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1.  Vitamin D-responsive SGPP2 variants associated with lung cell expression and lung function 
BMC Medical Genetics  2013;14:122.
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.
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).
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.
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.
PMCID: PMC3907038  PMID: 24274704
Vitamin D; Airflow obstruction; FEV1; SGPP2; FEV1/FVC
Free radical biology & medicine  2012;52(9):1577-1583.
Not all cigarette smokers develop chronic obstructive pulmonary disease (COPD), and discovering susceptibility factors is an important research priority. The oxidative burden of smoking may overwhelm antioxidant defenses, and vulnerabilities may exist as a result of sequence variants in genes encoding antioxidant enzymes. This study explored the association between genetic variation in a network of antioxidant enzymes and lung phenotypes. Linear models evaluated single locus marker associations in 2,387 European and African American participants in the Health, Aging, and Body Composition (Health ABC) Study. After correcting for multiple comparisons, 15 statistically significant associations were identified, all of which were for SNP by smoking interactions. The most statistically significant findings were in genes encoding members of the isocitrate dehydrogenase gene family (IDH3A, IDH3B, IDH2). For rs6107100 (IDH3B) the variant genotype was associated with a difference of 6% in the FEV1/FVC ratio in African American current smokers, but the SNP had little or no association with FEV1/FVC in former and never smokers (nominal pinteraction=5 × 10−6). A variant in peroxiredoxin gene (rs9787810, PRDX5) was associated with lower %predicted FEV1 and a lower ratio in European American current smokers, with little or no association in other smoking groups (nominal pinteraction=0.0001 and 0.0003, respectively). The studied genes have not been reported in previous candidate gene association studies, and thus the findings suggest novel mechanisms and targets for future research, and provide evidence for a contribution of sequence variation in genes encoding antioxidant enzymes to susceptibility in smokers.
PMCID: PMC3390784  PMID: 22387199
Antioxidant enzymes; Lung function
3.  Dietary Antioxidants and FEV1 Decline: the Health, Aging and Body Composition Study 
The European Respiratory Journal  2011;39(4):979-984.
Increased antioxidant defenses are hypothesized to decrease age- and smoking-related decline in lung function.
The relation of dietary antioxidants, smoking, and forced expiratory volume in the 1st second of effort (FEV1) was investigated in community-dwelling older adults in the Health, Aging, and Body Composition Study. 1,443 participants completed a food frequency questionnaire, self-reported smoking history, and had measurements of FEV1 at both baseline and after 4 years of follow-up. The association of dietary intake of nutrients and foods with antioxidant properties and rate of FEV1 decline was investigated using hierarchical linear regression models.
In continuing smokers (current smokers at both time points), higher vitamin C and higher intake of fruits and vegetables were associated with an 18 and 24 ml/year slower rate of FEV1 decline compared to lower intake (P<0.0001 and 0.003, respectively). In quitters (current smoker at study baseline, quit during follow-up), higher intake was associated with an attenuated rate of decline for each nutrient studied (p<0.003, all models). In non-smoking participants, there was little or no association of diet and rate of decline in FEV1.
The intake of nutrients with antioxidant properties may modulate lung function decline in older adults exposed to cigarette smoke.
PMCID: PMC3390780  PMID: 22005919
Aging; Dietary Intake; Lung Function Measurements; Oxidants/Antioxidants; Smoking and Health
4.  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 | O’Connor, 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.
PMCID: PMC3267376  PMID: 21946350
5.  Randomised Vitamin E Supplementation and Risk of Chronic Lung Disease in the Women’s Health Study 
Thorax  2011;66(4):320-325.
The oxidant/antioxidant balance in lung tissue is hypothesised to contribute to chronic obstructive pulmonary disease (COPD) risk. Observational studies consistently report higher antioxidant status associated with lower COPD risk, but few randomised studies have been reported.
A post-hoc analysis of 38,597 women without chronic lung disease at baseline was conducted in the Women’s Health Study (WHS) to test the effect of vitamin E on risk of incident chronic lung disease. The WHS was a randomised, double-blind, placebo-controlled, factorial trial of vitamin E (600 IU every other day) and aspirin (100 mg every other day) in female health professionals aged ≥45. Using Cox proportional hazards models, the effect of randomised vitamin E assignment on self-reported, physician-diagnosed chronic lung disease was evaluated.
During 10 years of follow-up (376,710 person-years), 760 first occurrences of chronic lung disease were reported in the vitamin E arm compared to 846 in the placebo arm (Hazard Ratio [HR] 0.90; 95% confidence interval [CI] 0.81–0.99; p=0.029). This 10% reduction in the risk of incident chronic lung disease was not modified by cigarette smoking, age, randomised aspirin assignment, multivitamin use, or dietary vitamin E intake (minimum P for interaction = 0.19). Current cigarette smoking was a strong predictor of chronic lung disease risk (HR 4.17; 95% CI 3.70–4.70; versus never smokers).
