Small cell neuroendocrine carcinoma of the prostate is likely to become increasingly common with recent advances in pharmacologic androgen suppression. Thus, developing molecular markers of small cell differentiation in prostate cancer will be important to guide diagnosis and therapy of this aggressive tumor.
We examined the status of RB1, TP53 and PTEN in prostatic small cell and acinar carcinomas via immunohistochemistry (IHC), copy number alteration analysis and sequencing of formalin fixed paraffin-embedded specimens.
We found Rb protein loss in 90% (26/29) of small cell carcinoma cases with RB1 allelic loss in 85% (11/13) of cases. Of acinar tumors occurring concurrently with prostatic small cell carcinoma, 43% (3/7) showed Rb protein loss. In contrast, only 7% (10/150) of primary high grade acinar carcinomas, 11% (4/35) of primary acinar carcinomas with neuroendocrine differentiation, and 15% (2/13) of metastatic castrate resistant acinar carcinomas showed Rb protein loss. Loss of PTEN protein was seen in 63% (17/27) of small cell carcinomas, with 38% (5/13) showing allelic loss. By IHC, accumulation of p53 was observed in 56% (14/25) of small cell carcinomas, with 60% (6/10) of cases showing TP53 mutation.
Loss of RB1 by deletion is a common event in prostatic small cell carcinoma and can be detected by validated IHC assay. As Rb protein loss rarely occurs in high grade acinar tumors, these data suggest that Rb loss is a critical event in the development of small cell carcinomas and may be a useful diagnostic and potential therapeutic target.
Prostatic adenocarcinoma; small cell carcinoma; tumor suppressor; RB1; TP53; PTEN
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
We aimed to evaluate the role of robot-assisted radical prostatectomy (RARP) in the management of high-risk prostate cancer (PCa), with a focus on oncological, functional and perioperative outcomes. Further, we also aimed to briefly describe our novel modification to conventional RARP that allows immediate organ retrieval and examination for intra-operative surgical margin assessment. A literature search of PubMed was performed for articles on the management of high-risk PCa. Papers written in English and concerning clinical outcomes following RARP for locally advanced and high-risk PCa were selected. Outcomes data from our own center were also included. A total of 10 contemporary series were evaluated. Biopsy Gleason score ≥ 8 was the most common cause for classification of patients into the high-risk PCa group. Biochemical failure rate, in the few series that looked at long-term follow-up, varied from 9% to 26% at 1 year. The positive surgical margin rate varied from 12% to 53.3%. Urinary continence rates varied from 78% to 92% at 1 year. The overall complication rates varied from 2.4% to 30%, with anastomotic leak and lymphocele being the most common complications. Long-term data on oncological control following RARP in high-risk patients is lacking. Short-term oncological outcomes and functional outcomes are equivalent to open radical prostatectomy (RP). Safety outcomes are better in patients undergoing RARP when compared with open RP. Improved tools for predicting the presence of organ-confined disease (OCD) are available. High-risk patients with OCD would be ideal candidates for RARP and would benefit most from surgery alone.
Functional outcomes; High–risk; oncological outcomes; prostate cancer; robotics
Robotic and laparoscopic surgical training is an integral part of resident education in urology, yet the effect of resident involvement on outcomes of minimally-invasive urologic procedures remains largely unknown. We assess the impact of resident participation on surgical outcomes using a large multi-institutional prospective database.
Relying on the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Participant User Files (2005–2011), we abstracted the 3 most frequently performed minimally-invasive urologic oncology procedures. These included radical prostatectomy, radical nephrectomy and partial nephrectomy. Multivariable logistic regression models were constructed to assess the impact of trainee involvement (PGY 1–2: junior, PGY 3–4: senior, PGY ≥5: chief) versus attending-only on operative time, length-of-stay, 30-day complication, reoperation and readmission rates.
