerbation
11.  Human Rhinoviruses in Severe Respiratory Disease in Very Low Birth Weight Infants 
Pediatrics  2012;129(1):e60-e67.
Objectives:
To assess incidence, burden of illness, and risk factors for human rhinoviruses (HRVs) in a cohort of very low birth weight (VLBW) infants.
Methods:
A 2-year prospective cohort study was conducted among VLBW premature infants in Buenos Aires, Argentina. Infants were enrolled in the NICU from June 1, 2003, to May 31, 2005, and managed monthly and with every acute respiratory illness (ARI) during the first year of life. Nasal wash samples were obtained during every respiratory episode and tested for HRV, respiratory syncytial virus (RSV), human parainfluenza viruses, influenza viruses, and human metapneumovirus using reverse transcriptase-polymerase chain reaction.
Results:
Of 119 patients, 66 (55%) had HRV-associated ARIs. The incidence of HRV-associated ARI was 123 events per 100 child-years of follow-up. Of those infants experiencing an episode of bronchiolitis, 40% had HRV versus 7% with RSV. The incidence of HRV-associated bronchiolitis was 75 per 100 infant-years of follow-up. HRV was associated with 12 of 36 hospitalizations (33%), and RSV was associated with 9 of 36 hospitalizations (25%). The incidence of HRV-associated hospitalization was 12 per 100 infant-years of follow-up. The risk of HRV-associated hospitalization was higher for infants with bronchopulmonary dysplasia and those who were not breastfed.
Conclusions:
HRV is an important and frequent pathogen associated with severe respiratory infections in VLBW infants. Bronchopulmonary dysplasia and the absence of breastfeeding are risk factors for hospitalization. The results of our study reveal that HRV is the predominant pathogen of respiratory infections in premature infants.
doi:10.1542/peds.2011-0583
PMCID: PMC3255465  PMID: 22201153
premature infants; rhinovirus; very low birth weight
12.  Racial discrimination is associated with a measure of red blood cell oxidative stress: a potential pathway for racial health disparities 
Background
There are racial health disparities in many conditions for which oxidative stress is hypothesized to be a precursor. These include cardiovascular disease, diabetes, and premature aging. Small clinical studies suggest that psychological stress may increase oxidative stress. However, confirmation of this association in epidemiological studies has been limited by homogenous populations and unmeasured potential confounders.
Purpose
We tested the cross-sectional association between self-reported racial discrimination and red blood cell (RBC) oxidative stress in a biracial, socioeconomically heterogeneous population with well-measured confounders.
Methods
We performed a cross-sectional analysis of a consecutive series of 629 participants enrolled in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Conducted by the National Institute on Aging Intramural Research Program, HANDLS is a prospective epidemiological study of a socioeconomically diverse cohort of 3721 whites and African Americans aged 30–64 years. Racial discrimination was based on self-report. RBC oxidative stress was measured by fluorescent heme degradation products. Potential confounders were age, smoking status, obesity, and C-reactive protein.
Results
Participants had a mean age of 49 years (SD = 9.27). In multivariable linear regression models, racial discrimination was significantly associated with RBC oxidative stress (Beta=0.55 P<0.05) after adjustment for age, smoking, C-reactive protein level, and obesity. When stratified by race, discrimination was not associated with RBC oxidative stress in Whites but was associated significantly for African-Americans (Beta=0.36, P<0.05).
Conclusions
These findings suggest that there may be identifiable cellular pathways by which racial discrimination amplifies cardiovascular and other age-related disease risks.
doi:10.1007/s12529-011-9188-z
PMCID: PMC3496810  PMID: 21913047
health disparities; racial discrimination; oxidative stress; accelerated aging
13.  Impact of Apolipoprotein E ε4 and HIV on Cognition and Brain Atrophy: Antagonistic Pleiotropy and Premature Brain Aging 
NeuroImage  2011;58(4):1017-1027.
Objective
The apolipoprotein E (APOE) ε4 allele may accelerate the progression of HIV disease, and increase the risk for developing HIV-associated neurocognitive disorder (HAND). Whether APOEε4 allele(s) and age may influence brain atrophy in HIV patients is unknown and was evaluated.
