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1.  Genome-Wide Study of Percent Emphysema on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study 
Rationale: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.
Objectives: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.
Methods: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than −950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.
Measurements and Main Results: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10−8) and PPT2 (rs10947233; P = 3.2 × 10−8), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase–related gene MAN2B1 (rs10411619; P = 1.1 × 10−9; minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10−10; MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10−8; MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase–related gene, MAN1C1 (rs12130495; P = 9.9 × 10−6; MAF, 13.3%) was associated with percent emphysema.
Conclusions: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
doi:10.1164/rccm.201306-1061OC
PMCID: PMC3977717  PMID: 24383474
emphysema; computed tomography; multiethnic; cohort study; genetic association
2.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | OConnor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
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.
doi:10.1038/ng.3011
PMCID: PMC4140093  PMID: 24929828
3.  Asthma Outcomes: Pulmonary Physiology 
Background
Outcomes of pulmonary physiology have a central place in asthma clinical research.
Objective
At the request of National Institutes of Health (NIH) institutes and other federal agencies, an expert group was convened to provide recommendations on the use of pulmonary function measures as asthma outcomes that should be assessed in a standardized fashion in future asthma clinical trials and studies to allow for cross-study comparisons.
Methods
Our subcommittee conducted a comprehensive search of PubMed to identify studies that focused on the validation of various airway response tests used in asthma clinical research. The subcommittee classified the instruments as core (to be required in future studies), supplemental (to be used according to study aims and in a standardized fashion), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011.
Results
A list of pulmonary physiology outcomes that applies to both adults and children older than 6 years was created. These outcomes were then categorized into core, supplemental, and emerging. Spirometric outcomes (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1/FVC) are proposed as core outcomes for study population characterization, for observational studies, and for prospective clinical trials. Bronchodilator reversibility and pre- and post-bronchodilator FEV1 also are core outcomes for study population characterization and observational studies.
Conclusions
The subcommittee considers pulmonary physiology outcomes of central importance in asthma and proposes spirometric outcomes as core outcomes for all future NIH-initiated asthma clinical research.
doi:10.1016/j.jaci.2011.12.986
PMCID: PMC4263032  PMID: 22386510
Spirometry; airway responsiveness; peak expiratory flow monitoring; lung volumes; gas exchange
4.  Reassessment of Omalizumab-Dosing Strategies and Pharmacodynamics in Inner-City Children and Adolescents 
BACKGROUND
Treatment regimens for omalizumab are guided by a dosing table that is based on total serum IgE and body weight. Limited data exist about onset and offset of omalizumab efficacy in children and adolescents or subgroups that most benefit from treatment.
OBJECTIVES
Post hoc analyses were conducted to (1) examine patient characteristics of those eligible and ineligible for omalizumab, (2) describe onset of effect after initiation of omalizumab and offset of treatment effect after stopping therapy, and (3) determine whether the efficacy differs by age, asthma severity, dosing regimen, and prespecified biomarkers.
METHODS
Inner-city children and adolescents with persistent allergic asthma were enrolled in the Inner-City Anti-IgE Therapy for Asthma trial that compared omalizumab with placebo added to guidelines-based therapy for 60 weeks.
RESULTS
Two hundred ninety-three of 889 participants (33%) clinically suitable for omalizumab were ineligible for dosing according to a modified dosing table specifying IgE level and body weight criteria. Baseline symptoms were comparable among those eligible and ineligible to receive omalizumab, but other characteristics (rate of health care utilization and skin test results) differed. The time of onset of omalizumab effect was <30 days and time of offset was between 30 and 120 days. No difference in efficacy was noted by age or asthma severity, but high exhaled nitric oxide, blood eosinophils, and body mass index predicted efficacy.
CONCLUSIONS
A significant portion of children and adolescents particularly suited for omalizumab because of asthma severity status may be ineligible due to IgE >1300 IU/mL. Omalizumab reduced asthma symptoms and exacerbations rapidly; features associated with efficacy can be identified to guide patient selection.
doi:10.1016/j.jaip.2013.01.011
PMCID: PMC4254887  PMID: 24565455
Asthma exacerbations; Biomarkers; Dosing regimens; Inhaled corticosteroids; Omalizumab; Pharmacodynamics; Response predictors
5.  Short-Term Exposure to Air Pollution and Lung Function in the Framingham Heart Study 
Rationale: Short-term exposure to ambient air pollution has been associated with lower lung function. Few studies have examined whether these associations are detectable at relatively low levels of pollution within current U.S. Environmental Protection Agency (EPA) standards.
Objectives: To examine exposure to ambient air pollutants within EPA standards and lung function in a large cohort study.
