PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (39)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
more »
2.  Asthma Treatments and Mental Health Visits After a Food and Drug Administration Label Change for Leukotriene Inhibitors 
Clinical therapeutics  2015;37(6):1280-1291.
Purpose
In 2009, the US Food and Drug Administration (FDA) mandated a label change for leukotriene inhibitors (LTIs) to include neuropsychiatric adverse events (eg, depression and suicidality) as a precaution. This study investigated how this label change affected the use of LTIs and other asthma controller medications, mental health visits, and suicide attempts.
Methods
We analyzed data (2005–2010) from 5 large health plans in the US Population-Based Effectiveness in Asthma and Lung Diseases (PEAL) Network. The study cohort included children and adolescents (n = 30,000), young adults (n = 20,000), and adults (n = 90,000) with asthma. We used interrupted time series to examine changes in rates of LTI dispensings, non-LTI dispensings, mental health visits, and suicide attempts (using a validated algorithm based on a combination of diagnoses of injury or poisoning and psychiatric conditions).
Findings
The label change was associated with abrupt reductions in LTI use among all age groups (relative reductions of 8.3%, 15.1%, and 6.0% among adolescents, young adults, and adults, respectively, compared with expected rates at 1 year after the warnings). Although we detected immediate offset increases in non-LTI asthma medication use, these increases were not sustained among adolescents and young adults. There were small increases in mental health visits among LTI users.
Implications
The FDA label change for LTIs communicated possible risk of neuropsychiatric events. Communication and enhanced awareness may have increased reporting of mental health symptoms among young adults and adults. It is important to assess intended and unintended consequences of FDA warnings and label changes.
doi:10.1016/j.clinthera.2015.03.027
PMCID: PMC5101625  PMID: 25920571
asthma; drug tolerability; FDA; leukotriene inhibitors; montelukast; risk communication
4.  Urine Club Cell 16-kDa Secretory Protein and Childhood Wheezing Illnesses After Lower Respiratory Tract Infections in Infancy 
Background: Infants with lower respiratory tract infections (LRTIs) are at an increased risk of developing childhood wheezing illnesses (including asthma), but it is not currently possible to predict those at risk for these long-term outcomes. The current objective was to examine whether urine levels of club cell 16-kDa secretory protein (CC16) at the time of an infant LRTI are associated with the development of childhood wheezing illnesses.
Methods: Prospective study of 133 previously healthy infants enrolled during a healthcare visit for a LRTI and followed longitudinally for childhood wheezing illnesses. Urine levels of CC16 at the time of enrollment were measured after validating a commercially available enzyme-linked immunosorbent assay kit for serum. The outcome of interest was parental report of subsequent childhood wheeze (defined as ≥1 episode of wheezing following the initial LRTI) at the 1-year follow-up visit. Logistic regression was used for the main analysis.
Results: The median (interquartile range) urine levels of CC16 (ng/mg of creatinine) at the time of an infant LRTI were 11.1 (7.7–20.1) for infants with subsequent childhood wheeze and 13.4 (8.3–61.1) for those without (p = 0.11). In the main multivariate analysis using a logarithmic transformation of the urine levels of CC16, a twofold increase in urine levels of CC16 was associated with ∼30% decreased odds (OR = 0.74 [95% confidence interval (CI) 0.56–0.98], p = 0.04) of subsequent childhood wheeze after adjustment for potential confounders.
Conclusions: An inverse association was found between urine levels of CC16 at the time of an infant LRTI and the odds of subsequent childhood wheeze. Urine CC16 may be a useful biomarker of the development of childhood wheezing illnesses after LRTIs in infancy.
doi:10.1089/ped.2015.0528
PMCID: PMC4580139  PMID: 26421213
6.  Seasonal Timing of Infant Bronchiolitis, Apnea and Sudden Unexplained Infant Death 
PLoS ONE  2016;11(7):e0158521.
Rates of Sudden Unexplained Infant Death (SUID), bronchiolitis, and central apnea increase in winter in temperate climates. Though associations between these three conditions are suggested, more work is required to establish if there is a causal pathway linking bronchiolitis to SUID through inducing central apnea. Utilizing a large population-based cohort of infants studied over a 20-year period (n = 834,595, from birth years 1989–2009)), we analyzed ecological associations between timing of SUID cases, bronchiolitis, and apnea healthcare visits. Data were analyzed between 2013 and 2015. We used a Cox Proportional Hazards model to analyze possible interactions between maternal smoking and maternal asthma with infant bronchiolitis on time to SUID. SUID and bronchiolitis both occurred more frequently in winter. An increase in bronchiolitis clinical visits occurred within a few days prior to apnea visits. We found a temporal relationship between infant bronchiolitis and apnea. In contrast, no peak in SUID cases was seen during peaks of bronchiolitis. Among those without any bronchiolitis visits, maternal smoking was associated with an increased risk of SUID: Hazard Ratio (HR) of 2.38 (95% CI: 2.11, 2.67, p-value <0.001). Maternal asthma was associated with an increased risk of SUID among infants with at least one bronchiolitis visit: HR of 2.40 (95% CI: 1.04, 5.54, p-value = 0.04). Consistent trends between bronchiolitis, apnea, and SUID were not established due to small numbers of SUID cases. However, interaction analysis revealed potential differential associations of bronchiolitis and SUID by maternal smoking, maternal asthma status.
