@article {6096, title = {Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Sep 25}, pages = {1082-90}, abstract = {

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 {\texttimes} 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as 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.

}, keywords = {Child, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Pulmonary Disease, Chronic Obstructive, Respiratory Function Tests}, issn = {1546-1718}, doi = {10.1038/ng.941}, author = {Soler Artigas, Maria and Loth, Daan W and Wain, Louise V and Gharib, Sina A and Obeidat, Ma{\textquoteright}en and Tang, Wenbo and Zhai, Guangju and Zhao, Jing Hua and Smith, Albert Vernon and Huffman, Jennifer E and Albrecht, Eva and Jackson, Catherine M and Evans, David M and Cadby, Gemma and Fornage, Myriam and Manichaikul, Ani and Lopez, Lorna M and Johnson, Toby and Aldrich, Melinda C and Aspelund, Thor and Barroso, In{\^e}s and Campbell, Harry and Cassano, Patricia A and Couper, David J and Eiriksdottir, Gudny and Franceschini, Nora and Garcia, Melissa and Gieger, Christian and Gislason, Gauti Kjartan and Grkovic, Ivica and Hammond, Christopher J and Hancock, Dana B and Harris, Tamara B and Ramasamy, Adaikalavan and Heckbert, Susan R and Heli{\"o}vaara, Markku and Homuth, Georg and Hysi, Pirro G and James, Alan L and Jankovic, Stipan and Joubert, Bonnie R and Karrasch, Stefan and Klopp, Norman and Koch, Beate and Kritchevsky, Stephen B and Launer, Lenore J and Liu, Yongmei and Loehr, Laura R and Lohman, Kurt and Loos, Ruth J F and Lumley, Thomas and Al Balushi, Khalid A and Ang, Wei Q and Barr, R Graham and Beilby, John and Blakey, John D and Boban, Mladen and Boraska, Vesna and Brisman, Jonas and Britton, John R and Brusselle, Guy G and Cooper, Cyrus and Curjuric, Ivan and Dahgam, Santosh and Deary, Ian J and Ebrahim, Shah and Eijgelsheim, Mark and Francks, Clyde and Gaysina, Darya and Granell, Raquel and Gu, Xiangjun and Hankinson, John L and Hardy, Rebecca and Harris, Sarah E and Henderson, John and Henry, Amanda and Hingorani, Aroon D and Hofman, Albert and Holt, Patrick G and Hui, Jennie and Hunter, Michael L and Imboden, Medea and Jameson, Karen A and Kerr, Shona M and Kolcic, Ivana and Kronenberg, Florian and Liu, Jason Z and Marchini, Jonathan and McKeever, Tricia and Morris, Andrew D and Olin, Anna-Carin and Porteous, David J and Postma, Dirkje S and Rich, Stephen S and Ring, Susan M and Rivadeneira, Fernando and Rochat, Thierry and Sayer, Avan Aihie and Sayers, Ian and Sly, Peter D and Smith, George Davey and Sood, Akshay and Starr, John M and Uitterlinden, Andr{\'e} G and Vonk, Judith M and Wannamethee, S Goya and Whincup, Peter H and Wijmenga, Cisca and Williams, O Dale and Wong, Andrew and Mangino, Massimo and Marciante, Kristin D and McArdle, Wendy L and Meibohm, Bernd and Morrison, Alanna C and North, Kari E and Omenaas, Ernst and Palmer, Lyle J and Pietil{\"a}inen, Kirsi H and Pin, Isabelle and Pola Sbreve Ek, Ozren and Pouta, Anneli and Psaty, Bruce M and Hartikainen, Anna-Liisa and Rantanen, Taina and Ripatti, Samuli and Rotter, Jerome I and Rudan, Igor and Rudnicka, Alicja R and Schulz, Holger and Shin, So-Youn and Spector, Tim D and Surakka, Ida and Vitart, Veronique and V{\"o}lzke, Henry and Wareham, Nicholas J and Warrington, Nicole M and Wichmann, H-Erich and Wild, Sarah H and Wilk, Jemma B and Wjst, Matthias and Wright, Alan F and Zgaga, Lina and Zemunik, Tatijana and Pennell, Craig E and Nyberg, Fredrik and Kuh, Diana and Holloway, John W and Boezen, H Marike and Lawlor, Debbie A and Morris, Richard W and Probst-Hensch, Nicole and Kaprio, Jaakko and Wilson, James F and Hayward, Caroline and K{\"a}h{\"o}nen, Mika and Heinrich, Joachim and Musk, Arthur W and Jarvis, Deborah L and Gl{\"a}ser, Sven and Jarvelin, Marjo-Riitta and Ch Stricker, Bruno H and Elliott, Paul and O{\textquoteright}Connor, George T and Strachan, David P and London, Stephanie J and Hall, Ian P and Gudnason, Vilmundur and Tobin, Martin D} } @article {6092, title = {Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.}, journal = {Am J Respir Crit Care Med}, volume = {186}, year = {2012}, month = {2012 Oct 01}, pages = {622-32}, abstract = {

