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1.  Extracellular Superoxide Dismutase and Risk of COPD 
COPD  2009;6(4):307-312.
Chronic obstructive pulmonary disease (COPD) is a major public health problem worldwide. COPD is strongly related to cigarette smoke exposure, but not all smokers develop the disease. It is thought that COPD progresses slowly over time stimulated by environmental exposures, including free radicals from cigarette smoke, which ultimately establish chronic inflammation and result in a progressive destruction of lung tissues. COPD is known to occur in family clusters, which has prompted interest in determining genetic risk factors for the disease. Several genetic studies have identified an association between extracellular superoxide dismutase (ECSOD) polymorphisms and risk for developing COPD. ECSOD is an antioxidant protein that scavenges superoxide free radicals from cigarette smoke and protects the lungs from free radical damage and chronic inflammation.
PMCID: PMC4075061  PMID: 19811392
COPD; ECSOD; Genetic Association; free radicals
2.  Impact of self-reported Gastroesophageal reflux disease in subjects from COPDGene cohort 
Respiratory Research  2014;15(1):62.
Background
The coexistence of gastroesophageal reflux disease (GERD) and COPD has been recognized, but there has been no comprehensive evaluation of the impact of GERD on COPD-related health status and patient-centered outcomes.
Methods
Cross-sectional and longitudinal study of 4,483 participants in the COPDGene cohort who met GOLD criteria for COPD. Physician-diagnosed GERD was ascertained by questionnaire. Clinical features, spirometry and imaging were compared between COPD subjects without versus with GERD. We evaluated the relationship between GERD and symptoms, exacerbations and markers of microaspiration in univariate and multivariate models. Associations were additionally tested for the confounding effect of covariates associated with a diagnosis of GERD and the use of proton-pump inhibitor medications (PPIs). To determine whether GERD is simply a marker for the presence of other conditions independently associated with worse COPD outcomes, we also tested models incorporating a GERD propensity score.
Results
GERD was reported by 29% of subjects with female predominance. Subjects with GERD were more likely to have chronic bronchitis symptoms, higher prevalence of prior cardiovascular events (combined myocardial infarction, coronary artery disease and stroke 21.3% vs. 13.4.0%, p < 0.0001). Subjects with GERD also had more severe dyspnea (MMRC score 2.2 vs. 1.8, p < 0.0001), and poorer quality of life (QOL) scores (St. George’s Respiratory Questionnaire (SGRQ) total score 41.8 vs. 34.9, p < 0.0001; SF36 Physical Component Score 38.2 vs. 41.4, p < 0.0001). In multivariate models, a significant relationship was detected between GERD and SGRQ (3.4 points difference, p < 0.001) and frequent exacerbations at baseline (≥2 exacerbation per annum at inclusion OR 1.40, p = 0.006). During a mean follow-up time of two years, GERD was also associated with frequent (≥2/year exacerbations OR 1.40, p = 0.006), even in models in which PPIs, GERD-PPI interactions and a GERD propensity score were included. PPI use was associated with frequent exacerbator phenotype, but did not meaningfully influence the GERD-exacerbation association.
Conclusions
In COPD the presence of physician-diagnosed GERD is associated with increased symptoms, poorer QOL and increased frequency of exacerbations at baseline and during follow-up. These associations are maintained after controlling for PPI use. The PPI-exacerbations association could result from confounding-by-indication.
doi:10.1186/1465-9921-15-62
PMCID: PMC4049804  PMID: 24894541
COPD; Gastroesophageal reflux; Comorbidity; Exacerbations; Quality-of-life; Chronic bronchitis
3.  Breeding Experience, Alternative Reproductive Strategies and Reproductive Success in a Captive Colony of Zebra Finches (Taeniopygia guttata) 
PLoS ONE  2014;9(2):e89808.