doi:10.1371/journal.pone.0158521
PMCID: PMC4942135  PMID: 27404386
7.  Respiratory Syncytial Virus whole-genome sequencing identifies convergent evolution of sequence duplication in the C-terminus of the G gene 
Scientific Reports  2016;6:26311.
Respiratory Syncytial Virus (RSV) is responsible for considerable morbidity and mortality worldwide and is the most important respiratory viral pathogen in infants. Extensive sequence variability within and between RSV group A and B viruses and the ability of multiple clades and sub-clades of RSV to co-circulate are likely mechanisms contributing to the evasion of herd immunity. Surveillance and large-scale whole-genome sequencing of RSV is currently limited but would help identify its evolutionary dynamics and sites of selective immune evasion. In this study, we performed complete-genome next-generation sequencing of 92 RSV isolates from infants in central Tennessee during the 2012–2014 RSV seasons. We identified multiple co-circulating clades of RSV from both the A and B groups. Each clade is defined by signature N- and O-linked glycosylation patterns. Analyses of specific RSV genes revealed high rates of positive selection in the attachment (G) gene. We identified RSV-A viruses in circulation with and without a recently reported 72-nucleotide G gene sequence duplication. Furthermore, we show evidence of convergent evolution of G gene sequence duplication and fixation over time, which suggests a potential fitness advantage of RSV with the G sequence duplication.
doi:10.1038/srep26311
PMCID: PMC4876326  PMID: 27212633
8.  Genes associated with RSV lower respiratory tract infection and asthma: the application of genetic epidemiological methods to understand causality 
Future virology  2015;10(7):883-897.
Infants with respiratory syncytial virus (RSV) lower respiratory tract infections (LRIs) are at increased risk for childhood asthma. The objectives of this article are to review the genes associated with both RSV LRI and asthma, review analytic approaches to assessing shared genetic risk and propose a future perspective on how these approaches can help us to understand the role of infant RSV infection as both an important risk factor for asthma and marker of shared genetic etiology between the two conditions. The review of shared genes and thus pathways associated with severity of response to RSV infection and asthma risk can help us to understand mechanisms of disease and ultimately propose new and novel targets for primary prevention of both diseases.
doi:10.2217/fvl.15.55
PMCID: PMC4603287  PMID: 26478738
asthma; bronchiolitis; genome-wide association study; human genetics; infant; lower respiratory tract infection; respiratory syncytial virus; review; wheezing
9.  Identifying genetically driven clinical phenotypes using linear mixed models 
Nature Communications  2016;7:11433.
We hypothesized that generalized linear mixed models (GLMMs), which estimate the additive genetic variance underlying phenotype variability, would facilitate rapid characterization of clinical phenotypes from an electronic health record. We evaluated 1,288 phenotypes in 29,349 subjects of European ancestry with single-nucleotide polymorphism (SNP) genotyping on the Illumina Exome Beadchip. We show that genetic liability estimates are primarily driven by SNPs identified by prior genome-wide association studies and SNPs within the human leukocyte antigen (HLA) region. We identify 44 (false discovery rate q<0.05) phenotypes associated with HLA SNP variation and show that hypothyroidism is genetically correlated with Type I diabetes (rG=0.31, s.e. 0.12, P=0.003). We also report novel SNP associations for hypothyroidism near HLA-DQA1/HLA-DQB1 at rs6906021 (combined odds ratio (OR)=1.2 (95% confidence interval (CI): 1.1–1.2), P=9.8 × 10−11) and for polymyalgia rheumatica near C6orf10 at rs6910071 (OR=1.5 (95% CI: 1.3–1.6), P=1.3 × 10−10). Phenome-wide application of GLMMs identifies phenotypes with important genetic drivers, and focusing on these phenotypes can identify novel genetic associations.