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 FEV(1) and its ratio to FVC (FEV(1)/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 FEV(1)/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.

}, keywords = {Aged, Female, Forced Expiratory Volume, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Receptors, Nicotinic, Receptors, Serotonin, 5-HT4, Smoking, Vital Capacity}, issn = {1535-4970}, doi = {10.1164/rccm.201202-0366OC}, author = {Wilk, Jemma B and Shrine, Nick R G and Loehr, Laura R and Zhao, Jing Hua and Manichaikul, Ani and Lopez, Lorna M and Smith, Albert Vernon and Heckbert, Susan R and Smolonska, Joanna and Tang, Wenbo and Loth, Daan W and Curjuric, Ivan and Hui, Jennie and Cho, Michael H and Latourelle, Jeanne C and Henry, Amanda P and Aldrich, Melinda and Bakke, Per and Beaty, Terri H and Bentley, Amy R and Borecki, Ingrid B and Brusselle, Guy G and Burkart, Kristin M and Chen, Ting-Hsu and Couper, David and Crapo, James D and Davies, Gail and Dupuis, Jos{\'e}e and Franceschini, Nora and Gulsvik, Amund and Hancock, Dana B and Harris, Tamara B and Hofman, Albert and Imboden, Medea and James, Alan L and Khaw, Kay-Tee and Lahousse, Lies and Launer, Lenore J and Litonjua, Augusto and Liu, Yongmei and Lohman, Kurt K and Lomas, David A and Lumley, Thomas and Marciante, Kristin D and McArdle, Wendy L and Meibohm, Bernd and Morrison, Alanna C and Musk, Arthur W and Myers, Richard H and North, Kari E and Postma, Dirkje S and Psaty, Bruce M and Rich, Stephen S and Rivadeneira, Fernando and Rochat, Thierry and Rotter, Jerome I and Soler Artigas, Maria and Starr, John M and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Wijmenga, Cisca and Zanen, Pieter and Province, Michael A and Silverman, Edwin K and Deary, Ian J and Palmer, Lyle J and Cassano, Patricia A and Gudnason, Vilmundur and Barr, R Graham and Loos, Ruth J F and Strachan, David P and London, Stephanie J and Boezen, H Marike and Probst-Hensch, Nicole and Gharib, Sina A and Hall, Ian P and O{\textquoteright}Connor, George T and Tobin, Martin D and Stricker, Bruno H} } @article {6088, title = {Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1003098}, abstract = {

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/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 FEV(1) and FEV(1)/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 P(JMA = )5.00{\texttimes}10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35{\texttimes}10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28{\texttimes}10(-8)) were associated with FEV(1)/FVC or FEV(1) 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.