Methods
Automated morphometry on magnetic resonance images, using FreeSurfer analyses, neuropsychological testing and APOE genotyping were performed in 139 subjects [70 seronegative controls (SN); 69 clinically-stable HIV subjects].
Results
Compared to SN, HIV subjects had smaller volumes throughout the brain regardless of their HAND status. Compared to APOEε4− subjects, SN controls with APOEε4 had better memory and larger global brain volumes (cerebral white matter and cortex) while HIV subjects with the APOEε4 allele(s) had poorer cognition (verbal fluency, learning, executive function and memory) and smaller cerebral and cerebellar white matter and subcortical structures. Further stratification of age showed that younger (<50 years) APOEε4+SN subjects had larger putamen and cerebral white matter, while younger APOEε4+HIV subjects had poorer performance on verbal fluency and smaller brain volumes [3-way (HIV-status × APOEε4 × Age) interaction-p-values=0.005 to 0.03].
Interpretation
These findings suggest that APOEε4 allele(s) may show antagonistic pleiotropy on cognition and brain atrophy in SN controls, but may lead to premature aging with neurodegeneration in younger HIV patients prior to the development of HAND. Potential mechanisms for such interactions may include stronger neuro-inflammation or greater amyloid deposition in younger HIV subjects with APOEε4 allele(s). Early screening for the APOEε4 allele and brain atrophy with morphometry may guide neuroprotective intervention of cognitively normal HIV subjects prior to the development of HAND. Longitudinal follow-up studies and larger sample sizes are needed to validate these cross-sectional results.
doi:10.1016/j.neuroimage.2011.07.010
PMCID: PMC3171637  PMID: 21803164
HIV; APOE; age; morphometry; brain
14.  Genetic and Functional Evidence Implicating DLL1 as the Gene That Influences Susceptibility to Visceral Leishmaniasis at Chromosome 6q27 
The Journal of Infectious Diseases  2011;204(3):467-477.
Background. Visceral leishmaniasis (VL) is caused by Leishmania donovani and Leishmania infantum chagasi. Genome-wide linkage studies from Sudan and Brazil identified a putative susceptibility locus on chromosome 6q27.
Methods. Twenty-two single-nucleotide polymorphisms (SNPs) at genes PHF10, C6orf70, DLL1, FAM120B, PSMB1, and TBP were genotyped in 193 VL cases from 85 Sudanese families, and 8 SNPs at genes PHF10, C6orf70, DLL1, PSMB1, and TBP were genotyped in 194 VL cases from 80 Brazilian families. Family-based association, haplotype, and linkage disequilibrium analyses were performed. Multispecies comparative sequence analysis was used to identify conserved noncoding sequences carrying putative regulatory elements. Quantitative reverse-transcription polymerase chain reaction measured expression of candidate genes in splenic aspirates from Indian patients with VL compared with that in the control spleen sample.
Results. Positive associations were observed at PHF10, C6orf70, DLL1, PSMB1, and TBP in Sudan, but only at DLL1 in Brazil (combined P = 3 × 10−4 at DLL1 across Sudan and Brazil). No functional coding region variants were observed in resequencing of 22 Sudanese VL cases. DLL1 expression was significantly (P = 2 × 10−7) reduced (mean fold change, 3.5 [SEM, 0.7]) in splenic aspirates from patients with VL, whereas other 6q27 genes showed higher levels (1.27 × 10−6 < P < .01) than did the control spleen sample. A cluster of conserved noncoding sequences with putative regulatory variants was identified in the distal promoter of DLL1.
Conclusions. DLL1, which encodes Delta-like 1, the ligand for Notch3, is strongly implicated as the chromosome 6q27 VL susceptibility gene.
doi:10.1093/infdis/jir284
PMCID: PMC3132144  PMID: 21742847
16.  Host factors and viral factors associated with severity of human rhinovirus infant respiratory illness 
Background
Risk factors for severe human rhinovirus (HRV) associated infant illness are unknown.
Objectives
To examine the role of HRV in infant respiratory illness, and assess viral and host risk factors for HRV disease severity.