Use of general linear mixed models (GLMMs) in genetic variance analysis can quantify the relative contribution of additive effects from genetic variation on a given trait. Here, Jonathan Mosley and colleagues apply GLMM in a phenome-wide analysis and show that genetic variations in the HLA region are associated with 44 phenotypes, 5 phenotypes which were not previously reported in GWASes.
doi:10.1038/ncomms11433
PMCID: PMC4848547  PMID: 27109359
10.  Novel Loci Associated with Usual Sleep Duration: The CHARGE Consortium Genome-Wide Association Study 
Gottlieb, Daniel J. | Hek, Karin | Chen, Ting-hsu | Watson, Nathaniel F. | Eiriksdottir, Gudny | Byrne, Enda M. | Cornelis, Marilyn | Warby, Simon C. | Bandinelli, Stefania | Cherkas, Lynn | Evans, Daniel S. | Grabe, Hans J. | Lahti, Jari | Li, Man | Lehtimäki, Terho | Lumley, Thomas | Marciante, Kristin D. | Pérusse, Louis | Psaty, Bruce M. | Robbins, John | Tranah, Gregory J. | Vink, Jacqueline M. | Wilk, Jemma B. | Stafford, Jeanette M. | Bellis, Claire | Biffar, Reiner | Bouchard, Claude | Cade, Brian | Curhan, Gary C. | Eriksson, Johan G. | Ewert, Ralf | Ferrucci, Luigi | Fülöp, Tibor | Gehrman, Philip R. | Goodloe, Robert | Harris, Tamara B. | Heath, Andrew C. | Hernandez, Dena | Hofman, Albert | Hottenga, Jouke-Jan | Hunter, David J. | Jensen, Majken K. | Johnson, Andrew D. | Kähönen, Mika | Kao, Linda | Kraft, Peter | Larkin, Emma K. | Lauderdale, Diane S. | Luik, Annemarie I. | Medici, Marco | Montgomery, Grant W. | Palotie, Aarno | Patel, Sanjay R. | Pistis, Giorgio | Porcu, Eleonora | Quaye, Lydia | Raitakari, Olli | Redline, Susan | Rimm, Eric B. | Rotter, Jerome I. | Smith, Albert V. | Spector, Tim D. | Teumer, Alexander | Uitterlinden, André G. | Vohl, Marie-Claude | Widen, Elisabeth | Willemsen, Gonneke | Young, Terry | Zhang, Xiaoling | Liu, Yongmei | Blangero, John | Boomsma, Dorret I. | Gudnason, Vilmundur | Hu, Frank | Mangino, Massimo | Martin, Nicholas G. | O’Connor, George T. | Stone, Katie L. | Tanaka, Toshiko | Viikari, Jorma | Gharib, Sina A. | Punjabi, Naresh M. | Räikkönen, Katri | Völzke, Henry | Mignot, Emmanuel | Tiemeier, Henning
Molecular psychiatry  2014;20(10):1232-1239.
Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study of usual sleep duration was conducted using 18 population-based cohorts totaling 47,180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35–80 kb upstream from the thyroid-specific transcription factor PAX8 (lowest p=1.1 ×10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest p=9.3 × 10−4). The strongest combined association was at rs1823125 (p=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 minutes longer per night. The alleles associated with longer sleep duration were associated in previous genome-wide association studies with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
doi:10.1038/mp.2014.133
PMCID: PMC4430294  PMID: 25469926
Sleep; Genome-wide association study
11.  Novel Loci Associated with Usual Sleep Duration: The CHARGE Consortium Genome-Wide Association Study 
Gottlieb, Daniel J. | Hek, Karin | Chen, Ting-hsu | Watson, Nathaniel F. | Eiriksdottir, Gudny | Byrne, Enda M. | Cornelis, Marilyn | Warby, Simon C. | Bandinelli, Stefania | Cherkas, Lynn | Evans, Daniel S. | Grabe, Hans J. | Lahti, Jari | Li, Man | Lehtimäki, Terho | Lumley, Thomas | Marciante, Kristin D. | Pérusse, Louis | Psaty, Bruce M. | Robbins, John | Tranah, Gregory J. | Vink, Jacqueline M. | Wilk, Jemma B. | Stafford, Jeanette M. | Bellis, Claire | Biffar, Reiner | Bouchard, Claude | Cade, Brian | Curhan, Gary C. | Eriksson, Johan G. | Ewert, Ralf | Ferrucci, Luigi | Fülöp, Tibor | Gehrman, Philip R. | Goodloe, Robert | Harris, Tamara B. | Heath, Andrew C. | Hernandez, Dena | Hofman, Albert | Hottenga, Jouke-Jan | Hunter, David J. | Jensen, Majken K. | Johnson, Andrew D. | Kähönen, Mika | Kao, Linda | Kraft, Peter | Larkin, Emma K. | Lauderdale, Diane S. | Luik, Annemarie I. | Medici, Marco | Montgomery, Grant W. | Palotie, Aarno | Patel, Sanjay R. | Pistis, Giorgio | Porcu, Eleonora | Quaye, Lydia | Raitakari, Olli | Redline, Susan | Rimm, Eric B. | Rotter, Jerome I. | Smith, Albert V. | Spector, Tim D. | Teumer, Alexander | Uitterlinden, André G. | Vohl, Marie-Claude | Widen, Elisabeth | Willemsen, Gonneke | Young, Terry | Zhang, Xiaoling | Liu, Yongmei | Blangero, John | Boomsma, Dorret I. | Gudnason, Vilmundur | Hu, Frank | Mangino, Massimo | Martin, Nicholas G. | O’Connor, George T. | Stone, Katie L. | Tanaka, Toshiko | Viikari, Jorma | Gharib, Sina A. | Punjabi, Naresh M. | Räikkönen, Katri | Völzke, Henry | Mignot, Emmanuel | Tiemeier, Henning
Molecular psychiatry  2014;20(10):1232-1239.
Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study of usual sleep duration was conducted using 18 population-based cohorts totaling 47,180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35-80 kb upstream from the thyroid-specific transcription factor PAX8 (lowest p=1.1 × 10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest p=9.3 × 10−4). The strongest combined association was at rs1823125 (p=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 minutes longer per night. The alleles associated with longer sleep duration were associated in previous genome-wide association studies with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
doi:10.1038/mp.2014.133
PMCID: PMC4430294  PMID: 25469926
Sleep; Genome-wide association study
12.  A simple respiratory severity score that may be used in evaluation of acute respiratory infection 
BMC Research Notes  2016;9:85.
Background
Acute respiratory infections are ubiquitous and may have long-term implications on respiratory health. There are many scoring systems used to objectively measure severity of respiratory infections in clinical and research settings. A respiratory severity score derived exclusively from physical exam components (RSS-HR) was studied as an objective measure of disease severity and was compared to a previously described score that uses pulse oximetry as a component of its score (RSS-SO).
Findings
A score was derived from 497 infants. The RSS-HR median score was higher in infants that were hospitalized (8.0) versus outpatient (4.0, p < 0.001), and those with lower respiratory tract infections (LRTI) (6.5) versus upper respiratory infections (URI) (1.0, p < 0.001). When discriminating upper versus LRTIs the concordance index of regression for RSS-HR was 0.91 and RSS-SO was 0.93.
Conclusions
RSS-HR distinguishes disease severity based on level of care, as well as LRTI versus URI.
doi:10.1186/s13104-016-1899-4
PMCID: PMC4751705  PMID: 26868120
Pediatrics; Respiratory infections; Pulmonary
13.  Primary Adherence to Controller Medications for Asthma Is Poor 
Rationale: Few previous studies have evaluated primary adherence (whether a new prescription is filled within 30 d) to controller medications in individuals with persistent asthma.
Objective: To compare adherence to the major controller medication regimens for asthma.
Methods: This was a retrospective cohort study of enrollees from five large health plans. We used electronic medical data on patients of all ages with asthma who had experienced an asthma-related exacerbation in the prior 12 months. We studied adherence measures including proportion of days covered and primary adherence (first prescription filled within 30 d).
Measurements and Main Results: Our population included 69,652 subjects who had probable persistent asthma and were prescribed inhaled corticosteroids (ICSs), leukotriene antagonists (LTRAs), or ICS/long-acting β-agonists (ICS/LABAs). The mean age was 37 years and 58% were female. We found that 14–20% of subjects who were prescribed controller medicines for the first time did not fill their prescriptions. The mean proportion of days covered was 19% for ICS, 30% for LTRA, and 25% for ICS/LABA over 12 months. Using multivariate logistic regression, subjects prescribed LTRA were less likely to be primary adherent than subjects prescribed ICS (odds ratio, 0.82; 95% confidence interval, 0.74–0.92) or ICS/LABA (odds ratio, 0.88; 95% confidence interval, 0.80–0.97). Black and Latino patients were less likely to fill the prescription compared with white patients.
Conclusions: Adherence to controller medications for asthma is poor. In this insured population, primary adherence to ICSs was better than to LTRAs and ICS/LABAs. Adherence as measured by proportion of days covered was better for LTRAs and ICS/LABAs than for ICSs.
doi:10.1513/AnnalsATS.201410-459OC
PMCID: PMC4342835  PMID: 25569765
asthma; adherence; medications; inhaled corticosteroids; leukotriene antagonists
14.  New Risk Factors for Adult-Onset Incident Asthma. A Nested Case–Control Study of Host Antioxidant Defense 
Rationale: Host antioxidant defense, consisting of enzymatic antioxidant activity and nonenzymatic antioxidant micronutrients, is implicated in asthma pathogenesis. Studies of antioxidant defense and adult incident asthma have either used measures of antioxidants estimated from questionnaires or not considered enzymatic aspects of host defense.