Methods: We included 3,262 participants of the Framingham Offspring and Third Generation cohorts living within 40 km of the Harvard Supersite monitor in Boston, Massachusetts (5,358 examinations, 1995–2011) who were not current smokers, with previous-day pollutant levels in compliance with EPA standards. We compared lung function (FEV1 and FVC) after previous-day exposure to particulate matter less than 2.5 μm in diameter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) in the “moderate” range of the EPA Air Quality Index to exposure in the “good” range. We also examined linear relationships between moving averages of pollutant concentrations 1, 2, 3, 5, and 7 days before spirometry and lung function.
Measurements and Main Results: Exposure to pollutant concentrations in the “moderate” range of the EPA Air Quality Index was associated with a 20.1-ml lower FEV1 for PM2.5 (95% confidence interval [CI], −33.4, −6.9), a 30.6-ml lower FEV1 for NO2 (95% CI, −60.9, −0.2), and a 55.7-ml lower FEV1 for O3 (95% CI, −100.7, −10.8) compared with the “good” range. The 1- and 2-day moving averages of PM2.5, NO2, and O3 before testing were negatively associated with FEV1 and FVC.
Conclusions: Short-term exposure to PM2.5, NO2, and O3 within current EPA standards was associated with lower lung function in this cohort of adults.
doi:10.1164/rccm.201308-1414OC
PMCID: PMC3919078  PMID: 24200465
chronic obstructive pulmonary disease; asthma; air pollutants; U.S. Environmental Protection Agency
6.  Obesity in relation to lung cancer incidence in African American women 
Cancer causes & control : CCC  2013;24(9):1695-1703.
Purpose
Although a number of studies have found an inverse association between body mass index (BMI) and risk of lung cancer, there is little information on this relation in African Americans, who experience a higher incidence of lung cancer.
Methods
We assessed the relation of BMI to incidence of lung cancer in the Black Women’s Health Study, an ongoing prospective follow-up of 59,000 women in the United States. Cox proportional hazard models were used to estimate hazard ratios for various levels of BMI relative to BMI 18.5–24.9 kg/m2 (“normal weight”) with adjustment for age, education, pack-years of smoking, and other covariates. Two other anthropometric measures, waist circumference (WC) and waist/hip ratio (WHR) were also assessed. A total of 323 primary lung cancer cases were identified from 1995 to 2011.
Results
The hazard ratio (HR) for BMI ≥30 relative to BMI 18.5–24.9 was 0.69 (95% confidence interval 0.51–0.92). As expected, cigarette smoking was strongly associated with increased risk of lung cancer. In analyses stratified by smoking status, the HR for BMI ≥30 relative to BMI 18.5–24.9 was 0.62 (0.38–1.00) among current smokers, 0.90 (0.56–1.42) among former smokers, and 0.83 (0.41–1.70) among never smokers (p for interaction= 0.28). Control for pack-years of smoking or age started smoking had little effect on the hazard ratios. WC and WHR were not materially associated with lung cancer risk.
Conclusion
Our results indicate that high BMI is associated with a lower risk of lung cancer in African American women, particularly among current smokers.
doi:10.1007/s10552-013-0245-6
PMCID: PMC3737410  PMID: 23744044
8.  Replication and fine mapping of asthma-associated loci in individuals of African ancestry 
Human genetics  2013;132(9):1039-1047.
Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RLML18R1, and 10pl4, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry.
doi:10.1007/s00439-013-1310-7
PMCID: PMC3975655  PMID: 23666277
9.  Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function 
Tang, Wenbo | Kowgier, Matthew | Loth, Daan W. | Soler Artigas, María | Joubert, Bonnie R. | Hodge, Emily | Gharib, Sina A. | Smith, Albert V. | Ruczinski, Ingo | Gudnason, Vilmundur | Mathias, Rasika A. | Harris, Tamara B. | Hansel, Nadia N. | Launer, Lenore J. | Barnes, Kathleen C. | Hansen, Joyanna G. | Albrecht, Eva | Aldrich, Melinda C. | Allerhand, Michael | Barr, R. Graham | Brusselle, Guy G. | Couper, David J. | Curjuric, Ivan | Davies, Gail | Deary, Ian J. | Dupuis, Josée | Fall, Tove | Foy, Millennia | Franceschini, Nora | Gao, Wei | Gläser, Sven | Gu, Xiangjun | Hancock, Dana B. | Heinrich, Joachim | Hofman, Albert | Imboden, Medea | Ingelsson, Erik | James, Alan | Karrasch, Stefan | Koch, Beate | Kritchevsky, Stephen B. | Kumar, Ashish | Lahousse, Lies | Li, Guo | Lind, Lars | Lindgren, Cecilia | Liu, Yongmei | Lohman, Kurt | Lumley, Thomas | McArdle, Wendy L. | Meibohm, Bernd | Morris, Andrew P. | Morrison, Alanna C. | Musk, Bill | North, Kari E. | Palmer, Lyle J. | Probst-Hensch, Nicole M. | Psaty, Bruce M. | Rivadeneira, Fernando | Rotter, Jerome I. | Schulz, Holger | Smith, Lewis J. | Sood, Akshay | Starr, John M. | Strachan, David P. | Teumer, Alexander | Uitterlinden, André G. | Völzke, Henry | Voorman, Arend | Wain, Louise V. | Wells, Martin T. | Wilk, Jemma B. | Williams, O. Dale | Heckbert, Susan R. | Stricker, Bruno H. | London, Stephanie J. | Fornage, Myriam | Tobin, Martin D. | OConnor, George T. | Hall, Ian P. | Cassano, Patricia A.