A total of 5459 minimally-invasive radical prostatectomies, 1740 minimally-invasive radical nephrectomies and 786 minimally-invasive partial nephrectomies were performed during the study period, for which data on resident surgeon involvement was available. In multivariable analyses, resident involvement was not associated with increased odds of overall complications, reoperation, or readmission rates for minimally-invasive prostatectomy, radical and partial nephrectomy. However, operative time was prolonged when residents were involved irrespective of the type of procedure. Length-of-stay was decreased with senior resident involvement in minimally-invasive partial nephrectomies (odds ratio [OR] 0.49, p = 0.04) and prostatectomies (OR 0.68, p = 0.01). The major limitations of this study include its retrospective observational design, inability to adjust for the case complexity and surgeon/hospital characteristics, and the lack of information regarding the minimally-invasive approach utilized (whether robotic or laparoscopic).
Resident involvement is associated with increased operative time in minimally-invasive urologic oncology procedures. However, it does not adversely affect the complication, reoperation or readmission rates, as well as length-of-stay.
We report the contemporary outcomes of radical cystectomy (RC) in patients with bladder cancer using a national, prospective perioperative database specifically developed to assess the quality of surgical care.
The National Surgical Quality Improvement Program (NSQIP) database was queried from 2006 to 2011 for RC. Data on postoperative complications, operative time, length of stay, blood transfusions, readmission, and mortality within 30 days from surgery were abstracted.
Overall, 1094 patients undergoing RC were identified. Rates of overall complications, transfusions, prolonged length of hospitalization, readmission, and perioperative mortality were 31.1%, 34.4%, 25.9%, 20.2%, and 2.7%, respectively. Body mass index represented an independent predictor of overall complications on multivariate analysis (p = 0.04). Baseline comorbidity status was associated with increased odds of postoperative complications, prolonged operative time, transfusion, prolonged hospitalization, and perioperative mortality. In particular, patients with cardiovascular comorbidities were 2.4 times more likely to die within 30 days following cystectomy compared to their healthier counterparts (p = 0.04). Men had lower odds of prolonged operative time and blood transfusions (p ≤ 0.03). Finally, the receipt of a continent urinary diversion was the only predictor of readmission (p = 0.02). Our results are limited by their retrospective nature and by the lack of adjustment for hospital and tumour volume.
Complications, transfusions, readmission, and perioperative mortality remain relatively common events in patients undergoing RC for bladder cancer. In an era where many advocate the need for prospective multi-institutional data collection as a means of improving quality of care, our study provides data on short-term outcomes after RC from a national quality improvement initiative.
Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
Kidney transplantation is the standard of care for patients with end stage renal disease. While open surgery remains the gold standard, minimally invasive surgery has recently been introduced for the recipient undergoing kidney transplantation. We review the evolution of techniques of minimally invasive surgery for kidney transplantation with specific emphasis on technical aspects of robotic assisted kidney transplantation.
da Vinci surgical system; kidney recipient; laparoscopy; robotic assistance
Rationale: Although asthma is usually considered to originate in childhood, adult-onset disease is being increasingly reported.
Objectives: To contrast the proportion and natural history of adult-onset versus pediatric-onset asthma in a community-based cohort. We hypothesized that asthma in women is predominantly of adult onset rather than of pediatric onset.
Methods: This study used data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort in the United States over a 25-year period. Adult- and pediatric-onset asthma phenotypes were studied, as defined by age at onset of 18 years or older. Subjects with asthma were categorized by sex, obesity, atopy, smoking, and race by mean age/examination year, using a three-way analysis of covariance model. Natural history of disease was examined using probabilities derived from a Markov chain model.
Measurements and Main Results: Asthma of adult onset became the dominant (i.e., exceeded 50%) phenotype in women by age 40 years. The age by which adult-onset asthma became the dominant phenotype was further lowered for obese, nonatopic, ever-smoking, or white women. The prevalence trend with increasing time for adult-onset disease was greater among subjects with nonatopic than atopic asthma among both sexes. Furthermore, adult-onset asthma had remarkable sex-related differences in risk factors. In both sexes, the quiescent state for adult-onset asthma was less frequent and also “less stable” over time than for pediatric-onset asthma.