Methods
We utilized a prospective cohort of term, previously healthy infants enrolled during an inpatient or outpatient visit for acute upper or lower respiratory illness during fall-spring months 2004-2008. Illness severity was determined using an ordinal bronchiolitis severity score with higher scores indicating more severe disease. HRV was identified by real-time RT-PCR. The VP4/VP2 region from HRV positive specimens was sequenced to determine species.
Results
Of 630 infants with bronchiolitis or URI, 162 (26%) had HRV; HRV was associated with 18% of bronchiolitis and 47% of URI. Among infants with HRV, 104 (64%) had HRV alone. Host factors associated with more severe HRV illness included maternal and family history of atopy (median score 3.5, IQR [1.0-7.8] vs. 2.0 [1.0-5.2], and 3.5 [1.0-7.5] vs.2.0 [0-4.0]). In adjusted analyses maternal history of atopy conferred an increase in risk for more severe HRV bronchiolitis (OR=2.39, 95% CI:1.14-4.99, p=0.02). In a similar model, maternal asthma was also associated with greater HRV bronchiolitis severity (OR=2.49, 95% CI: 1.10-5.67, p=0.03). Among HRV, 35% were HRVA, 6% HRVB, and 30% HRVC.
Conclusion
HRV was a frequent cause of bronchiolitis and URI among previously healthy term infants requiring hospitalization or unscheduled outpatient visits. Substantial genetic diversity was seen amongst the HRV, and predominant groups varied by season and year. Host factors including maternal atopy were associated with more severe infant HRV illness.
doi:10.1016/j.jaci.2010.11.041
PMCID: PMC3070861  PMID: 21269669
Rhinovirus; HRVC; infants; atopy; asthma; bronchiolitis; maternal
17.  Increased Furfural Tolerance Due to Overexpression of NADH-Dependent Oxidoreductase FucO in Escherichia coli Strains Engineered for the Production of Ethanol and Lactate▿ 
Applied and Environmental Microbiology  2011;77(15):5132-5140.
Furfural is an important fermentation inhibitor in hemicellulose sugar syrups derived from woody biomass. The metabolism of furfural by NADPH-dependent oxidoreductases, such as YqhD (low Km for NADPH), is proposed to inhibit the growth and fermentation of xylose in Escherichia coli by competing with biosynthesis for NADPH. The discovery that the NADH-dependent propanediol oxidoreductase (FucO) can reduce furfural provided a new approach to improve furfural tolerance. Strains that produced ethanol or lactate efficiently as primary products from xylose were developed. These strains included chromosomal mutations in yqhD expression that permitted the fermentation of xylose broths containing up to 10 mM furfural. Expression of fucO from plasmids was shown to increase furfural tolerance by 50% and to permit the fermentation of 15 mM furfural. Product yields with 15 mM furfural were equivalent to those of control strains without added furfural (85% to 90% of the theoretical maximum). These two defined genetic traits can be readily transferred to enteric biocatalysts designed to produce other products. A similar strategy that minimizes the depletion of NADPH pools by native detoxification enzymes may be generally useful for other inhibitory compounds in lignocellulosic sugar streams and with other organisms.
doi:10.1128/AEM.05008-11
PMCID: PMC3147458  PMID: 21685167
18.  New human rhinovirus species and their significance in asthma exacerbation and airway remodeling 
doi:10.1016/j.iac.2010.08.007
PMCID: PMC2967460  PMID: 21029937
asthma; rhinovirus; bronchiolitis; exacerbation
19.  Serum Antibody Kinetics following Nasal or Parenteral Challenge with Meningococcal Polysaccharide in Healthy Adults▿  
Limited data are available on the kinetics of meningococcal serogroup C (MenC)-specific antibody responses following parenteral or nasal challenge in those who have received prior MenC vaccination (polysaccharide or conjugate). Young adults who had previously received either meningococcal A/C polysaccharide (MACP) or MenC conjugate (MCC) vaccine or naïve subjects were challenged with MACP via one of two routes, nasal or parenteral. Blood samples were taken prevaccination and on days 1 to 4 and day 10 postvaccination. MenC serum bactericidal antibody (SBA) and MenC-specific IgG were measured. Following parenteral challenge, MenC SBA and IgG responses were seen to occur between 4 and 7 days postchallenge. A lower proportion of subjects responded following nasal challenge, with naïve subjects showing little change in SBA geometric mean titer (GMT) and IgG geometric mean concentration (GMC) over the 10 days following challenge. Increases in SBA GMTs were seen between 4 and 7 days after nasal challenge in those who had received prior MCC and between 7 and 10 days in those who had received prior MACP, and the responses in the prior-MACP group were of lower magnitude than the responses of the prior-MCC group. The data presented here indicate that, following MCC vaccination, memory has been induced at the mucosal level, and these subjects were able to respond with increases in SBA levels. These results demonstrate that the speed of response (primary or secondary) to challenge with MenC polysaccharide via the nasal or parenteral route does not differ and support concerns that immunological memory alone is too slow to provide protection.