PLoS ONE  2014;9(7):e100776.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0100776
PMCID: PMC4077649  PMID: 24983941
10.  APOM and High-Density Lipoprotein are associated with Lung Function and Percent Emphysema 
The European respiratory journal  2013;43(4):1003-1017.
Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD.
We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema.
We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9, were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema.
These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema.
doi:10.1183/09031936.00147612
PMCID: PMC4041087  PMID: 23900982
Apolipoproteins; Cholesterol; Percent Emphysema; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive
11.  Network-guided sparse regression modeling for detection of gene-by-gene interactions 
Bioinformatics  2013;29(10):1241-1249.
Motivation: Genetic variants identified by genome-wide association studies to date explain only a small fraction of total heritability. Gene-by-gene interaction is one important potential source of unexplained total heritability. We propose a novel approach to detect such interactions that uses penalized regression and sparse estimation principles, and incorporates outside biological knowledge through a network-based penalty.
Results: We tested our new method on simulated and real data. Simulation showed that with reasonable outside biological knowledge, our method performs noticeably better than stage-wise strategies (i.e. selecting main effects first, and interactions second, from those main effects selected) in finding true interactions, especially when the marginal strength of main effects is weak. We applied our method to Framingham Heart Study data on total plasma immunoglobulin E (IgE) concentrations and found a number of interactions among different classes of human leukocyte antigen genes that may interact to influence the risk of developing IgE dysregulation and allergy.
Availability: The proposed method is implemented in R and available at http://math.bu.edu/people/kolaczyk/software.html.
Contact: chenlu@bu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt139
PMCID: PMC3711507  PMID: 23599501
12.  A Dynamic Bronchial Airway Gene Expression Signature of Chronic Obstructive Pulmonary Disease and Lung Function Impairment 
Rationale: Molecular phenotyping of chronic obstructive pulmonary disease (COPD) has been impeded in part by the difficulty in obtaining lung tissue samples from individuals with impaired lung function.
Objectives: We sought to determine whether COPD-associated processes are reflected in gene expression profiles of bronchial airway epithelial cells obtained by bronchoscopy.
Methods: Gene expression profiling of bronchial brushings obtained from 238 current and former smokers with and without COPD was performed using Affymetrix Human Gene 1.0 ST Arrays.
Measurements and Main Results: We identified 98 genes whose expression levels were associated with COPD status, FEV1% predicted, and FEV1/FVC. In silico analysis identified activating transcription factor 4 (ATF4) as a potential transcriptional regulator of genes with COPD-associated airway expression, and ATF4 overexpression in airway epithelial cells in vitro recapitulates COPD-associated gene expression changes. Genes with COPD-associated expression in the bronchial airway epithelium had similarly altered expression profiles in prior studies performed on small-airway epithelium and lung parenchyma, suggesting that transcriptomic alterations in the bronchial airway epithelium reflect molecular events found at more distal sites of disease activity. Many of the airway COPD-associated gene expression changes revert toward baseline after therapy with the inhaled corticosteroid fluticasone in independent cohorts.
Conclusions: Our findings demonstrate a molecular field of injury throughout the bronchial airway of active and former smokers with COPD that may be driven in part by ATF4 and is modifiable with therapy. Bronchial airway epithelium may ultimately serve as a relatively accessible tissue in which to measure biomarkers of disease activity for guiding clinical management of COPD.
doi:10.1164/rccm.201208-1449OC
PMCID: PMC3707363  PMID: 23471465
chronic obstructive pulmonary disease; gene expression profiling; biologic markers
13.  Abuse during Childhood and Adolescence and Risk of Adult-Onset Asthma in African American Women 
Background
Experiences of violence contribute to the occurrence of childhood asthma but there is little information on the effect of early life abuse on adult-onset asthma.
Objective
We prospectively assessed the relation between physical and sexual abuse during childhood and adolescence and the incidence of adult-onset asthma in the Black Women’s Health Study.
Methods
We followed 28,456 women from 1995 through 2011 with biennial mailed questionnaires. Experiences of physical and sexual abuse that occurred during childhood and adolescence were obtained in 2005. Cox regression models were used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI).