Conclusions: Using a large national cohort, this study challenges the dictum that most asthma in adults originates in childhood. Studies of the differences between pediatric- and adult-onset asthma may provide greater insight into the phenotypic heterogeneity of asthma.
adult-onset; pediatric-onset; obesity; nonatopic; recrudescent
Clinical studies of the associations of vitamin E with lung function have reported conflicting results. However, these reports primarily examine the α-tocopherol isoform of vitamin E and have not included the isoform γ-tocopherol which we recently demonstrated in vitro opposes the function of α-tocopherol. We previously demonstrated, in vitro and in animal studies, that the vitamin E isoform α-tocopherol protects, but the isoform γ-tocopherol promotes lung inflammation and airway hyperresponsiveness.
To translate these findings to humans, we conducted analysis of 4526 adults in the Coronary Artery Risk Development in Young Adults (CARDIA) multi-center cohort with available spirometry and tocopherol data in blacks and whites. Spirometry was obtained at years 0, 5, 10, and 20 and serum tocopherol was from years 0, 7 and 15 of CARDIA.
In cross-sectional regression analysis at year 0, higher γ-tocopherol associated with lower FEV1 (p = 0.03 in blacks and p = 0.01 in all participants) and FVC (p = 0.01 in blacks, p = 0.05 in whites, and p = 0.005 in all participants), whereas higher α-tocopherol associated with higher FVC (p = 0.04 in blacks and whites and p = 0.01 in all participants). In the lowest quartile of α-tocopherol, higher γ-tocopherol associated with a lower FEV1 (p = 0.05 in blacks and p = 0.02 in all participants). In contrast, in the lowest quartile of γ-tocopherol, higher α-tocopherol associated with a higher FEV1 (p = 0.03) in blacks. Serum γ-tocopherol >10 μM was associated with a 175–545 ml lower FEV1 and FVC at ages 21–55 years.
Increasing serum concentrations of γ-tocopherol were associated with lower FEV1 or FVC, whereas increasing serum concentrations of α-tocopherol was associated with higher FEV1 or FVC. Based on the prevalence of serum γ-tocopherol >10 μM in adults in CARDIA and the adult U.S. population in the 2011 census, we expect that the lower FEV1 and FVC at these concentrations of serum γ-tocopherol occur in up to 4.5 million adults in the population.
α-tocopherol; γ-tocopherol; FEV1; FVC; Human
Robot-assisted vaginal vault suspension (RAVVS) for pelvic organ prolapse (POP) represents a minimally-invasive alternative to abdominal sacrocolpopexy. We measured perioperative outcomes and utilization rates of RAVVS.
RAVVS (n = 2381) and open VVS (OVVS, n = 11080) data were extracted from the 2009–2010 Nationwide Inpatient Sample. Propensity score-matched analysis compared patients undergoing RAVVS or OVVS for complications, mortality, prolonged length-of-stay, and elevated hospital charges.
Use of RAVVS for POP increased from 2009 to 2010 (16.3% to 19.2%). Patients undergoing RAVVS were more likely to be white (77.2% vs. 69.6%), to carry private insurance (52.8% vs. 46.0%) and to have fewer comorbidities (Charlson Comorbidity Index [CCI] ≥1 = 17.5% vs. 26.6%). They were more likely to undergo surgery at urban (98.2% vs. 93.7%) and academic centres (75.7% vs. 56.7%). Patients undergoing RAVVS were less likely to receive a blood-transfusion (0.7% vs. 1.8%, p < 0.001) or experience prolonged length-of-stay (9.3% vs. 25.1%, p < 0.001). They had more intraoperative complications (6.0% vs. 4.2%, p < 0.001), and higher median hospital charges ($32 402 vs. $24 136, p < 0.001). Overall postoperative complications were equivalent (17.9%, p = 1.0), though there were differences in wound (0.4% vs. 1.3%, p < 0.001), genitourinary (4.9% vs. 6.5%, p = 0.009), and surgical (6.6% vs. 4.9%, p = 0.007) complications.