Birds exhibit a remarkable diversity of different reproductive strategies both between and within species. Species such as the zebra finch (Taeniopygia guttata) may evolve the flexible use of alternative reproductive strategies, as well as benefit from prior breeding experience, which allows them to adaptively respond to unpredictable environments. In birds, the flexible use of alternative reproductive strategies, such as extra-pair mating, has been reported to be associated with fast reproduction, high mortality and environmental variability. However, little is known about the role of previous breeding experience in the adaptive use of alternative reproductive strategies. Here we performed an in-depth study of reproductive outcomes in a population of domesticated zebra finches, testing the impact of prior breeding experience on the use of alternative reproductive strategies and reproductive success. We provide evidence that older females with prior breeding experience are quicker to initiate a clutch with a new partner and have increased success in chick rearing, even in a captive colony of zebra finches with minimal foraging demands. We also find evidence that the breeding experience of other females in the same social group influences reproductive investment by female zebra finches. Furthermore, we demonstrate that the use of alternative reproductive strategies in female zebra finches is associated with previous failed breeding attempts with the same pair partner. The results provide evidence that age and breeding experience play important roles in the flexible use of both facultative and adaptive reproductive strategies in female zebra finches.
doi:10.1371/journal.pone.0089808
PMCID: PMC3937349  PMID: 24587051
4.  Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis 
Nature genetics  2013;45(6):613-620.
We performed a genome-wide association study in non-Hispanic white subjects with fibrotic idiopathic interstitial pneumonias (N=1616) and controls (N=4683); replication was assessed in 876 cases and 1890 controls. We confirmed association with TERT and MUC5B on chromosomes 5p15 and 11p15, respectively, the chromosome 3q26 region near TERC, and identified 7 novel loci (PMeta = 2.4×10−8 to PMeta = 1.1×10−19). The novel loci include FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), and chromosomal regions 7q22 and 15q14-15. Our results demonstrate that genes involved in host defense, cell-cell adhesion, and DNA repair contribute to the risk of fibrotic IIP.
doi:10.1038/ng.2609
PMCID: PMC3677861  PMID: 23583980
5.  Automated Telecommunication to Obtain Longitudinal Follow-up in a Multicenter Cross-sectional COPD Study 
COPD  2012;9(5):466-472.
Background
It can be challenging to maintain longitudinal follow-up of subjects in clinical studies. COPDGene is a multicenter, observational study designed to identify genetic factors associated with COPD and to characterize COPD-related phenotypes. To obtain follow-up data on patient's vital status and outcomes, the COPDGene Longitudinal Follow-up (LFU) Program was developed to supplement its parent study.
Methods/Results
We used a telecommunication system that employed automated telephone contact or web-based questions to obtain longitudinal follow-up data in our subjects. A branching questionnaire asked about exacerbations, new therapies, smoking status, development of co-morbid conditions, and general health status. Study coordinators contacted subjects who did not respond to one of the automated methods. We enrolled 10,383 subjects in the COPDGene study. As of August 29, 2011, 7,959 subjects completed 19,955 surveys. On the first survey, 68.8% of subjects who completed their survey did so by electronic means, while 31.3% required coordinator phone follow-up. On each subsequent survey the number of subjects who completed their survey by electronic means increased, while the number of subjects who required coordinator follow-up decreased. Despite many of the patients in the cohort being chronically ill and elderly, there was broad acceptance of the system with over half the cohort using electronic response methods.
Conclusions
The COPDGene LFU Study demonstrated that telecommunications was an effective way to obtain longitudinal follow-up of subjects in a large multicenter study. Web-based and automated phone contacts are accepted by research subjects and could serve as a model for LFU in future studies.
doi:10.3109/15412555.2012.690010
PMCID: PMC3698488  PMID: 22676387
COPD; COPDGene; Emphysema; Longitudinal data collection; Exacerbations; Follow-up studies; Elderly
6.  Pulmonary Arterial Enlargement and Acute Exacerbations of COPD 
The New England journal of medicine  2012;367(10):913-921.
BACKGROUND
Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations.
METHODS
We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation.
RESULTS
Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations.