}, keywords = {Forced Expiratory Volume, Gene Expression, Genome, Human, Genome-Wide Association Study, HLA-DQ Antigens, HLA-DQ beta-Chains, Humans, Lung, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, Inwardly Rectifying, Pulmonary Disease, Chronic Obstructive, Receptors, Cell Surface, Smoking, SOX9 Transcription Factor, Vital Capacity}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003098}, author = {Hancock, Dana B and Soler Artigas, Maria and Gharib, Sina A and Henry, Amanda and Manichaikul, Ani and Ramasamy, Adaikalavan and Loth, Daan W and Imboden, Medea and Koch, Beate and McArdle, Wendy L and Smith, Albert V and Smolonska, Joanna and Sood, Akshay and Tang, Wenbo and Wilk, Jemma B and Zhai, Guangju and Zhao, Jing Hua and Aschard, Hugues and Burkart, Kristin M and Curjuric, Ivan and Eijgelsheim, Mark and Elliott, Paul and Gu, Xiangjun and Harris, Tamara B and Janson, Christer and Homuth, Georg and Hysi, Pirro G and Liu, Jason Z and Loehr, Laura R and Lohman, Kurt and Loos, Ruth J F and Manning, Alisa K and Marciante, Kristin D and Obeidat, Ma{\textquoteright}en and Postma, Dirkje S and Aldrich, Melinda C and Brusselle, Guy G and Chen, Ting-Hsu and Eiriksdottir, Gudny and Franceschini, Nora and Heinrich, Joachim and Rotter, Jerome I and Wijmenga, Cisca and Williams, O Dale and Bentley, Amy R and Hofman, Albert and Laurie, Cathy C and Lumley, Thomas and Morrison, Alanna C and Joubert, Bonnie R and Rivadeneira, Fernando and Couper, David J and Kritchevsky, Stephen B and Liu, Yongmei and Wjst, Matthias and Wain, Louise V and Vonk, Judith M and Uitterlinden, Andr{\'e} G and Rochat, Thierry and Rich, Stephen S and Psaty, Bruce M and O{\textquoteright}Connor, George T and North, Kari E and Mirel, Daniel B and Meibohm, Bernd and Launer, Lenore J and Khaw, Kay-Tee and Hartikainen, Anna-Liisa and Hammond, Christopher J and Gl{\"a}ser, Sven and Marchini, Jonathan and Kraft, Peter and Wareham, Nicholas J and V{\"o}lzke, Henry and Stricker, Bruno H C and Spector, Timothy D and Probst-Hensch, Nicole M and Jarvis, Deborah and Jarvelin, Marjo-Riitta and Heckbert, Susan R and Gudnason, Vilmundur and Boezen, H Marike and Barr, R Graham and Cassano, Patricia A and Strachan, David P and Fornage, Myriam and Hall, Ian P and Dupuis, Jos{\'e}e and Tobin, Martin D and London, Stephanie J} } @article {6582, title = {Genome-wide association analysis identifies six new loci associated with forced vital capacity.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Jul}, pages = {669-77}, abstract = {

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 {\texttimes} 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from 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 the pathogenesis of restrictive lung disease.