The increasing use of RAVVS from 2009 to 2010 suggests a growth in the adoption of robotics to manage POP. We show that RAVVS is associated with decreased length of stay, fewer blood transfusions, as well as lower postoperative wound, genitourinary and vascular complications. The benefits of RAVVS are mitigated by higher hospital charges and higher rates of intra-operative complications.
Oncogenic signaling pathways are tightly regulated by negative feedback circuits and relief of these circuits represents a common mechanism of tumor drug resistance. Although the significance of these feedback pathways for signal transduction is evident, their relevance for cellular differentiation and morphogenesis in a genetically-defined context is unclear. In this study, we used isogenic benign mammary organotypic cultures to interrogate the role of mTOR-mediated negative feedback in the specific setting of PTEN inactivation. We found that mTOR signaling promoted basal-like differentiation and repressed nuclear hormone receptor expression after short-term PTEN loss in murine cell cultures analyzed ex vivo. Unexpectedly, we found that PTEN inactivation inhibited growth factor-induced epithelial invasion, and that downstream mTOR-mediated signaling feedback was both necessary and sufficient for this effect. Mechanistically, using isogenic MCF10A cells with and without somaticPTEN deletion, we showed that mTOR inhibition promoted EGF-mediated epithelial invasion by de-repressing upstream EGFR, SRC and PI3K signaling. In addition to offering new signal transduction insights, these results bring to light a number of important and potentially clinically relevant cellular consequences of mTOR inhibition in the specific context of PTEN loss, including modulation of hormone and growth factor responsiveness and promotion of epithelial invasion. Our findings prompt future investigations of the possibility that mTOR inhibitor therapy may not only be ineffective but even deleterious in tumors with PTEN loss.
PTEN; mTORC1; feedback; invasion; breast
Almost 3 billion people worldwide burn solid fuels indoors. These fuels include biomass and coal. Although indoor solid fuel smoke is likely a greater problem in developing countries, wood burning populations in developed countries may also be at risk from these exposures. Despite the large population at risk worldwide, the effect of exposure to indoor solid fuel smoke has not been adequately studied. Indoor air pollution from solid fuel use is strongly associated with COPD (both emphysema and chronic bronchitis), acute respiratory tract infections, and lung cancer (primarily coal use) and weakly associated with asthma, tuberculosis, and interstitial lung disease. Tobacco use further potentiates the development of respiratory disease among subjects exposed to solid fuel smoke. There is a need to perform additional interventional studies in this field. It is also important to increase awareness about the health effects of solid fuel smoke inhalation among physicians and patients as well as trigger preventive actions through education, research, and policy change in both developing and developed countries.
Biomass; Solid fuel; COPD; Asthma; Lung cancer; Respiratory tract infection
Adipokines, factors produced by adipose tissue, may be proinflammatory (such as leptin and resistin) or anti-inflammatory (such as adiponectin). Effects of these adipokines on the lungs have the potential to evoke or exacerbate asthma. This review summarizes basic mechanistic data through population-based and clinical studies addressing the potential role of adipokines in asthma. Augmenting circulating concentrations of adiponectin attenuates allergic airway inflammation and airway hyperresponsiveness in mice. Murine data is supported by human data that suggest that low serum adiponectin is associated with greater risk for asthma among women and peripubertal girls. Further, higher serum total adiponectin may be associated with lower clinical asthma severity among children and women with asthma. In contrast, exogenous administration of leptin results in augmented allergic airway hyperresponsiveness in mice. Alveolar macrophages obtained from obese asthmatics are uniquely sensitive to leptin in terms of their potential to augment inflammation. Consistent with this basic mechanistic data, epidemiologic studies demonstrate that higher serum leptin is associated with greater asthma prevalence and/or severity and that these associations may be stronger among women, postpubertal girls, and prepubertal boys. The role of adipokines in asthma is still evolving, and it is not currently known whether modulation of adipokines may be helpful in asthma prevention or treatment.
Adipokines; Leptin; Adiponectin; Asthma; Chronic Obstructive Pulmonary Disease
Rationale: Our previous cross-sectional study showed that serum adiponectin is inversely associated with asthma among women. However, it is not known if serum adiponectin predicts future development of asthma or if asthma affects subsequent serum adiponectin concentrations among women.