CONCLUSIONS
Pulmonary artery enlargement (a PA:A ratio of >1), as detected by CT, was associated with severe exacerbations of COPD. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT00608764 and NCT00292552.)
doi:10.1056/NEJMoa1203830
PMCID: PMC3690810  PMID: 22938715
7.  A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13 
Human Molecular Genetics  2011;21(4):947-957.
The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10−9). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV1 (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.
doi:10.1093/hmg/ddr524
PMCID: PMC3298111  PMID: 22080838
8.  Early-Onset Chronic Obstructive Pulmonary Disease Is Associated with Female Sex, Maternal Factors, and African American Race in the COPDGene Study 
Rationale: The characterization of young adults who develop late-onset diseases may augment the detection of novel genes and promote new pathogenic insights.
Methods: We analyzed data from 2,500 individuals of African and European ancestry in the COPDGene Study. Subjects with severe, early-onset chronic obstructive pulmonary disease (COPD) (n = 70, age < 55 yr, FEV1 < 50% predicted) were compared with older subjects with COPD (n = 306, age > 64 yr, FEV1 < 50% predicted).
Measurements and Main Results: Subjects with severe, early-onset COPD were predominantly females (66%), P = 0.0004. Proportionally, early-onset COPD was seen in 42% (25 of 59) of African Americans versus 14% (45 of 317) of non-Hispanic whites, P < 0.0001. Other risk factors included current smoking (56 vs. 17%, P < 0.0001) and self-report of asthma (39 vs. 25%, P = 0.008). Maternal smoking (70 vs. 44%, P = 0.0001) and maternal COPD (23 vs. 12%, P = 0.03) were reported more commonly in subjects with early-onset COPD. Multivariable regression analysis found association with African American race, odds ratio (OR), 7.5 (95% confidence interval [CI], 2.3–24; P = 0.0007); maternal COPD, OR, 4.7 (95% CI, 1.3–17; P = 0.02); female sex, OR, 3.1 (95% CI, 1.1–8.7; P = 0.03); and each pack-year of smoking, OR, 0.98 (95% CI, 0.96–1.0; P = 0.03).
Conclusions: These observations support the hypothesis that severe, early-onset COPD is prevalent in females and is influenced by maternal factors. Future genetic studies should evaluate (1) gene-by-sex interactions to address sex-specific genetic contributions and (2) gene-by-race interactions.
doi:10.1164/rccm.201011-1928OC
PMCID: PMC3175544  PMID: 21562134
chronic obstructive pulmonary disease; female; African Americans
9.  Genome-Wide Association Analysis of Body Mass in Chronic Obstructive Pulmonary Disease 
Cachexia, whether assessed by body mass index (BMI) or fat-free mass index (FFMI), affects a significant proportion of patients with chronic obstructive pulmonary disease (COPD), and is an independent risk factor for increased mortality, increased emphysema, and more severe airflow obstruction. The variable development of cachexia among patients with COPD suggests a role for genetic susceptibility. The objective of the present study was to determine genetic susceptibility loci involved in the development of low BMI and FFMI in subjects with COPD. A genome-wide association study (GWAS) of BMI was conducted in three independent cohorts of European descent with Global Initiative for Chronic Obstructive Lung Disease stage II or higher COPD: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE; n = 1,734); Norway-Bergen cohort (n = 851); and a subset of subjects from the National Emphysema Treatment Trial (NETT; n = 365). A genome-wide association of FFMI was conducted in two of the cohorts (ECLIPSE and Norway). In the combined analyses, a significant association was found between rs8050136, located in the first intron of the fat mass and obesity–associated (FTO) gene, and BMI (P = 4.97 × 10−7) and FFMI (P = 1.19 × 10−7). We replicated the association in a fourth, independent cohort consisting of 502 subjects with COPD from COPDGene (P = 6 × 10−3). Within the largest contributing cohort of our analysis, lung function, as assessed by forced expiratory volume at 1 second, varied significantly by FTO genotype. Our analysis suggests a potential role for the FTO locus in the determination of anthropomorphic measures associated with COPD.
doi:10.1165/rcmb.2010-0294OC
PMCID: PMC3266061  PMID: 21037115
chronic obstructive pulmonary disease genetics; chronic obstructive pulmonary disease epidemiology; chronic obstructive pulmonary disease metabolism; genome-wide association study
10.  Clinical and Radiographic Predictors of GOLD–Unclassified Smokers in the COPDGene Study 
Rationale: A significant proportion of smokers have lung function impairment characterized by a reduced FEV1 with a preserved FEV1/FVC ratio. These smokers are a poorly characterized group due to their systematic exclusion from chronic obstructive pulmonary disease (COPD) studies.