Objectives: We conducted the first study designed and powered to investigate the association of antioxidant defenses on adult incident asthma.
Methods: In a nested case–control study, we followed Shanghai women (aged 40–70 years) without prevalent asthma at baseline, over 8 years. Subjects with incident asthma were ascertained prospectively by gold standard testing of symptomatic women and matched to two asymptomatic control subjects.
Measurements and Main Results: Baseline urinary F2-isoprostanes, plasma concentrations of antioxidant micronutrients (tocopherols, xanthines, carotenes, and lycopene), and antioxidant enzyme activity (platelet-activating factor acetylhydrolase [PAF-AH] and superoxide dismutase) were measured from samples collected before disease onset. Among 65,372 women, 150 (0.24%) developed asthma. F2-isoprostane levels before asthma onset were not different between cases and control subjects. Doubling of α-tocopherol concentrations and PAF-AH activity was associated with 50 and 37% decreased risk of incident asthma (α-tocopherol: adjusted odds ratio = 0.52; 95% confidence interval, 0.32–0.84; PAF-AH: adjusted odds ratio = 0.63; 95% confidence interval, 0.42–0.93).
Conclusions: In this prospective study, α-tocopherol, within normal reference ranges, and PAF-AH enzymatic activity were associated with decreased asthma development. These modifiable risk factors may be an effective strategy to test for primary asthma prevention.
doi:10.1164/rccm.201405-0948OC
PMCID: PMC4299629  PMID: 25408961
asthma; incidence study; antioxidants; platelet-activating factor acetylhydrolase; α-tocopherol
15.  A Study of the Relationship between the Interleukin-6 Gene and Obstructive Sleep Apnea 
Introduction
Because obstructive sleep apnea (OSA) is associated with increased levels of inflammatory cytokines, we examined the relationship between OSA and polymorphisms for interleukin-6 (IL-6).
Methods
6 single nucleotide polymorphisms (SNPs) within IL-6 were genotyped in 259 African-Americans from the Cleveland Family Study with replication conducted in the Cardiovascular Health Study (n=124). OSA was dichotomized into apnea hypopnea index (AHI)>15 or on treatment vs. absent: AHI<5. Logistic regression was conducted, adjusting for age and sex in models with and without body mass index (BMI).
Results
SNP IL6-6021 was associated with a decreased risk of OSA after adjusting for BMI (Odds Ratio for T allele 0.24; 95%CI [0.09–0.67]; p=0.006; q=0.07) under an additive model. This same allele was associated with increased BMI. The results from the replication sample were consistent in direction though not statistically significant (p=0.23). The SNPs were studied in European-Americans, although the minor allele frequency in IL6-6021 was too low (4%) for meaningful comparisons.
Conclusion
A synonymous SNP within the IL-6 coding region was protective of OSA in African-Americans; with qualitatively similar findings observed in another cohort. This suggests that variants in IL-6 may influence the risk of OSA in a pathway that is not explained by obesity.
PMCID: PMC3078635  PMID: 21207764
16.  Genomewide linkage of Obstructive Sleep Apnea and High Density Lipoprotein Cholesterol in a Filipino Family 
Journal of sleep research  2010;19(2):349-357.
Summary
Increasing evidence supports an association between obstructive sleep apnoea and metabolic syndrome in both children and adults suggesting a genetic component. However, the genetic relationship between the diseases remains unclear.
We performed a bivariate linkage scan on a single Filipino family with a high prevalence of obstructive sleep apnoea and metabolic syndrome to explore the genetic pathways underlying these diseases. A large rural family (N=50, 50% adults) underwent a 10cM genome-wide scan. Fasting blood was used to measure insulin, triglycerides, total cholesterol and HDL cholesterol. Attended overnight polysomnography was used to quantify the respiratory disturbance index (RDI), a measure of sleep apnea. BMI z-scores and insulin resistance scores were calculated. Bivariate multipoint linkage analyses were performed on RDI and metabolic syndrome components.