}, keywords = {Cohort Studies, Databases, Genetic, Follow-Up Studies, Forced Expiratory Volume, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Lung Diseases, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, Respiratory Function Tests, Spirometry, Vital Capacity}, issn = {1546-1718}, doi = {10.1038/ng.3011}, author = {Loth, Daan W and Soler Artigas, Maria and Gharib, Sina A and Wain, Louise V and Franceschini, Nora and Koch, Beate and Pottinger, Tess D and Smith, Albert Vernon and Duan, Qing and Oldmeadow, Chris and Lee, Mi Kyeong and Strachan, David P and James, Alan L and Huffman, Jennifer E and Vitart, Veronique and Ramasamy, Adaikalavan and Wareham, Nicholas J and Kaprio, Jaakko and Wang, Xin-Qun and Trochet, Holly and K{\"a}h{\"o}nen, Mika and Flexeder, Claudia and Albrecht, Eva and Lopez, Lorna M and de Jong, Kim and Thyagarajan, Bharat and Alves, Alexessander Couto and Enroth, Stefan and Omenaas, Ernst and Joshi, Peter K and Fall, Tove and Vi{\~n}uela, Ana and Launer, Lenore J and Loehr, Laura R and Fornage, Myriam and Li, Guo and Wilk, Jemma B and Tang, Wenbo and Manichaikul, Ani and Lahousse, Lies and Harris, Tamara B and North, Kari E and Rudnicka, Alicja R and Hui, Jennie and Gu, Xiangjun and Lumley, Thomas and Wright, Alan F and Hastie, Nicholas D and Campbell, Susan and Kumar, Rajesh and Pin, Isabelle and Scott, Robert A and Pietil{\"a}inen, Kirsi H and Surakka, Ida and Liu, Yongmei and Holliday, Elizabeth G and Schulz, Holger and Heinrich, Joachim and Davies, Gail and Vonk, Judith M and Wojczynski, Mary and Pouta, Anneli and Johansson, Asa and Wild, Sarah H and Ingelsson, Erik and Rivadeneira, Fernando and V{\"o}lzke, Henry and Hysi, Pirro G and Eiriksdottir, Gudny and Morrison, Alanna C and Rotter, Jerome I and Gao, Wei and Postma, Dirkje S and White, Wendy B and Rich, Stephen S and Hofman, Albert and Aspelund, Thor and Couper, David and Smith, Lewis J and Psaty, Bruce M and Lohman, Kurt and Burchard, Esteban G and Uitterlinden, Andr{\'e} G and Garcia, Melissa and Joubert, Bonnie R and McArdle, Wendy L and Musk, A Bill and Hansel, Nadia and Heckbert, Susan R and Zgaga, Lina and van Meurs, Joyce B J and Navarro, Pau and Rudan, Igor and Oh, Yeon-Mok and Redline, Susan and Jarvis, Deborah L and Zhao, Jing Hua and Rantanen, Taina and O{\textquoteright}Connor, George T and Ripatti, Samuli and Scott, Rodney J and Karrasch, Stefan and Grallert, Harald and Gaddis, Nathan C and Starr, John M and Wijmenga, Cisca and Minster, Ryan L and Lederer, David J and Pekkanen, Juha and Gyllensten, Ulf and Campbell, Harry and Morris, Andrew P and Gl{\"a}ser, Sven and Hammond, Christopher J and Burkart, Kristin M and Beilby, John and Kritchevsky, Stephen B and Gudnason, Vilmundur and Hancock, Dana B and Williams, O Dale and Polasek, Ozren and Zemunik, Tatijana and Kolcic, Ivana and Petrini, Marcy F and Wjst, Matthias and Kim, Woo Jin and Porteous, David J and Scotland, Generation and Smith, Blair H and Viljanen, Anne and Heli{\"o}vaara, Markku and Attia, John R and Sayers, Ian and Hampel, Regina and Gieger, Christian and Deary, Ian J and Boezen, H Marike and Newman, Anne and Jarvelin, Marjo-Riitta and Wilson, James F and Lind, Lars and Stricker, Bruno H and Teumer, Alexander and Spector, Timothy D and Mel{\'e}n, Erik and Peters, Marjolein J and Lange, Leslie A and Barr, R Graham and Bracke, Ken R and Verhamme, Fien M and Sung, Joohon and Hiemstra, Pieter S and Cassano, Patricia A and Sood, Akshay and Hayward, Caroline and Dupuis, Jos{\'e}e and Hall, Ian P and Brusselle, Guy G and Tobin, Martin D and London, Stephanie J} } @article {6604, title = {Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e100776}, abstract = {

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 {\texttimes} 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 {\texttimes} 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.