Objectives: To characterize the clinical, functional, and radiographic features of Global Initiative for Chronic Obstructive Lung Disease (GOLD)-Unclassified (FEV1/FVC ≥ 0.7 and FEV1 < 80% predicted) and lower limits of normal (LLN)-unclassified (FEV1/FVC ≥ LLN and FEV1 < LLN) subjects compared to smokers with normal lung function and subjects with COPD.
Methods: Data from the first 2,500 subjects enrolled in the COPDGene study were analyzed. All subjects had 10 or more pack-years of smoking and were between the ages of 45 and 80 years. Multivariate regression models were constructed to determine the clinical and radiological variables associated with GOLD-Unclassified (GOLD-U) and LLN-Unclassified status. Separate multivariate regressions were performed in the subgroups of subjects with complete radiologic measurement variables available.
Measurements and Main Results: GOLD-U smokers account for 9% of smokers in COPDGene and have increased body mass index (BMI), a disproportionately reduced total lung capacity, and a higher proportion of nonwhite subjects and subjects with diabetes. GOLD-U subjects exhibit increased airway wall thickness compared to smoking control subjects and decreased gas trapping and bronchodilator responsiveness compared to subjects with COPD. When LLN criteria were used to define the “unclassified” group, African American subjects were no longer overrepresented. Both GOLD-U and LLN-Unclassified subjects demonstrated a wide range of lung function impairment, BMI, and percentage of total lung emphysema.
Conclusions: Subjects with reduced FEV1 and a preserved FEV1/FVC ratio are a heterogeneous group with significant symptoms and functional limitation who likely have a variety of underlying etiologies beyond increased BMI.
Clinical trial registered with www.clinicaltrials.gov (NCT000608764).
doi:10.1164/rccm.201101-0021OC
PMCID: PMC3172890  PMID: 21493737
lung diseases, classification; lung diseases, diagnosis; lung diseases, epidemiology
11.  Deprivation of maternal care has long-lasting consequences for the hypothalamic–pituitary–adrenal axis of zebra finches 
Early-life stress caused by the deprivation of maternal care has been shown to have long-lasting effects on the hypothalamic–pituitary–adrenal (HPA) axis in offspring of uniparental mammalian species. We asked if deprivation of maternal care in biparental species alters stress responsiveness of offspring, using a biparental avian species—the zebra finch, Taeniopygia guttata. In our experiment, one group of birds was raised by both male and female parents (control), and another was raised by males alone (maternally deprived). During adulthood, offspring of both groups were subjected to two stressors (restraint and isolation), and corticosterone concentrations were measured. Additionally, we measured baseline levels of the two corticosteroid receptors—glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)—in the hippocampus, hypothalamus and cerebellum. Our results suggest that maternally deprived offspring are hyper-responsive to isolation in comparison with controls. Furthermore, mRNA levels of both GR and MR receptors are altered in maternally deprived offspring in comparison with controls. Thus, absence of maternal care has lasting consequences for HPA function in a biparental species where paternal care is available.
doi:10.1098/rspb.2011.1265
PMCID: PMC3248735  PMID: 21775332
zebra finch; stress; corticosterone; mineralocorticoid receptor; glucocorticoid receptor; maternal deprivation
12.  Structure and Activity of CPNGRC: A Modified CD13/APN Peptidic Homing Motif 
Chemical biology & drug design  2010;75(6):551-562.