In this large, randomised trial, assignment to 600 IU of vitamin E led to a 10% reduction in the risk of chronic lung disease in women.
PMCID: PMC3062677  PMID: 21257986
pulmonary disease; chronic obstructive; antioxidants; tocopherols; intervention studies; randomised controlled trial
6.  Folate network genetic variation, plasma homocysteine, and global genomic methylation content: a genetic association study 
BMC Medical Genetics  2011;12:150.
Sequence variants in genes functioning in folate-mediated one-carbon metabolism are hypothesized to lead to changes in levels of homocysteine and DNA methylation, which, in turn, are associated with risk of cardiovascular disease.
330 SNPs in 52 genes were studied in relation to plasma homocysteine and global genomic DNA methylation. SNPs were selected based on functional effects and gene coverage, and assays were completed on the Illumina Goldengate platform. Age-, smoking-, and nutrient-adjusted genotype--phenotype associations were estimated in regression models.
Using a nominal P ≤ 0.005 threshold for statistical significance, 20 SNPs were associated with plasma homocysteine, 8 with Alu methylation, and 1 with LINE-1 methylation. Using a more stringent false discovery rate threshold, SNPs in FTCD, SLC19A1, and SLC19A3 genes remained associated with plasma homocysteine. Gene by vitamin B-6 interactions were identified for both Alu and LINE-1 methylation, and epistatic interactions with the MTHFR rs1801133 SNP were identified for the plasma homocysteine phenotype. Pleiotropy involving the MTHFD1L and SARDH genes for both plasma homocysteine and Alu methylation phenotypes was identified.
No single gene was associated with all three phenotypes, and the set of the most statistically significant SNPs predictive of homocysteine or Alu or LINE-1 methylation was unique to each phenotype. Genetic variation in folate-mediated one-carbon metabolism, other than the well-known effects of the MTHFR c.665C>T (known as c.677 C>T, rs1801133, p.Ala222Val), is predictive of cardiovascular disease biomarkers.
PMCID: PMC3266217  PMID: 22103680
7.  Cardiac Autonomic Dysfunction: Effects from Particulate Air Pollution and Protection by Dietary Methyl Nutrients and Metabolic Polymorphisms 
Circulation  2008;117(14):1802-1809.
Particulate air pollution is associated with cardiovascular mortality and morbidity. To help identify mechanisms of action and protective/susceptibility factors, we evaluated whether the effect of particulate matter <2.5 µm in aerodynamic diameter (PM2.5) on heart rate variability (HRV) was modified by dietary intakes of methyl nutrients (folate, vitamin B6, B12, methionine) and related gene polymorphisms (C677T MTHFR and C1420T cSHMT).
Methods and Results
HRV and dietary data were obtained between 2000–2005 from 549 elderly men from the Normative Aging Study. In carriers of [CT/TT] MTHFR genotypes, the standard deviation of normal-to-normal intervals (SDNN) was 17.1% (95% CI, 6.5, 26.4; p=0.002) lower than in CC MTHFR subjects. In the same [CT/TT] MTHFR subjects, each 10 µg/m3 increase in PM2.5 in the 48 hours before the examination was associated with a further 8.8% (95%CI: 0.2, 16.7; p=0.047) decrease in SDDN. In [CC] cSHMT carriers, PM2.5 was associated with a 11.8% (95%CI: 1.8, 20.8; p=0.02) decrease in SDDN. No PM2.5-SSDN association was found in subjects with either [CC] MTHFR or [CT/TT] cSHMT genotypes. The negative effects of PM2.5 were abrogated in subjects with higher intakes (>median levels) of B6, B12, or methionine. PM2.5 was negatively associated with HRV in subjects with lower intakes, but no PM2.5 effect was found in the higher intake groups.
Genetic and nutritional variations in the methionine cycle affect HRV, either independently or by modifying the effects of PM2.5.
PMCID: PMC3093965  PMID: 18378616
heart rate; nervous system; autonomic; metabolism; aging; epidemiology
8.  No association between cSHMT genotypes and risk of breast cancer in the Nurses’ Health Study 
Increased breast cancer risk has been observed with both low folate status and a functional polymorphism in methylenetetrahydrofolate reductase (MTHFR 677C→T). Cytoplasmic serine hydroxymethyltransferase (cSHMT) affects the flow of one-carbon units through the folate metabolic network, but there is little research on a role for genetic variation in cSHMT in determining breast cancer risk.
A nested case-control study within the Nurses’ Health Study was used to investigate an association between cSHMT (1420C→T) and breast cancer risk.
No evidence for an association of cSHMT genotype and breast cancer was 10 observed. There was also no evidence of a gene-gene interaction between cSHMT and MTHFR.
There was no evidence of an association between cSHMT genotype and breast cancer occurrence. Further research in populations with differing average folate intake may be needed to fully understand the interactions of folate nutrition, sequence variation in folate genes, and breast cancer risk.