Obstructive sleep apnea prevalence was 46% (n=23; 9 adults, 14 children) in our participants. Metabolic syndrome phenotype was present in 40% of adults (n=10) and 48% of children (n=12). Linkage peaks with a LOD score > 3 were demonstrated on chromosome 19q13·4 (LOD=3·04) for the trait pair RDI and high density lipoprotein (HDL) cholesterol. Candidate genes identified in this region include the killer-like immunoglobulin receptor (KIR) genes. These genes are associated with modulating inflammatory responses in reaction to cellular stress and initiation of atherosclerotic plaque formation. We have identified a novel locus for genetic links between RDI and lipid factors associated with metabolic syndrome in a chromosomal region containing genes associated with inflammatory responses.
doi:10.1111/j.1365-2869.2009.00797.x
PMCID: PMC4599778  PMID: 20149069
bivariate; metabolic syndrome; obesity; respiratory disturbance index; inflammation; gene
17.  β2-Adrenergic receptor promoter haplotype influences the severity of acute viral respiratory tract infection during infancy: a prospective cohort study 
BMC Medical Genetics  2015;16:82.
Background
Despite the significant interest in β2-Adrenergic receptor (ADRB2) polymorphisms related to asthma, whether ADRB2 genetic variants are similarly associated with acute respiratory tract infections have not been studied. We hypothesized that genetic variants in ADRB2 associated with a response to asthma therapy during an asthma exacerbation were also associated with severity of acute respiratory tract infections.
Methods
To test this hypothesis, we genotyped 5 common polymorphisms in the promoter region and coding block of the ADRB2 gene (loci -2387, -2274, -1343, +46, and +79) from 374 Caucasian and African American term infants who were enrolled at the time of acute respiratory illness over four respiratory viral seasons. Severity of respiratory tract infections was measured using a bronchiolitis severity score (BSS; range = 0-12, clinically significant difference = 0.5) with a higher score indicating more severe disease. We assigned the promoter, coding and combined promoter and coding haplotypes to the unphased genotype data. The associations between each of these five single-nucleotide polymorphisms (SNPs) as well as the haplotypes and infant BSS were analyzed using nonparametric univariate analysis and multivariable proportional odds model separately in Caucasians and African Americans.
Results
There was no significant association between infant BSS and each of the SNPs in both Caucasians and African Americans. However, promoter haplotype CCA was associated with a decreased BSS in African Americans in a dose dependent manner. The median (interquartile range) BSS of infants with no copies of the CCA haplotype, one copy, and two copies of the CCA haplotype were 5.5 (2.0, 8.0), 4.0 (1.0, 7.5), and 3.0 (1.0, 4.0), respectively. This dose dependent relationship persisted after adjusting for infant age, gender, daycare exposure, secondhand smoke exposure, prior history of breastfeeding, siblings at home, and enrollment season (adjusted odds ratio: 0.59, 95 % confidence interval: 0.36, 0.98). There was no similar protective relationship of haplotype CCA on severity of respiratory tract infections identified in Caucasians.
Conclusions
ADRB2 genotype may be predictive of severity of acute respiratory tract infections in African Americans, and potentially identify a subset of infants who may respond to beta-agonist therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12881-015-0229-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12881-015-0229-3
PMCID: PMC4570703  PMID: 26369942
18.  SYSTEMS BIOLOGY ANALYSES OF GENE EXPRESSION AND GENOME WIDE ASSOCIATION STUDY DATA IN OBSTRUCTIVE SLEEP APNEA 
The precise molecular etiology of obstructive sleep apnea (OSA) is unknown; however recent research indicates that several interconnected aberrant pathways and molecular abnormalities are contributors to OSA. Identifying the genes and pathways associated with OSA can help to expand our understanding of the risk factors for the disease as well as provide new avenues for potential treatment. Towards these goals, we have integrated relevant high dimensional data from various sources, such as genome-wide expression data (microarray), protein-protein interaction (PPI) data and results from genome-wide association studies (GWAS) in order to define sub-network elements that connect some of the known pathways related to the disease as well as define novel regulatory modules related to OSA. Two distinct approaches are applied to identify sub-networks significantly associated with OSA. In the first case we used a biased approach based on sixty genes/proteins with known associations with sleep disorders and/or metabolic disease to seed a search using commercial software to discover networks associated with disease followed by information theoretic (mutual information) scoring of the sub-networks. In the second case we used an unbiased approach and generated an interactome constructed from publicly available gene expression profiles and PPI databases, followed by scoring of the network with p-values from GWAS data derived from OSA patients to uncover sub-networks significant for the disease phenotype. A comparison of the approaches reveals a number of proteins that have been previously known to be associated with OSA or sleep. In addition, our results indicate a novel association of Phosphoinositide 3-kinase, the STAT family of proteins and its related pathways with OSA.
PMCID: PMC4465214  PMID: 21121029
19.  Respiratory Severity Score Separates Upper Versus Lower Respiratory Tract Infections and Predicts Measures of Disease Severity 
Background: A respiratory severity score (RSS) describing acute respiratory illness (ARI) severity would be useful for research and clinical purposes.