NGR peptides have been designed as vehicles for the delivery of chemotherapeutics, magnetic resonance imaging (MRI) contrast agents, and fluorescence labels to tumor cells, and cardiac angiogenic tissue. Specificity is derived via an interaction with APN, also known as CD13, a cell surface receptor that is highly expressed in angiogenic tissue. Peptides containing the CNGRC homing sequence tethered to a pro-apoptotic peptide sequence have the ability to specifically induce apoptosis in tumor cells. We have now identified a modification to the Asn-Gly-Arg (NGR) homing sequence motif that improves overall binding affinity to Aminopeptidase N (APN). Through the addition of a proline residue, the new peptide with sequence, CPNGRC, inhibits APN proteolytic activity with an IC50 of 10 μM, a value that is 30-fold lower than that for CNGRC. Both peptides are cyclized via a disulfide bridge between cysteines. Steady-state kinetic experiments suggest that efficient APN inhibition is achieved through the highly cooperative binding of two molecules of CPNGRC. We have used NMR-derived structural constraints for the elucidation of the solution structures CNGRC and CPNGRC. Resulting structures of CNGRC and CPNGRC have significant differences in the backbone torsion angles, which may contribute to the enhanced binding affinity and demonstrated enzyme inhibition by CPNGRC.
doi:10.1111/j.1747-0285.2010.00974.x
PMCID: PMC2890305  PMID: 20374250
13.  Sex-Dependent Species Discrimination in Auditory Forebrain of Naturally Hybridizing Birds 
Brain, Behavior and Evolution  2009;74(4):258-267.
Pairs of individuals breed together only if they recognize each other as the same species, but the process of recognizing conspecifics can depend on flexible criteria even when species-specific signals are innate and fixed. This study examines species recognition in naturally hybridizing sister species, California and Gambel's quail (Callipepla californica and Callipepla gambelii), that have vocalizations which are not learned. Specifically, this study tests whether being raised in a vocalizing mixed-species cohort affects neural activity in the adult auditory forebrain in response to heterospecific and conspecific calls. After hatching, quail chicks were raised either with their own kind or with both species. Once reaching reproductive condition, each adult was played a recording that was one of three types: Gambel's quail opposite-sex contact calls; California quail opposite-sex contact calls; or synthetic tones. Brains were collected following playback and assessed for neuronal activity by quantifying expression of the protein of the immediate early gene, ZENK, in two brain regions, the caudomedial nidopallium (NCM) and the caudomedial mesopallium (CMM). ZENK levels were greater in NCM of males than females, but female NCM cells responded differentially to conspecific compared to heterospecific calls. Namely, females had more immuno-positive NCM cells when they heard conspecific calls rather than heterospecific male calls. Early experience with heterospecific broodmates did not alter neural responses in the NCM or CMM to heterospecific vocalizations. This study suggests that the NCM plays a role in species discrimination but that rearing condition does not alter the response in these non-vocal-learning species.
doi:10.1159/000264661
PMCID: PMC2837888  PMID: 19996584
Species discrimination; Vocalization; Zenk; Forebrain; Caudomedial nidopallium; Mesopallium; Quail
14.  Genetic Epidemiology of COPD (COPDGene) Study Design 
COPD  2010;7(1):32-43.
Background
COPDGeneis a multicenter observational study designed to identify genetic factors associated with COPD. It will also characterize chest CT phenotypes in COPD subjects, including assessment of emphysema, gas trapping, and airway wall thickening. Finally, subtypes of COPD based on these phenotypes will be used in a comprehensive genome-wide study to identify COPD susceptibility genes.
Methods/Results
COPDGene will enroll 10,000 smokers with and without COPD across the GOLD stages. Both Non-Hispanic white and African-American subjects are included in the cohort. Inspiratory and expiratory chest CT scans will be obtained on all participants. In addition to the cross-sectional enrollment process, these subjects will be followed regularly for longitudinal studies. A genome-wide association study (GWAS) will be done on an initial group of 4000 subjects to identify genetic variants associated with case-control status and several quantitative phenotypes related to COPD. The initial findings will be verified in an additional 2000 COPD cases and 2000 smoking control subjects, and further validation association studies will be carried out.