doi:10.1128/CVI.00503-10
PMCID: PMC3067375  PMID: 21248159
20.  Genetics and visceral leishmaniasis: of mice and man 
Parasite immunology  2009;31(5):254-266.
SUMMARY
Ninety percent of the 500,000 annual new cases of visceral leishmaniasis occur in India/Bangladesh/Nepal, Sudan and Brazil. Importantly, 80-90% of human infections are sub-clinical or asymptomatic, usually associated with strong cell-mediated immunity. Understanding the environmental and genetic risk factors that determine why two people with the same exposure to infection differ in susceptibility could provide important leads for improved therapies. Recent research using candidate gene association analysis and genome-wide linkage studies (GWLS) in collections of families from Sudan, Brazil and India have identified a number of genes/regions related both to environmental risk factors (e.g. iron), as well as genes that determine type 1 versus type 2 cellular immune responses. However, until now all of the allelic association studies carried out have been underpowered to find genes of small effect sizes (odds ratios or OR<2), and GWLS using multicase pedigrees have only been powered to find single major genes, or at best oligogenic control. The accumulation of large DNA banks from India and Brazil now makes it possible to undertake genome-wide asscociation studies (GWAS), which are ongoing as part of phase two of the Wellcome Trust Case Control Consortium. Data from this analysis should seed research into novel genes and mechanisms that influence susceptibility to visceral leishmaniasis.
doi:10.1111/j.1365-3024.2009.01102.x
PMCID: PMC3160815  PMID: 19388946
leishmaniasis; candidate genes; genome scans
21.  Real-world comparison of two molecular methods for detection of respiratory viruses 
Virology Journal  2011;8:332.
Background
Molecular polymerase chain reaction (PCR) based assays are increasingly used to diagnose viral respiratory infections and conduct epidemiology studies. Molecular assays have generally been evaluated by comparing them to conventional direct fluorescent antibody (DFA) or viral culture techniques, with few published direct comparisons between molecular methods or between institutions. We sought to perform a real-world comparison of two molecular respiratory viral diagnostic methods between two experienced respiratory virus research laboratories.
Methods
We tested nasal and throat swab specimens obtained from 225 infants with respiratory illness for 11 common respiratory viruses using both a multiplex assay (Respiratory MultiCode-PLx Assay [RMA]) and individual real-time RT-PCR (RT-rtPCR).
Results
Both assays detected viruses in more than 70% of specimens, but there was discordance. The RMA assay detected significantly more human metapneumovirus (HMPV) and respiratory syncytial virus (RSV), while RT-rtPCR detected significantly more influenza A. We speculated that primer differences accounted for these discrepancies and redesigned the primers and probes for influenza A in the RMA assay, and for HMPV and RSV in the RT-rtPCR assay. The tests were then repeated and again compared. The new primers led to improved detection of HMPV and RSV by RT-rtPCR assay, but the RMA assay remained similar in terms of influenza detection.