Results
During 417,931 person-years of follow-up, 1160 participants reported physician diagnosed asthma and concurrent use of asthma medication. Compared with women who experienced no abuse during childhood or adolescence, the multivariable IRR for any childhood abuse was 1.24 (95% CI 1.06–1.45) and for any adolescent abuse it was 1.10 (95% CI 0.88–1.36). The IRR was higher for childhood physical abuse (IRR=1.29, 95% CI 1.07–1.49) than for childhood sexual abuse (IRR=1.15, 95% CI 0.88–1.49). IRRs for physical and sexual abuse during adolescence were compatible with 1.0. The association between childhood abuse and asthma incidence was stronger in older compared with younger women.
Conclusion
In this large cohort of African American women, there was a positive association between adult-onset asthma and childhood physical abuse, and weaker associations for childhood sexual abuse and any abuse during adolescence. Given the high prevalence of asthma and of childhood abuse, the association is of public health importance.
doi:10.1016/j.jaci.2012.10.023
PMCID: PMC3615035  PMID: 23219171
Asthma; child abuse; adolescent abuse; incidence; longitudinal studies; cohort studies; African Americans; women
14.  Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD 
Human genetics  2012;132(1):79-90.
Rationale
Accelerated lung function decline is a key COPD phenotype; however its genetic control remains largely unknown.
Methods
We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European-American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry.
Measurements and Main Results
Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status.
Conclusions
We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.
doi:10.1007/s00439-012-1219-6
PMCID: PMC3536920  PMID: 22986903
COPD; lung function decline; GWAS; genome wide association; genes; polymorphisms
15.  MUC5B Promoter Polymorphism and Interstitial Lung Abnormalities 
The New England journal of medicine  2013;368(23):2192-2200.
BACKGROUND
A common promoter polymorphism (rs35705950) in MUC5B, the gene encoding mucin 5B, is associated with idiopathic pulmonary fibrosis. It is not known whether this polymorphism is associated with interstitial lung disease in the general population.
METHODS
We performed a blinded assessment of interstitial lung abnormalities detected in 2633 participants in the Framingham Heart Study by means of volumetric chest computed tomography (CT). We evaluated the relationship between the abnormalities and the genotype at the rs35705950 locus.
RESULTS
Of the 2633 chest CT scans that were evaluated, interstitial lung abnormalities were present in 177 (7%). Participants with such abnormalities were more likely to have shortness of breath and chronic cough and reduced measures of total lung and diffusion capacity, as compared with participants without such abnormalities. After adjustment for covariates, for each copy of the minor rs35705950 allele, the odds of interstitial lung abnormalities were 2.8 times greater (95% confidence interval [CI], 2.0 to 3.9; P<0.001), and the odds of definite CT evidence of pulmonary fibrosis were 6.3 times greater (95% CI, 3.1 to 12.7; P<0.001). Although the evidence of an association between the MUC5B genotype and interstitial lung abnormalities was greater among participants who were older than 50 years of age, a history of cigarette smoking did not appear to influence the association.
CONCLUSIONS
The MUC5B promoter polymorphism was found to be associated with interstitial lung disease in the general population. Although this association was more apparent in older persons, it did not appear to be influenced by cigarette smoking. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00005121.)
doi:10.1056/NEJMoa1216076
PMCID: PMC3747636  PMID: 23692170
16.  Vitamin D-responsive SGPP2 variants associated with lung cell expression and lung function 
BMC Medical Genetics  2013;14:122.
Background
Vitamin D is associated with lung health in epidemiologic studies, but mechanisms mediating observed associations are poorly understood. This study explores mechanisms for an effect of vitamin D in lung through an in vivo gene expression study, an expression quantitative trait loci (eQTL) analysis in lung tissue, and a population-based cohort study of sequence variants.
Methods
Microarray analysis investigated the association of gene expression in small airway epithelial cells with serum 25(OH)D in adult non-smokers. Sequence variants in candidate genes identified by the microarray were investigated in a lung tissue eQTL database, and also in relation to cross-sectional pulmonary function in the Health, Aging, and Body Composition (Health ABC) study, stratified by race, with replication in the Framingham Heart Study (FHS).
Results
13 candidate genes had significant differences in expression by serum 25(OH)D (nominal p < 0.05), and a genome-wide significant eQTL association was detected for SGPP2. In Health ABC, SGPP2 SNPs were associated with FEV1 in both European- and African-Americans, and the gene-level association was replicated in European-American FHS participants. SNPs in 5 additional candidate genes (DAPK1, FSTL1, KAL1, KCNS3, and RSAD2) were associated with FEV1 in Health ABC participants.
Conclusions
SGPP2, a sphingosine-1-phosphate phosphatase, is a novel vitamin D-responsive gene associated with lung function. The identified associations will need to be followed up in further studies.
doi:10.1186/1471-2350-14-122
PMCID: PMC3907038  PMID: 24274704
Vitamin D; Airflow obstruction; FEV1; SGPP2; FEV1/FVC
17.  Genome-wide association study of lung function decline in adults with and without asthma 
Background
Genome-wide association studies (GWAS) have identified determinants of chronic obstructive pulmonary disease, asthma and lung function level, however none addressed decline in lung function.