Conclusions
COPDGene will provide important new information about genetic factors in COPD, and will characterize the disease process using high resolution CT scans. Understanding genetic factors and CT phenotypes that define COPD will potentially permit earlier diagnosis of this disease and may lead to the development of treatments to modify progression.
doi:10.3109/15412550903499522
PMCID: PMC2924193  PMID: 20214461
15.  Learning enhances female control over reproductive investment in the Japanese quail 
The adaptive significance of learning is supported by studies showing its positive effects on mating behaviour, but they rarely go beyond fertilization success. Here we studied how learning contributes to qualitative reproductive investment, by testing the hypothesis that mating in the context that predicts male appearance has positive effects on female reproductive investment compared with unsignalled mating. Using Japanese quail (Coturnix japonica), we found that effects of mating in the context predicting mating opportunity depend on female body condition and receptivity, while the outcome of unexpected mating depends on male behaviour. In particular, among females mated with the familiar male in the context predicting that he will appear, female condition positively affected the number of fertilized eggs and egg mass and more receptive females tended to produce more sons. Additionally, conditioned females laid heavier eggs for daughters than for sons. In contrast, in females that were mated unexpectedly and with a novel male, the number of fertilized eggs was highly dependent on male behaviour and was negatively related to maternal body condition. Egg mass was not related to body condition, and there were no indications of sex allocation. This is, to our knowledge, the first study demonstrating how female body condition and behaviour interact with the context of mating in shaping maternal reproductive investment.
doi:10.1098/rspb.2009.0762
PMCID: PMC2817173  PMID: 19535375
Pavlovian conditioning; mate familiarity; body condition; maternal effects; sex allocation; fertilization success
16.  Variants in FAM13A are associated with chronic obstructive pulmonary disease 
Nature genetics  2010;42(3):200-202.
Substantial evidence suggests that there is genetic susceptibility to chronic obstructive pulmonary disease (COPD). To identify common genetic risk variants, we performed a genome-wide association study in 2940 cases and 1380 smoking controls with normal lung function. We demonstrate a novel susceptibility locus at 4q22.1 in FAM13A (rs7671167, OR=0.76, P=8.6×10−8) and provide evidence of replication in one case-control and two family-based cohorts (for all studies, combined P=1.2×10−11).
doi:10.1038/ng.535
PMCID: PMC2828499  PMID: 20173748
17.  Extracellular Superoxide Dismutase and Oxidant Damage in Osteoarthritis 
Arthritis and rheumatism  2005;52(11):3479-3491.
Objective
To use human cartilage samples and a mouse model of osteoarthritis (OA) to determine whether extracellular superoxide dismutase (EC-SOD) is a constituent of cartilage and to evaluate whether there is a relationship between EC-SOD deficiency and OA.
Methods
Samples of human cartilage were obtained from femoral heads at the time of joint replacement surgery for OA or femoral neck fracture. Samples of mouse tibial cartilage obtained from STR/ort mice and CBA control mice were compared at 5, 15, and 35 weeks of age. EC-SOD was measured by enzyme-linked immunosorbent assay, Western blotting, and immunohistochemistry techniques. Real-time quantitative reverse transcription-polymerase chain reaction was used to measure messenger RNA for EC-SOD and for endothelial cell, neuronal, and inducible nitric oxide synthases. Nitrotyrosine formation was assayed by Western blotting in mouse cartilage and by fluorescence immunohistochemistry in human cartilage.
Results
Human articular cartilage contained large amounts of EC-SOD (mean ± SEM 18.8 ± 3.8 ng/gm wet weight of cartilage). Cartilage from patients with OA had an ~4-fold lower level of EC-SOD compared with cartilage from patients with hip fracture. Young STR/ort mice had decreased levels of EC-SOD in tibial cartilage before histologic evidence of disease occurred, as well as significantly more nitrotyrosine formation at all ages studied.