Objectives: To determine longitudinal association between serum adiponectin and incident asthma among women.
Methods: We used data from examinations at Years 10, 15, and 20 of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. In our primary analysis, the association of CARDIA Year 15 serum adiponectin concentration with Year 20 incident asthma was evaluated. In our secondary analysis, the converse direction, that is, the association of CARDIA Year 10 prevalent asthma with Year 15 serum adiponectin, was evaluated, using logistic regression techniques.
Measurements and Main Results: Our primary analysis included 1,450 women, mostly premenopausal. Multivariable analyses demonstrated that the lowest tertile of Year 15 serum adiponectin concentration (<7 mg/L) predicted significantly higher risk for incident asthma at Year 20 among women (odds ratio, 2.07; 95% confidence interval, 1.05, 4.10), and particularly among current smokers (interaction P = 0.051). Further, low serum adiponectin was more important than body mass index in predicting the risk for incident asthma among women. We also showed that the converse relationship was not true; that is, Year 10 prevalent asthma did not predict Year 15 serum adiponectin concentrations in women.
Conclusions: Serum adiponectin affects future risk for asthma in women and not vice versa. Measures that raise systemic adiponectin concentrations may lead to newer ways to prevent asthma among women, particularly among those who smoke.
incident asthma; obesity; adiponectin; adipokine; women
Adiponectin is associated with asthma. The direction of this association is not known in humans. In mice, this association is bidirectional - allergen inhalation affects serum adiponectin and exogenous adiponectin administration affects asthma. We sought to evaluate whether allergen inhalation affects serum adiponectin in human asthma.
This study included eight sensitized mild asthmatics and six healthy controls. Asthmatics were challenged with inhaled specific allergen (positive allergen skin test), methacholine, and irrelevant allergen (negative allergen skin test). Controls were challenged with irrelevant allergen. Sequential serum samples were obtained before and nine times after each challenge. Serum adiponectin (primary outcome), leptin, adiponectin-to-leptin ratio, eotaxin, and tumor necrosis factor-alpha - response curves, area under the curves, baseline and peak concentrations, were evaluated. Statistical analysis used repeated measures ANOVA and paired t-tests.
There were no significant differences in outcome measures among the challenges in asthmatics or when compared to controls. Type II error is an unlikely explanation for these findings since the study was adequately powered to detect changes in serum adiponectin, as reported in the literature. Further, pooled data showed that serum adiponectin diurnal variation curves were lower in asthma than in controls.
Serum adiponectin concentrations are lower in asthma than controls. Specific allergen inhalation in asthma does not acutely affect serum adiponectin concentrations. The reverse association i.e. effect of adiponectin on asthma needs further study. If future studies prove adiponectin to be a protective factor for asthma, modulating adiponectin may open a new approach towards managing asthma.
Adipokine; Adiponectin; Allergen inhalation challenge; Asthma; Leptin
The association of murine asthma with adiposity may be mediated by adiponectin, an anti-inflammatory adipokine with reduced serum concentrations in the obese. We studied whether serum adiponectin concentration was associated with human asthma and explained the association between adiposity and asthma, particularly in women and in pre-menopausal women.
A cross-sectional analysis of 2,890 eligible subjects at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort and its YALTA ancillary study, and had either current asthma or never asthma at that evaluation, was performed. Obesity was defined as body mass index (BMI) ≥ 30 kg/m2. Multivariable logistic regression analysis was performed with dependent variable current asthma status.
Women, but not men, with current asthma had lower mean unadjusted serum adiponectin concentration than those with never asthma (p < 0.001; p for sex interaction < 0.001). Similarly, current asthma was related to obese status only in women (OR 3.31, 95% CI 2.00, 5.46, p for sex interaction 0.004); this association was little affected by adjusting for serum adiponectin. Prevalence of current asthma in pre-menopausal women was reduced in the highest vs. lowest tertile of serum adiponectin concentration (OR 0.46, 95% CI 0.26, 0.84, p 0.03), after adjusting for BMI. However, the interaction between serum adiponectin concentration and BMI category on current asthma status was not significant in pre-menopausal women or women overall.