Aim
We conducted the first GWAS on age-related decline in forced expiratory volume in the first second (FEV1) and in its ratio to forced vital capacity (FVC) stratified a priori by asthma status.
Methods
Discovery cohorts included adults of European ancestry (1441 asthmatics, 2677 non-asthmatics; Epidemiological Study on the Genetics and Environment of Asthma (EGEA); Swiss Cohort Study on Air Pollution And Lung And Heart Disease In Adults (SAPALDIA); European Community Respiratory Health Survey (ECRHS)). The associations of FEV1 and FEV1/FVC decline with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed-up by in silico replication (1160 asthmatics, 10858 non-asthmatics: Atherosclerosis Risk in Communities (ARIC); Framingham Heart Study (FHS); British 1958 Birth Cohort (B58C); Dutch asthma study).
Results
Main signals identified differed between asthmatics and non-asthmatics. None of the SNPs reached genome-wide significance. The association between the height related gene DLEU7 and FEV1 decline suggested for non-asthmatics in the discovery phase was replicated (discovery P=4.8×10−6; replication P=0.03) and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, associated with FEV1/FVC decline in asthmatics (P=5.3×10−8) did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline.
Conclusions
Genetic heterogeneity of lung function may be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status.
doi:10.1016/j.jaci.2012.01.074
PMCID: PMC3340499  PMID: 22424883
Asthma; cohort studies; genome-wide association; lung function decline; heterogeneity
18.  Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction 
Wilk, Jemma B. | Shrine, Nick R. G. | Loehr, Laura R. | Zhao, Jing Hua | Manichaikul, Ani | Lopez, Lorna M. | Smith, Albert Vernon | Heckbert, Susan R. | Smolonska, Joanna | Tang, Wenbo | Loth, Daan W. | Curjuric, Ivan | Hui, Jennie | Cho, Michael H. | Latourelle, Jeanne C. | Henry, Amanda P. | Aldrich, Melinda | Bakke, Per | Beaty, Terri H. | Bentley, Amy R. | Borecki, Ingrid B. | Brusselle, Guy G. | Burkart, Kristin M. | Chen, Ting-hsu | Couper, David | Crapo, James D. | Davies, Gail | Dupuis, Josée | Franceschini, Nora | Gulsvik, Amund | Hancock, Dana B. | Harris, Tamara B. | Hofman, Albert | Imboden, Medea | James, Alan L. | Khaw, Kay-Tee | Lahousse, Lies | Launer, Lenore J. | Litonjua, Augusto | Liu, Yongmei | Lohman, Kurt K. | Lomas, David A. | Lumley, Thomas | Marciante, Kristin D. | McArdle, Wendy L. | Meibohm, Bernd | Morrison, Alanna C. | Musk, Arthur W. | Myers, Richard H. | North, Kari E. | Postma, Dirkje S. | Psaty, Bruce M. | Rich, Stephen S. | Rivadeneira, Fernando | Rochat, Thierry | Rotter, Jerome I. | Artigas, María Soler | Starr, John M. | Uitterlinden, André G. | Wareham, Nicholas J. | Wijmenga, Cisca | Zanen, Pieter | Province, Michael A. | Silverman, Edwin K. | Deary, Ian J. | Palmer, Lyle J. | Cassano, Patricia A. | Gudnason, Vilmundur | Barr, R. Graham | Loos, Ruth J. F. | Strachan, David P. | London, Stephanie J. | Boezen, H. Marike | Probst-Hensch, Nicole | Gharib, Sina A. | Hall, Ian P. | OConnor, George T. | Tobin, Martin D. | Stricker, Bruno H.
Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.
Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations.
Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.
Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
doi:10.1164/rccm.201202-0366OC
PMCID: PMC3480517  PMID: 22837378
chronic obstructive pulmonary disease; single-nucleotide polymorphism; genes
19.  A Genome Wide Association Study of Plasma Total IgE Concentration in the Framingham Heart Study 
Background
Atopy and plasma IgE concentration are genetically complex traits, and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active investigation.
Objective
To ascertain the genetic risk factors which lead to IgE dysregulation.
Methods
A genome wide association study (GWAS) was performed in 6,819 participants from the Framingham Heart Study (FHS). Seventy of the top SNPs were selected based on p-values and linkage disequilibrium among neighboring SNPs and evaluated in a meta-analysis with five independent populations from the KORA, B58C, and CAMP cohorts.