Conclusion
EC-SOD, the major scavenger of reactive oxygen species in extracellular spaces, is decreased in humans with OA and in an animal model of OA. Our findings suggest that inadequate control of reactive oxygen species plays a role in the pathophysiology of OA.
doi:10.1002/art.21387
PMCID: PMC2755499  PMID: 16255039
18.  Do hormonal control systems produce evolutionary inertia? 
Hormonal control systems are complex in design and well integrated. Concern has been raised that these systems might act as evolutionary constraints when animals are subject to anthropogenic environmental change. Three systems are examined in vertebrates, especially birds, that are important for assessing this possibility: (i) the hypothalamic–pituitary–gonadal (HPG) axis, (ii) the activational effects of sex steroids on mating effort behaviour, and (iii) sexual differentiation. Consideration of how these systems actually work that takes adequate account of the brain's role and mechanisms suggests that the first two are unlikely to be impediments to evolution. The neural and molecular networks that regulate the HPG provide both phenotypic and evolutionary flexibility, and rapid evolutionary responses to selection have been documented in several species. The neuroendocrine and molecular cascades for behaviour provide many avenues for evolutionary change without requiring a change in peripheral hormone levels. Sexual differentiation has some potential to be a source of evolutionary inertia in birds and could contribute to the lack of diversity in certain reproductive (including life history) traits. It is unclear, however, whether that lack of diversity would impede adaptation to rapid environmental change given the role of behavioural flexibility in avian reproduction.
doi:10.1098/rstb.2007.0005
PMCID: PMC2606723  PMID: 18048293
hypothalamic–pituitary–gonadal axis; mating behaviour; hormonal activation; sexual differentiation; Japanese quail; constraint
19.  Monogamy on the fast track 
Biology Letters  2007;3(6):617-619.
Social monogamy has evolved multiple times and is particularly common in birds. It is not well understood why some of these species are continuously and permanently paired while others occasionally ‘divorce’ (switch partners). Although several hypotheses have been considered, experimental tests are uncommon. Estrildid finches are thought to be permanently paired because being short-lived opportunistic breeders, they cannot afford the time to form a new pair relationship. Here it is shown through a controlled experimental manipulation that zebra finches (Taeniopygia guttata) allowed to remain with their partners to breed again are faster to initiate a clutch (by approx. 3 days) than birds separated from their mates that have to re-pair, supporting the hypothesis that continuous pairing speeds up initiation of reproduction, a benefit of long-term monogamy in a small, short-lived, gregarious species.
doi:10.1098/rsbl.2007.0388
PMCID: PMC2391224  PMID: 17848359
monogamy; mating systems; opportunistic breeder; zebra finch; clutch initiation
20.  LATERALITY IN SYRINX MUSCLE MORPHOLOGY OF THE JAPANESE QUAIL (Coturnix japonica) 
Physiology & behavior  2006;90(4):682-686.
In the Japanese quail, normally only males crow, but treatment of adult females with testosterone (T) facilitates the behavior. The sternotrachealis muscles are thought to adjust the length of the trachea during inspiration and/or expiration and control rigidity of the cartilages of the vocal organ (syrinx) during phonation. These muscles are heavier in males than females, and T increases their mass in females [1,2]. To investigate sex differences in morphology and potential effects of T in more detail, we examined several components of male, female, and T-treated female quail syrinx. No group effects were detected on overall tracheal size, size of the tracheal lumen, quantity of cartilage, overall muscle volume, or cross-sectional muscle area. However, the area and estimated volume of the muscles were greater on the right than left, due to increased fiber number. The similarity across groups suggests that if the sternotrachealis muscles are critical for crowing, morphology in females is sufficient, and the sex difference in behavior has another source. In contrast, these muscles may not play as large a role as was hypothesized. If the increased number of fibers on the right has a functional consequence, it likely reflects one similar in the two sexes, for example a common role in vocalizations they each produce – the male’s crow and the female’s cricket call.
doi:10.1016/j.physbeh.2006.12.007
PMCID: PMC1862757  PMID: 17258241
Sex difference; Testosterone; Asymmetry; Vocalization
21.  No sex difference in yolk steroid concentrations of avian eggs at laying 
Biology Letters  2005;1(3):318-321.