High serum adiponectin concentration may protect against current asthma in pre-menopausal women, but does not explain the association between asthma and adiposity.
Asthma; Adiposity; Body mass index; Waist circumference; Adiponectin
Smoking-related respiratory diseases are a major cause of morbidity and mortality. However, the relationship between smoking and respiratory disease has not been well-studied among ethnic minorities in general and among women in particular.
The objective of this cross-sectional study was to evaluate the risk of airflow obstruction and to assess lung function among Hispanic and non-Hispanic white (NHW) female smokers in a New Mexico cohort.
Participants completed a questionnaire detailing smoking history and underwent spirometry testing. Outcomes studied included airflow obstruction, selected lung function parameters, and chronic mucus hyper-secretion. Chi square, logistic, and linear regression techniques were utilized.
Of the 1,433 eligible women participants, 248 (17.3%) were Hispanic; and 319 had airflow obstruction (22.3%). Hispanic smokers were more likely to be current smokers, and report lower pack-years of smoking, compared to NHW smokers (p < 0.05 for all analyses). Further, Hispanic smokers were at a reduced risk of airflow obstruction compared to NHW smokers, with an O.R. of 0.51, 95% C.I. 0.34, 0.78 (p = 0.002) after adjustment for age, BMI, pack-years and duration of smoking, and current smoking status. Following adjustment for covariates, Hispanic smokers also had a higher mean absolute and percent predicted post-bronchodilator FEV1/FVC ratio, as well as higher mean percent predicted FEV1 (p < 0.05 for all analyses).
Hispanic female smokers in this New Mexico-based cohort had lower risk of airflow obstruction and better lung function than NHW female smokers. Further, smoking history did not completely explain these associations.
Hispanic ethnicity; Smokers; Airflow obstruction; Pulmonary function; Chronic mucus hyper-secretion; Women
Adiponectin is a predominantly anti-inflammatory protein produced by adipose tissue with possible signalling activity in the lung. It is increasingly associated with inflammatory pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and in critical illness. Although mouse studies indicate causative associations between adiponectin and asthma and COPD, the human literature in this regard is inconclusive. Some, but not all, studies demonstrate that serum adiponectin concentrations are inversely associated with asthma prevalence among premenopausal women and peripubertal girls. On the other hand, serum adiponectin concentrations are associated with lower asthma severity among boys but greater severity among men. Further, case-control studies demonstrate higher systemic and airway adiponectin concentrations in primarily male COPD patients than controls. Systemic adiponectin is positively associated with lung function in healthy adults but inversely associated in studies of male subjects with COPD. Murine and human studies further show contradictory associations of systemic adiponectin with critical illness. Higher premorbid systemic adiponectin concentrations are associated with improved survival from sepsis in mice. On the other hand, higher systemic adiponectin concentrations on day 1 of critical illness are associated with lower survival in critically ill patients with respiratory failure. In the absence of adequate longitudinal data, it is not possible to determine whether the adiponectin derangements are the consequence or the cause of the disease studied. Future research will determine whether modulation of adiponectin, independent of BMI, may be helpful in the prevention or treatment of asthma, COPD or critical illness.
Asthma; COPD; Sepsis; Respiratory Failure; Adiponectin; Lung function
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest PJMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
Measures of pulmonary function provide important clinical tools for evaluating lung disease and its progression. Genome-wide association studies have identified numerous genetic risk factors for pulmonary function but have not considered interaction with cigarette smoking, which has consistently been shown to adversely impact pulmonary function. In over 50,000 study participants of European descent, we applied a recently developed joint meta-analysis method to simultaneously test associations of gene and gene-by-smoking interactions in relation to two major clinical measures of pulmonary function. Using this joint method to incorporate genetic main effects plus gene-by-smoking interaction, we identified three novel gene regions not previously related to pulmonary function: (1) DNER, (2) HLA-DQB1 and HLA-DQA2, and (3) KCNJ2 and SOX9. Expression analyses in human lung tissue from ours or prior studies indicate that these regions contain genes that are plausibly involved in pulmonary function. This work highlights the utility of employing novel methods for incorporating environmental interaction in genome-wide association studies to identify novel genetic regions.