Conclusions
Given the absence of a gold standard, clinical and research laboratories should regularly correlate the results of molecular assays with other PCR based assays, other laboratories, and with standard virologic methods to ensure consistency and accuracy.
doi:10.1186/1743-422X-8-332
PMCID: PMC3154182  PMID: 21714915
22.  Viral Respiratory Infections and Asthma: the Course Ahead 
Inquiries into the relationships between viral respiratory illnesses and the inception and exacerbation of asthma are being facilitated by recent advances in research approaches and technology. In this article, we identify important knowledge gaps and future research questions, and we discuss how new investigational tools, including improved respiratory virus detection techniques, will permit current and future researchers to define these relationships and the host, virus, developmental, and environmental mechanisms that regulate them. A better understanding of these processes should facilitate the development of improved strategies for the prevention and treatment of virus-induced wheezing illnesses and asthma exacerbations and, possibly, the ultimate goal of discovering effective approaches for the primary prevention of asthma.
doi:10.1016/j.jaci.2010.04.002
PMCID: PMC2880817  PMID: 20513518
viral respiratory infections; asthma; wheezing; asthma onset; asthma exacerbations; respiratory viruses; rhinovirus; respiratory syncytial virus; allergy
24.  Evidence for associations between the purinergic receptor P2X7 (P2RX7) and toxoplasmosis 
Genes and immunity  2010;11(5):374-383.
Congenital Toxoplasma gondii infection can result in intracranial calcification, hydrocephalus, and retinochoroiditis. Acquired infection is commonly associated with ocular disease. Pathology is characterized by strong pro-inflammatory responses. Ligation of ATP by purinergic receptor P2X7, encoded by P2RX7, stimulates pro-inflammatory cytokines and can lead directly to killing of intracellular pathogens. To determine whether P2X7 plays a role in susceptibility to congenital toxoplasmosis, we examined polymorphisms at P2RX7 in 149 child/parent trios from North America. We found association (FBAT Z scores ±2.429; P= 0.015) between the derived C(+)G(−) allele (f= 0.68; OR= 2.06; 95% CI: 1.14–3.75) at SNP rs1718119 (1068T>C; Thr-348-Ala), and a second synonymous variant rs1621388 in linkage disequilibrium with it, and clinical signs of disease per se. Analysis of clinical sub-groups showed no association with hydrocephalus, with effect sizes for associations with retinal disease and brain calcifications enhanced (OR=3.0 to 4.25; 0.004
doi:10.1038/gene.2010.31
PMCID: PMC2908187  PMID: 20535134
Toxoplasmosis; genetic polymorphisms; purinergic receptor P2X7; North America; Brazil
PLoS ONE  2010;5(12):e15807.
Background
Genome wide linkage studies (GWLS) have provided evidence for loci controlling visceral leishmaniasis on Chromosomes 1p22, 6q27, 22q12 in Sudan and 6q27, 9p21, 17q11-q21 in Brazil. Genome wide studies from the major focus of disease in India have not previously been reported.
Methods and Findings
We undertook a GWLS in India in which a primary ∼10 cM (515 microsatellites) scan was carried out in 58 multicase pedigrees (74 nuclear families; 176 affected, 353 total individuals) and replication sought in 79 pedigrees (102 nuclear families; 218 affected, 473 total individuals). The primary scan provided evidence (≥2 adjacent markers allele-sharing LOD≥0.59; nominal P≤0.05) for linkage on Chromosomes 2, 5, 6, 7, 8, 10, 11, 20 and X, with peaks at 6p25.3-p24.3 and 8p23.1-p21.3 contributed to largely by 31 Hindu families and at Xq21.1-q26.1 by 27 Muslim families. Refined mapping confirmed linkage across all primary scan families at 2q12.2-q14.1 and 11q13.2-q23.3, but only 11q13.2-q23.3 replicated (combined LOD = 1.59; P = 0.0034). Linkage at 6p25.3-p24.3 and 8p23.1-p21.3, and at Xq21.1-q26.1, was confirmed by refined mapping for primary Hindu and Muslim families, respectively, but only Xq21.1-q26.1 replicated across all Muslim families (combined LOD 1.49; P = 0.0045). STRUCTURE and SMARTPCA did not identify population genetic substructure related to religious group. Classification and regression tree, and spatial interpolation, analyses confirm geographical heterogeneity for linkages at 6p25.3-p24.3, 8p23.1-p21.3 and Xq21.1-q26.1, with specific clusters of families contributing LOD scores of 2.13 (P = 0.0009), 1.75 (P = 0.002) and 1.84 (P = 0.001), respectively.
Conclusions
GWLS has identified novel loci that show geographical heterogeneity in their influence on susceptibility to VL in India.
doi:10.1371/journal.pone.0015807
PMCID: PMC3013125  PMID: 21209823

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