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author:("gulik, amend")
1.  Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease 
Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility.
Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD.
Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10−8), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated.
Measurements and Main Results: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009–0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001–0.049), although these COPD associations were not replicated in two additional cohorts.
Conclusions: Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility.
Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).
doi:10.1164/rccm.201206-1013OC
PMCID: PMC3622441  PMID: 23144326
biomarker; chronic obstructive pulmonary disease; genome-wide association study
2.  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. | O’Connor, 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
3.  Genome-wide Association Study Identifies BICD1 as a Susceptibility Gene for Emphysema 
Rationale: Chronic obstructive pulmonary disease (COPD), characterized by airflow limitation, is a disorder with high phenotypic and genetic heterogeneity. Pulmonary emphysema is a major but variable component of COPD; familial data suggest that different components of COPD, such as emphysema, may be influenced by specific genetic factors.
Objectives: To identify genetic determinants of emphysema assessed through high-resolution chest computed tomography in individuals with COPD.
Methods: We performed a genome-wide association study (GWAS) of emphysema determined from chest computed tomography scans with a total of 2,380 individuals with COPD in three independent cohorts of white individuals from (1) a cohort from Bergen, Norway, (2) the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and (3) the National Emphysema Treatment Trial (NETT). We tested single-nucleotide polymorphism associations with the presence or absence of emphysema determined by radiologist assessment in two of the three cohorts and a quantitative emphysema trait (percentage of lung voxels less than –950 Hounsfield units) in all three cohorts.
Measurements and Main Results: We identified association of a single-nucleotide polymorphism in BICD1 with the presence or absence of emphysema (P = 5.2 × 10−7 with at least mild emphysema vs. control subjects; P = 4.8 × 10−8 with moderate and more severe emphysema vs. control subjects).
Conclusions: Our study suggests that genetic variants in BICD1 are associated with qualitative emphysema in COPD. Variants in BICD1 are associated with length of telomeres, which suggests that a mechanism linked to accelerated aging may be involved in the pathogenesis of emphysema.
Clinical trial registered with www.clinicaltrials.gov (NCT00292552).
doi:10.1164/rccm.201004-0541OC
PMCID: PMC3040393  PMID: 20709820
emphysema; chronic obstructive pulmonary disease; BICD1; single-nucleotide polymorphism
4.  Multistudy Fine Mapping of Chromosome 2q Identifies XRCC5 as a Chronic Obstructive Pulmonary Disease Susceptibility Gene 
Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.
Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.
Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.
Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 × 10−5 across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5.
Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.
doi:10.1164/rccm.200910-1586OC
PMCID: PMC2937234  PMID: 20463177
emphysema; genetic linkage; metaanalysis; single nucleotide polymorphism

Results 1-4 (4)