Results
Thirteen SNPs located in the region of three genes, FCER1A, STAT6, and IL-13, were found to have genome-wide significance in the FHS GWAS. The most significant SNPs from the three regions were rs2251746 (FCER1A, p-value 2.11×10-12), rs1059513 (STAT6, p-value 2.87×10-08), and rs1295686 (IL-13, p-value 3.55×10-08). Four additional gene regions - HLA-G, HLA-DQA2, HLA-A, and DARC - reached genome-wide statistical significance in meta-analysis combining FHS and replication cohorts, although the DARC association did not appear independent of SNPs in the nearby FCER1A gene.
Conclusion
This GWAS of the FHS has identified genetic loci in HLA genes that may have a role in the pathogenesis of IgE dysregulation and atopy. It also confirmed the association of known susceptibility loci, FCER1A, STAT6, and IL-13, for the dysregulation of total IgE.
doi:10.1016/j.jaci.2011.09.029
PMCID: PMC3293994  PMID: 22075330
total IgE; atopy; asthma; GWAS
20.  Distribution and Clinical Correlates of the Interleukin Receptor Family Member Soluble ST2 in the Framingham Heart Study 
Clinical chemistry  2012;58(12):1673-1681.
BACKGROUND
Soluble ST2 (sST2) is a cardiac biomarker whose concentration rises in response to myocardial strain. Increased sST2 concentrations may predict adverse outcomes in patients with heart failure and myocardial infarction. Because sST2 was largely undetectable with first-generation assays in ambulatory individuals, there are few data regarding its distribution and correlates in community-based populations.
METHODS
We measured sST2 using a highly sensitive ELISA in 3450 Framingham Heart Study participants who attended a routine examination. We used multivariable linear regression models to identify covariates associated with sST2 in the general sample. We obtained a reference sample (n = 1136) by excluding individuals with prevalent coronary disease, heart failure, atrial fibrillation, diabetes, hypertension, obesity, valvular disease, left ventricular systolic dysfunction, and pulmonary and renal dysfunction. We used empiric and quantile regression techniques to estimate the 2.5th, 50th, 97.5th, and 99th quantiles.
RESULTS
In the general sample (mean age 59 years, 55% women), systolic blood pressure (P = 0.006), antihypertensive medication use (P = 0.03), and diabetes (P < 0.001) were associated with sST2 concentrations. In the reference sample (mean age 55, 59% women), male sex (P < 0.0001) and older age (P = 0.004) were predictive of higher sST2 concentrations. Quantile and empirical methods were used to define the reference intervals. Using the empirical approach, upper 99% percentile values in different age groups ranged from 46.6 to 64.4 μg/L in men and 36.7 to 53.0 μg/L in women.
CONCLUSIONS
In a well-characterized, community-based cohort, values for sST2 differ between men and women, increase with age, and are associated with diabetes and hypertension.
doi:10.1373/clinchem.2012.192153
PMCID: PMC3557515  PMID: 23065477
21.  Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function 
Hancock, Dana B. | Artigas, María Soler | Gharib, Sina A. | Henry, Amanda | Manichaikul, Ani | Ramasamy, Adaikalavan | Loth, Daan W. | Imboden, Medea | Koch, Beate | McArdle, Wendy L. | Smith, Albert V. | Smolonska, Joanna | Sood, Akshay | Tang, Wenbo | Wilk, Jemma B. | Zhai, Guangju | Zhao, Jing Hua | Aschard, Hugues | Burkart, Kristin M. | Curjuric, Ivan | Eijgelsheim, Mark | Elliott, Paul | Gu, Xiangjun | Harris, Tamara B. | Janson, Christer | Homuth, Georg | Hysi, Pirro G. | Liu, Jason Z. | Loehr, Laura R. | Lohman, Kurt | Loos, Ruth J. F. | Manning, Alisa K. | Marciante, Kristin D. | Obeidat, Ma'en | Postma, Dirkje S. | Aldrich, Melinda C. | Brusselle, Guy G. | Chen, Ting-hsu | Eiriksdottir, Gudny | Franceschini, Nora | Heinrich, Joachim | Rotter, Jerome I. | Wijmenga, Cisca | Williams, O. Dale | Bentley, Amy R. | Hofman, Albert | Laurie, Cathy C. | Lumley, Thomas | Morrison, Alanna C. | Joubert, Bonnie R. | Rivadeneira, Fernando | Couper, David J. | Kritchevsky, Stephen B. | Liu, Yongmei | Wjst, Matthias | Wain, Louise V. | Vonk, Judith M. | Uitterlinden, André G. | Rochat, Thierry | Rich, Stephen S. | Psaty, Bruce M. | O'Connor, George T. | North, Kari E. | Mirel, Daniel B. | Meibohm, Bernd | Launer, Lenore J. | Khaw, Kay-Tee | Hartikainen, Anna-Liisa | Hammond, Christopher J. | Gläser, Sven | Marchini, Jonathan | Kraft, Peter | Wareham, Nicholas J. | Völzke, Henry | Stricker, Bruno H. C. | Spector, Timothy D. | Probst-Hensch, Nicole M. | Jarvis, Deborah | Jarvelin, Marjo-Riitta | Heckbert, Susan R. | Gudnason, Vilmundur | Boezen, H. Marike | Barr, R. Graham | Cassano, Patricia A. | Strachan, David P. | Fornage, Myriam | Hall, Ian P. | Dupuis, Josée | Tobin, Martin D. | London, Stephanie J.