Rationale: The epidemiology of cigarette smoking–related chronic obstructive pulmonary disease (COPD) is not well characterized in Hispanics in the United States. Understanding how ethnicity influences COPD is important for a number of reasons, from informing public health policies to dissecting the genetic and environmental effects that contribute to disease.
Objectives: The present study assessed differences in risk between Hispanics and non-Hispanic whites for longitudinal and cross-sectional COPD phenotypes. Genetic ancestry was used to verify findings based on self-reported ethnicity. Hispanics in New Mexico are primarily differentiated from non-Hispanic whites by their proportion of Native American ancestry.
Methods: The study was performed in a New Mexican cohort of current and former smokers. Self-reported Hispanic and non-Hispanic white ethnicity was validated by defining genetic ancestry proportions at the individual level using 48 single-nucleotide polymorphism markers. Self-reported ethnicity and genetic ancestry were independently used to assess associations with cross-sectional and longitudinal measures of lung function. Multivariable models were adjusted for indicators of smoking behavior.
Measurements and Main Results: Self-reported Hispanic ethnicity was significantly associated with lower odds of COPD (odds ratio, 0.49; 95% confidence interval, 0.35–0.71; P = 0.007), and this protection was validated by the observation that Hispanic smokers have reduced risk of rapid decline in lung function (odds ratio, 0.48; 95% confidence interval, 0.30–0.78; P = 0.003). Similar findings were noted when Native American genetic ancestry proportions were used as predictors instead of self-report of Hispanic ethnicity.
Conclusions: Hispanic ethnicity is inversely associated with cross-sectional and longitudinal spirometric COPD phenotypes even after adjustment for smoking. Native American genetic ancestry may account for this “Hispanic protection.”
Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD). We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
We have demonstrated in several studies that obesity and adipokines are more strongly associated with asthma in women than in men. The reason for this controversial sex difference is not known. Based on our prior studies, we hypothesize that sex-related difference in ectopic fat may explain the obesity-asthma association in women.
adipokine; leptin; adiponectin; physical activity; gonadal hormones; obesity
Rationale: Wood smoke–associated chronic obstructive pulmonary disease (COPD) is common in women in developing countries but has not been adequately described in developed countries.
Objectives: Our objective was to determine whether wood smoke exposure was a risk factor for COPD in a population of smokers in the United States and whether aberrant gene promoter methylation in sputum may modify this association.
Methods: For this cross-sectional study, 1,827 subjects were drawn from the Lovelace Smokers' Cohort, a predominantly female cohort of smokers. Wood smoke exposure was self-reported. Postbronchodilator spirometry was obtained, and COPD outcomes studied included percent predicted FEV1, airflow obstruction, and chronic bronchitis. Effect modification of wood smoke exposure with current cigarette smoke, ethnicity, sex, and promoter methylation of lung cancer-related genes in sputum on COPD outcomes were separately explored. Multivariable logistic and poisson regression models were used for binary and rate-based outcomes, respectively.
Measurements and Main Results: Self-reported wood smoke exposure was independently associated with a lower percent predicted FEV1 (point estimate [± SE] −0.03 ± 0.01) and a higher prevalence of airflow obstruction and chronic bronchitis (odds ratio, 1.96; 95% confidence interval, 1.52–2.52 and 1.64 (95% confidence interval, 1.31–2.06, respectively). These associations were stronger among current cigarette smokers, non-Hispanic whites, and men. Wood smoke exposure interacted in a multiplicative manner with aberrant promoter methylation of the p16 or GATA4 genes on lower percent predicted FEV1.
Conclusions: These studies identify a novel link between wood smoke exposure and gene promoter methylation that synergistically increases the risk for reduced lung function in cigarette smokers.
wood smoke; cigarette smokers; airflow obstruction; gene promoter methylation in sputum DNA