Yolk steroids of maternal origin have been proposed to influence genetic sex determination in birds, based on sex differences in yolk steroid concentrations of peafowl eggs incubated for 10 days. More recent reports dispute this proposal, as yolk steroids in eggs incubated for 3 days do not show such sex differences. To date, research examining this phenomenon has only analysed incubated eggs, although sex in avian species is determined before incubation begins. This may be a serious methodological flaw because incubation probably affects yolk steroid concentrations. Therefore, we investigated sex differences in yolk steroid concentrations of unincubated avian eggs. We withdrew yolk for steroid analysis from fresh, unincubated Japanese quail (Coturnix japonica) eggs by biopsy, and then incubated those eggs for 10 days, after which we harvested the embryonic material for genetic sexing and the incubated yolk for further steroid analysis. We found no sex differences in fresh Japanese quail eggs; however, sex differences were apparent in yolk steroids by day 10 of incubation, when female eggs had significantly more oestrogen in relation to androgen than male eggs. Concentrations of all yolk androgens decreased dramatically between laying and day 10 of incubation, whereas oestradiol (E2) concentrations increased marginally. Thus, yolk concentrations of androgens and E2 do not appear critical for avian sex determination.
doi:10.1098/rsbl.2005.0321
PMCID: PMC1617136  PMID: 17148197
avian yolk steroids; testosterone; oestrogen; sex determination; Coturnix japonica; incubation
22.  High progesterone during avian meiosis biases sex ratios toward females 
Biology Letters  2005;1(2):215-218.
Evidence of altered primary sex ratios in birds shows that mothers can manipulate the sex of their offspring before oviposition. In birds, females are the heterogametic sex (ZW) and males are homogametic (ZZ). Sex is determined in the first meiotic division, when one sex chromosome is retained in the oocyte and the other segregates to the polar body. Altered primary sex ratios suggest that birds may be capable of biasing the segregation of sex chromosomes during meiosis I. During the time of meiosis I, follicular steroid production is limited primarily to progesterone (P4). We experimentally manipulated the levels of P4 in female domestic chickens during the approximate time of meiosis I. We advanced the ovulation of the first egg of a sequence (or clutch) with a subcutaneous injection of P4. We found a significant effect of P4 dose on the sex of the resulting egg. The high progesterone group produced 25% males whereas the low progesterone group produced 61% males and the control group produced 63% males in the first ovulation of the sequence. We propose that variation in maternal progesterone during the critical time for genetic sex determination is the mechanism for primary sex ratio manipulation in birds.
doi:10.1098/rsbl.2004.0283
PMCID: PMC1626207  PMID: 17148170
sex ratio; sex allocation; progesterone; meiosis; domestic chicken
23.  Japanese quail (Coturnix japonica) inseminations are more likely to fertilize eggs in a context predicting mating opportunities. 
Theoretical developments in behavioural ecology have generated increased interest in the proximate mechanisms underlying fertilization, but little is known about how fertilization success is regulated by cues from the external or social environment in males and females. Here, we use a Pavlovian conditioning paradigm to show that inseminations resulting from mating male and female Japanese quail (Coturnix japonica) are more likely to fertilize eggs when they occur in a context predicting that an opposite-sex bird will appear than when they occur in a context predicting that an opposite-sex bird will not appear. This effect occurs when either the male or the female is the target of the conditioning. Thus, processes occurring during or after mating that contribute to fertilization success are subject to the influence of distal cues, confirming control by brain-level mechanisms. Conditioning is a widespread property of the nervous system and the demonstration that context conditioning can influence male and female reproductive success, and not simply mating success, has widespread implications for the fertilization successes of different types of copulation in natural mating systems.
doi:10.1098/rspb.2003.2421
PMCID: PMC1691436  PMID: 12964995

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