PLoS Genetics  2012;8(12):e1003098.
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.
Author Summary
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.
doi:10.1371/journal.pgen.1003098
PMCID: PMC3527213  PMID: 23284291
22.  A Multidimensional Computer Adaptive Test Approach to Dyspnea Assessment 
Objective
To develop and test a prototype dyspnea computer adaptive test.
Design
Prospective study.
Setting
Two outpatient medical facilities.
Participants
A convenience sample of 292 adults with COPD.
Interventions
Not applicable
Main Outcome Measure
We developed a modified and expanded item bank and computer adaptive test (CAT) for the Dyspnea Management Questionnaire (DMQ), an outcome measure consisting of four dyspnea dimensions: dyspnea intensity, dyspnea anxiety, activity avoidance, and activity self-efficacy.
Results
Factor analyses supported a four-dimensional model underlying the 71 DMQ items. The DMQ item bank achieved acceptable Rasch model fit statistics, good measurement breadth with minimal floor and ceiling effects, and evidence of high internal consistency reliability (α = 0.92 to 0.98). Using CAT simulation analyses, the DMQ-CAT showed high measurement accuracy compared to the total item pool (r = .83 to .97, p < .0001) and evidence of good to excellent concurrent (r = −.61 to −0.80, p < .0001) validity. All DMQ-CAT domains showed evidence for known-groups validity (p ≤ 0.001).
Conclusions
The DMQ-CAT reliably and validly captured four distinct dyspnea domains. Multidimensional dyspnea assessment in COPD is needed to better measure the effectiveness of pharmacologic, pulmonary rehabilitation, and psychosocial interventions in not only alleviating the somatic sensation of dyspnea but also reducing dysfunctional emotions, cognitions, and behaviors associated with dyspnea, especially for anxious patients.
doi:10.1016/j.apmr.2011.05.020
PMCID: PMC3526016  PMID: 21963123
Dyspnea; COPD; Outcomes assessment; Reliability; Validity
23.  Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA 
PLoS ONE  2012;7(9):e44008.
Rationale
Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies.
Objectives
To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations.
Methods
The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10−8) and three variants reported as suggestive (P<5×10−7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever.
Main Results
We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10−9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10−9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10−8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status.
Conclusions
Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
doi:10.1371/journal.pone.0044008
PMCID: PMC3461045  PMID: 23028483
24.  Umbilical cord plasma 25-hydroxyvitamin D concentration and immune function at birth: the Urban Environment and Childhood Asthma (URECA) study 
Background
Recent studies have reported conflicting data on the association between maternal intake of vitamin D during pregnancy and asthma.
Objective
Assess the influence of prenatal vitamin D status on immune function at birth.
Methods
In an inner-city birth cohort of 568 newborns, 520 of whom had at least one atopic parent, we measured umbilical cord (UC) plasma concentration of 25-hydroxy vitamin D (25(OH)D) and the cytokine responses of UC blood mononuclear cells (UCMCs) to stimuli including phytohemaglutinin (PHA), lipopolysaccharide (LPS), and peptidoglycan (PG). In a subset, UCMC expression of regulatory T-cell markers and the suppressive activity of CD4+CD25+ UCMCs was measured.
Results
The 25th, 50th, and 75th percentiles of UC plasma 25(OH)D level were 15.0, 20.2, and 25.6 ng/mL, respectively. Most cytokine responses of UCMC were not correlated with UC 25(OH)D concentration; however, IFN-γ release after LPS stimulation was weakly positively correlated with UC 25(OH)D concentration (r = 0.11, p =0.01). PHA responses were not significantly correlated with 25(OH)D concentration. The UC plasma 25(OH)D concentration was inversely related to the number of CD25+ (r= -0.20, p=0.06), CD25Bright (r= -0.21, p=0.05), and CD25+FoxP3 (r= -0.29, p=0.06) cells as a proportion of CD4+ T cells in UC blood (r = -0.26, p = 0.04) but not to the suppressive activity of CD4+CD25+ cells (r=0.17, p=0.22).