Methods: A total of 630 term infants presenting with ARI had their RSS measured.
Results: RSS was higher in those with lower respiratory tract infection (LRTI) compared with those with upper respiratory infection (URI; LRTI 6.5 [4–8.5]; URI 1 [0–2], p<0.001) and in hospitalized infants compared with outpatients (hospitalized 6.5 [4–9]; outpatient 1 [0–3], p<0.001).
Conclusions: RSS is higher in LRTI compared with URI and in hospitalized compared with nonhospitalized infants.
doi:10.1089/ped.2014.0463
PMCID: PMC4491158  PMID: 26155369
20.  Objectives, design and enrollment results from the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure Study (INSPIRE) 
Background
Respiratory syncytial virus (RSV) lower respiratory tract infection (LRI) during infancy has been consistently associated with an increased risk of childhood asthma. In addition, evidence supports that this relationship is causal. However, the mechanisms through which RSV contributes to asthma development are not understood. The INSPIRE (Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure) study objectives are to: 1) characterize the host phenotypic response to RSV infection in infancy and the risk of recurrent wheeze and asthma, 2) identify the immune response and lung injury patterns of RSV infection that are associated with the development of early childhood wheezing illness and asthma, and 3) determine the contribution of specific RSV strains to early childhood wheezing and asthma development. This article describes the INSPIRE study, including study aims, design, recruitment results, and enrolled population characteristics.
Methods/design
The cohort is a population based longitudinal birth cohort of term healthy infants enrolled during the first months of life over a two year period. Respiratory infection surveillance was conducted from November to March of the first year of life, through surveys administered every two weeks. In-person illness visits were conducted if infants met pre-specified criteria for a respiratory illness visit. Infants will be followed annually to ages 3-4 years for assessment of the primary endpoint: wheezing illness. Nasal, urine, stool and blood samples were collected at various time points throughout the study for measurements of host and viral factors that predict wheezing illness. Nested case-control studies will additionally be used to address other primary and secondary hypotheses.
Discussion
In the INSPIRE study, 1952 infants (48% female) were enrolled during the two enrollment years and follow-up will continue through 2016. The mean age of enrollment was 60 days. During winter viral season, more than 14,000 surveillance surveys were carried out resulting in 2,103 respiratory illness visits on 1189 infants. First year follow-up has been completed on over 95% percent of participants from the first year of enrollment.
With ongoing follow-up for wheezing and childhood asthma outcomes, the INSPIRE study will advance our understanding of the complex causal relationship between RSV infection and early childhood wheezing and asthma.
doi:10.1186/s12890-015-0040-0
PMCID: PMC4506623  PMID: 26021723
Infants; Bronchiolitis; Respiratory Syncytial Virus; Asthma; Rhinovirus; Allergic Rhinitis; Wheezing; Respiratory Tract Infections
21.  Statin Exposure Is Associated with Decreased Asthma-related Emergency Department Visits and Oral Corticosteroid Use 
Rationale: Statins, or HMG-CoA reductase inhibitors, may aid in the treatment of asthma through their pleiotropic antiinflammatory effects.
Objectives: To examine the effect of statin therapy on asthma-related exacerbations using a large population-based cohort.
Methods: Statin users aged 31 years or greater with asthma were identified from the Population-Based Effectiveness in Asthma and Lung population, which includes data from five health plans. Statin exposure and asthma exacerbations were assessed over a 24-month observation period. Statin users with a statin medication possession ratio greater than or equal to 80% were matched to non–statin users by age, baseline asthma therapy, site of enrollment, season at baseline, and propensity score, which was calculated based on patient demographics and Deyo-Charlson conditions. Asthma exacerbations were defined as two or more oral corticosteroid dispensings, asthma-related emergency department visits, or asthma-related hospitalizations. The association between statin exposure and each of the three outcome measures was assessed using conditional logistic regression.
Measurements and Main Results: Of the 14,566 statin users, 8,349 statin users were matched to a nonuser. After adjusting for Deyo-Charlson conditions that remained unbalanced after matching, among statin users, statin exposure was associated with decreased odds of having asthma-related emergency department visits (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.53–0.77; P < 0.0001) and two or more oral corticosteroid dispensings (OR, 0.90; 95% CI, 0.81–0.99; P = 0.04). There were no differences in asthma-related hospitalizations (OR, 0.91; 95% CI, 0.66–1.24; P = 0.52).
Conclusions: Among statin users with asthma, statin exposure was associated with decreased odds of asthma-related emergency department visits and oral corticosteroid dispensings.
doi:10.1164/rccm.201306-1017OC
PMCID: PMC3863744  PMID: 24093599
HMG-CoA reductase inhibitors; asthma therapy; exacerbations
22.  Mechanistic Phenotypes: An Aggregative Phenotyping Strategy to Identify Disease Mechanisms Using GWAS Data 
PLoS ONE  2013;8(12):e81503.