PMCID: PMC3033771  PMID: 19707223
breast cancer; cSHMT; MTHFR; folate
9.  Genetic Variation and Gene Expression in Antioxidant-Related Enzymes and Risk of Chronic Obstructive Pulmonary Disease: A Systematic Review 
Thorax  2008;63(11):956-961.
Observational epidemiologic studies of dietary antioxidant intake, serum antioxidant concentration, and lung outcomes suggest that lower levels of antioxidant defenses are associated with decreased lung function. Another approach to understanding the role of oxidant/antioxidant imbalance in risk of Chronic Obstructive Pulmonary Disease (COPD) is to investigate the role of genetic variation in antioxidant enzymes, and indeed family-based studies suggest a heritable component to lung disease. Many studies of the genes encoding antioxidant enzymes have considered COPD or COPD-related outcomes, and a systematic review is needed to summarise the evidence to date, and to provide insights for further research.
Genetic association studies of antioxidant enzymes and COPD/COPD-related traits, and comparative gene expression studies with disease or smoking as the exposure were systematically identified and reviewed. Antioxidant enzymes considered included enzymes involved in glutathione (GSH) metabolism, in the thioredoxin (TXN) system, superoxide dismutases (SOD), and catalase (CAT).
A total of 29 genetic association and 15 comparative gene expression studies met the inclusion criteria. The strongest and most consistent effects were in the genes GCL, GSTM1, GSTP1, and SOD3. This review also highlights the lack of studies for genes of interest, particularly GSR, GGT, and those related to TXN. There were limited opportunities to evaluate a gene’s contribution to disease risk through a synthesis of results from different study designs, as the majority of studies considered either association of sequence variants with disease or effect of disease on gene expression. Network-driven approaches that consider potential interaction between genes and amoung genes, smoke exposure, and antioxidant intake are needed to fully characterise the role of oxidant/antioxidant balance in pathogenesis.
PMCID: PMC3032799  PMID: 18566111
Chronic Obstructive Pulmonary Disease (COPD); Antioxidants; Oxidative Stress
10.  Disparate oxidant gene expression of airway epithelium compared to alveolar macrophages in smokers 
Respiratory Research  2009;10(1):111.
The small airway epithelium and alveolar macrophages are exposed to oxidants in cigarette smoke leading to epithelial dysfunction and macrophage activation. In this context, we asked: what is the transcriptome of oxidant-related genes in small airway epithelium and alveolar macrophages, and does their response differ substantially to inhaled cigarette smoke?
Using microarray analysis, with TaqMan RT-PCR confirmation, we assessed oxidant-related gene expression in small airway epithelium and alveolar macrophages from the same healthy nonsmoker and smoker individuals.
Of 155 genes surveyed, 87 (56%) were expressed in both cell populations in nonsmokers, with higher expression in alveolar macrophages (43%) compared to airway epithelium (24%). In smokers, there were 15 genes (10%) up-regulated and 7 genes (5%) down-regulated in airway epithelium, but only 3 (2%) up-regulated and 2 (1%) down-regulated in alveolar macrophages. Pathway analysis of airway epithelium showed oxidant pathways dominated, but in alveolar macrophages immune pathways dominated.
Thus, the response of different cell-types with an identical genome exposed to the same stress of smoking is different; responses of alveolar macrophages are more subdued than those of airway epithelium. These findings are consistent with the observation that, while the small airway epithelium is vulnerable, alveolar macrophages are not "diseased" in response to smoking.
Trial Registration ID: NCT00224185 and NCT00224198
PMCID: PMC2787510  PMID: 19919714
11.  A multivariate analysis of serum nutrient levels and lung function 
Respiratory Research  2008;9(1):67.
There is mounting evidence that estimates of intakes of a range of dietary nutrients are related to both lung function level and rate of decline, but far less evidence on the relation between lung function and objective measures of serum levels of individual nutrients. The aim of this study was to conduct a comprehensive examination of the independent associations of a wide range of serum markers of nutritional status with lung function, measured as the one-second forced expiratory volume (FEV1).
Using data from the Third National Health and Nutrition Examination Survey, a US population-based cross-sectional study, we investigated the relation between 21 serum markers of potentially relevant nutrients and FEV1, with adjustment for potential confounding factors. Systematic approaches were used to guide the analysis.
In a mutually adjusted model, higher serum levels of antioxidant vitamins (vitamin A, beta-cryptoxanthin, vitamin C, vitamin E), selenium, normalized calcium, chloride, and iron were independently associated with higher levels of FEV1. Higher concentrations of potassium and sodium were associated with lower FEV1.
Maintaining higher serum concentrations of dietary antioxidant vitamins and selenium is potentially beneficial to lung health. In addition other novel associations found in this study merit further investigation.
PMCID: PMC2565672  PMID: 18823528

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