Conclusion and Clinical Relevance
UC 25(OH)D concentration was not correlated with most UCMC cytokine responses to multiple stimuli. There was a suggestion of a weakly positive correlation with IFN-γ release after LPS stimulation. The proportions of CD25+, CD25bright, and CD25+FoxP3 cells to total CD4+ T cells were inversely correlated with UC 25(OH)D concentration. Our findings suggest that higher vitamin D levels at birth may be associated with a lower number of T regulatory cells. Vitamin D status in utero may influence immune regulation in early life.
doi:10.1111/j.1365-2222.2011.03712.x
PMCID: PMC3093441  PMID: 21481021
25.  Genome-wide association and large scale follow-up identifies 16 new loci influencing lung function 
Artigas, María Soler | Loth, Daan W | Wain, Louise V | Gharib, Sina A | Obeidat, Ma’en | Tang, Wenbo | Zhai, Guangju | Zhao, Jing Hua | Smith, Albert Vernon | Huffman, Jennifer E | Albrecht, Eva | Jackson, Catherine M | Evans, David M | Cadby, Gemma | Fornage, Myriam | Manichaikul, Ani | Lopez, Lorna M | Johnson, Toby | Aldrich, Melinda C | Aspelund, Thor | Barroso, Inês | Campbell, Harry | Cassano, Patricia A | Couper, David J | Eiriksdottir, Gudny | Franceschini, Nora | Garcia, Melissa | Gieger, Christian | Gislason, Gauti Kjartan | Grkovic, Ivica | Hammond, Christopher J | Hancock, Dana B | Harris, Tamara B | Ramasamy, Adaikalavan | Heckbert, Susan R | Heliövaara, Markku | Homuth, Georg | Hysi, Pirro G | James, Alan L | Jankovic, Stipan | Joubert, Bonnie R | Karrasch, Stefan | Klopp, Norman | Koch, Beate | Kritchevsky, Stephen B | Launer, Lenore J | Liu, Yongmei | Loehr, Laura R | Lohman, Kurt | Loos, Ruth JF | Lumley, Thomas | Al Balushi, Khalid A | Ang, Wei Q | Barr, R Graham | Beilby, John | Blakey, John D | Boban, Mladen | Boraska, Vesna | Brisman, Jonas | Britton, John R | Brusselle, Guy G | Cooper, Cyrus | Curjuric, Ivan | Dahgam, Santosh | Deary, Ian J | Ebrahim, Shah | Eijgelsheim, Mark | Francks, Clyde | Gaysina, Darya | Granell, Raquel | Gu, Xiangjun | Hankinson, John L | Hardy, Rebecca | Harris, Sarah E | Henderson, John | Henry, Amanda | Hingorani, Aroon D | Hofman, Albert | Holt, Patrick G | Hui, Jennie | Hunter, Michael L | Imboden, Medea | Jameson, Karen A | Kerr, Shona M | Kolcic, Ivana | Kronenberg, Florian | Liu, Jason Z | Marchini, Jonathan | McKeever, Tricia | Morris, Andrew D | Olin, Anna-Carin | Porteous, David J | Postma, Dirkje S | Rich, Stephen S | Ring, Susan M | Rivadeneira, Fernando | Rochat, Thierry | Sayer, Avan Aihie | Sayers, Ian | Sly, Peter D | Smith, George Davey | Sood, Akshay | Starr, John M | Uitterlinden, André G | Vonk, Judith M | Wannamethee, S Goya | Whincup, Peter H | Wijmenga, Cisca | Williams, O Dale | Wong, Andrew | Mangino, Massimo | Marciante, Kristin D | McArdle, Wendy L | Meibohm, Bernd | Morrison, Alanna C | North, Kari E | Omenaas, Ernst | Palmer, Lyle J | Pietiläinen, Kirsi H | Pin, Isabelle | Polašek, Ozren | Pouta, Anneli | Psaty, Bruce M | Hartikainen, Anna-Liisa | Rantanen, Taina | Ripatti, Samuli | Rotter, Jerome I | Rudan, Igor | Rudnicka, Alicja R | Schulz, Holger | Shin, So-Youn | Spector, Tim D | Surakka, Ida | Vitart, Veronique | Völzke, Henry | Wareham, Nicholas J | Warrington, Nicole M | Wichmann, H-Erich | Wild, Sarah H | Wilk, Jemma B | Wjst, Matthias | Wright, Alan F | Zgaga, Lina | Zemunik, Tatijana | Pennell, Craig E | Nyberg, Fredrik | Kuh, Diana | Holloway, John W | Boezen, H Marike | Lawlor, Debbie A | Morris, Richard W | Probst-Hensch, Nicole | Kaprio, Jaakko | Wilson, James F | Hayward, Caroline | Kähönen, Mika | Heinrich, Joachim | Musk, Arthur W | Jarvis, Deborah L | Gläser, Sven | Järvelin, Marjo-Riitta | Stricker, Bruno H Ch | Elliott, Paul | OConnor, George T | Strachan, David P | London, Stephanie J | Hall, Ian P | Gudnason, Vilmundur | Tobin, Martin D
Nature Genetics  2011;43(11):1082-1090.
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.
doi:10.1038/ng.941
PMCID: PMC3267376  PMID: 21946350

Results 1-25 (51)