A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with “mechanistic phenotypes”, comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03), driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10−5, FDR p = 0.03) (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L) while the additive model showed enrichment related to chromatid segregation (p = 4×10−6, FDR p = 0.005) (KIF25, PINX1). We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.
doi:10.1371/journal.pone.0081503
PMCID: PMC3861317  PMID: 24349080
23.  Longitudinal Analysis Casts Doubt on the Presence of Genetic Anticipation in Heritable Pulmonary Arterial Hypertension 
Rationale: Analysis of the age of onset in heritable pulmonary arterial hypertension (HPAH) has led to the hypothesis that genetic anticipation causes younger age of onset and death in subsequent generations. With accrual of pedigree data over multiple decades, we retested this hypothesis using analyses that eliminate the truncation of data that exists with shorter duration of follow-up.
Objectives: To analyze the pedigrees of families with mutations in bone morphogenetic protein receptor type 2 (BMPR2), afflicted in two or more generations with HPAH, eliminating time truncation bias by including families for whom we have at least 57 years of data.
Methods: We analyzed 355 individuals with BMPR2 mutations from 53 families in the Vanderbilt Pulmonary Hypertension Registry. We compared age at diagnosis or death in affected individuals (n = 249) by generation within families with multigenerational disease. We performed linear mixed effects models and we limited time-truncation bias by restricting date of birth to before 1955. This allowed for 57 years of follow-up (1955–2012) for mutation carriers to develop disease. We also conducted Kaplan-Meier analysis to include currently unaffected mutation carriers (n = 106).
Measurements and Main Results: Differences in age at diagnosis by generation were found in a biased analysis that included all birth years to the present, but this finding was eliminated when the 57-year observation limit was imposed. By Kaplan-Meier analysis, inclusion of currently unaffected mutation carriers strengthens the observation that bias of ascertainment exists when recent generations are included.
Conclusions: Genetic anticipation is likely an artifact of incomplete time of observation of kindreds with HPAH due to BMPR2 mutations.
doi:10.1164/rccm.201205-0886OC
PMCID: PMC3530218  PMID: 22923661
hereditary; pulmonary hypertension; genetics
24.  Shorter survival in familial versus idiopathic pulmonary arterial hypertension is associated with hemodynamic markers of impaired right ventricular function 
Pulmonary Circulation  2013;3(3):589-598.
Although individuals with familial pulmonary arterial hypertension (FPAH) have more severe hemodynamics, compared to individuals with idiopathic PAH (IPAH), it is unclear whether this translates into a survival difference. The influence of right ventricular (RV) function on survival in these groups is also unknown. We reviewed hemodynamic data and health information from a prospective institutional database of 57 FPAH and 66 IPAH patients registered with the Vanderbilt Pulmonary Hypertension Research Cohort. We compared hemodynamics at the time of diagnosis between the two groups and calculated pulmonary arteriolar capacitance (PC) and RV stroke work index (RVSWI). Using survival analysis, we compared freedom from a 5-year composite of death or lung transplantation in FPAH and IPAH patients. The composite outcome of death or transplant at 5 years from diagnosis was significantly increased in FPAH (log rank ). PC and RVSWI were significantly decreased in FPAH, compared to IPAH ( for both). In univariate analysis, PC (odds ratio [OR]: 0.17 [95% confidence interval (95% CI): 0.03–0.83]) and RVSWI (OR: 0.86 [95% CI: 0.77–0.95]) were predictors of mortality, as were cardiac index (OR: 0.17 [95% CI: 0.06–0.51]) and PVR (OR: 1.1 [95% CI: 1.01–1.12]). Among FPAH patients, RVSWI was lower in those who died or received a transplant than in survivors (), while PC was not (). We found significantly worse event-free survival and significantly lower PC and RVSWI in FPAH than in IPAH. In FPAH patients who died or underwent transplantation, RVSWI was lower than that in survivors, suggesting disproportionate RV dysfunction.
doi:10.1086/674326
PMCID: PMC4070798  PMID: 24618543
pulmonary arterial hypertension; familial pulmonary arterial hypertension; right ventricular function; hemodynamics
25.  Association of Genetic Loci with Sleep Apnea in European Americans and African-Americans: The Candidate Gene Association Resource (CARe) 
PLoS ONE  2012;7(11):e48836.
Although obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study.
Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×10−6. Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts.
Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis.
doi:10.1371/journal.pone.0048836
PMCID: PMC3498243  PMID: 23155414

Results 1-25 (39)