}, keywords = {Adult, Chromosomes, Human, Pair 11, Female, Gene Expression Regulation, Genetic Loci, Genome-Wide Association Study, Humans, Longitudinal Studies, Male, Respiration}, issn = {1932-6203}, doi = {10.1371/journal.pone.0100776}, author = {Tang, Wenbo and Kowgier, Matthew and Loth, Daan W and Soler Artigas, Maria and Joubert, Bonnie R and Hodge, Emily and Gharib, Sina A and Smith, Albert V and Ruczinski, Ingo and Gudnason, Vilmundur and Mathias, Rasika A and Harris, Tamara B and Hansel, Nadia N and Launer, Lenore J and Barnes, Kathleen C and Hansen, Joyanna G and Albrecht, Eva and Aldrich, Melinda C and Allerhand, Michael and Barr, R Graham and Brusselle, Guy G and Couper, David J and Curjuric, Ivan and Davies, Gail and Deary, Ian J and Dupuis, Jos{\'e}e and Fall, Tove and Foy, Millennia and Franceschini, Nora and Gao, Wei and Gl{\"a}ser, Sven and Gu, Xiangjun and Hancock, Dana B and Heinrich, Joachim and Hofman, Albert and Imboden, Medea and Ingelsson, Erik and James, Alan and Karrasch, Stefan and Koch, Beate and Kritchevsky, Stephen B and Kumar, Ashish and Lahousse, Lies and Li, Guo and Lind, Lars and Lindgren, Cecilia and Liu, Yongmei and Lohman, Kurt and Lumley, Thomas and McArdle, Wendy L and Meibohm, Bernd and Morris, Andrew P and Morrison, Alanna C and Musk, Bill and North, Kari E and Palmer, Lyle J and Probst-Hensch, Nicole M and Psaty, Bruce M and Rivadeneira, Fernando and Rotter, Jerome I and Schulz, Holger and Smith, Lewis J and Sood, Akshay and Starr, John M and Strachan, David P and Teumer, Alexander and Uitterlinden, Andr{\'e} G and V{\"o}lzke, Henry and Voorman, Arend and Wain, Louise V and Wells, Martin T and Wilk, Jemma B and Williams, O Dale and Heckbert, Susan R and Stricker, Bruno H and London, Stephanie J and Fornage, Myriam and Tobin, Martin D and O{\textquoteright}Connor, George T and Hall, Ian P and Cassano, Patricia A} } @article {6851, title = {Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study.}, journal = {Respir Res}, volume = {16}, year = {2015}, month = {2015}, pages = {81}, abstract = {

BACKGROUND: Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.

METHODS: We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.

RESULTS: We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P=0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P=0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P<0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P=0.09).

CONCLUSIONS: Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.

}, keywords = {Adult, Aged, Cohort Studies, Cross-Sectional Studies, DNA-Binding Proteins, Female, Genetic Variation, Humans, Longitudinal Studies, Male, Massachusetts, Metabolic Networks and Pathways, Middle Aged, Nuclear Proteins, Polymorphism, Single Nucleotide, Vitamin D}, issn = {1465-993X}, doi = {10.1186/s12931-015-0238-y}, author = {Hansen, J G and Gao, W and Dupuis, J and O{\textquoteright}Connor, G T and Tang, W and Kowgier, M and Sood, A and Gharib, S A and Palmer, L J and Fornage, M and Heckbert, S R and Psaty, B M and Booth, S L and Cassano, Patricia A} } @article {6860, title = {Integrative pathway genomics of lung function and airflow obstruction.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Dec 1}, pages = {6836-48}, abstract = {

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10{\textquoteright}s role in influencing lung{\textquoteright}s susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.

}, keywords = {Airway Obstruction, Animals, Cell Proliferation, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Immune System, Lung, Male, Metabolic Networks and Pathways, Mice, Phenotype, Polymorphism, Single Nucleotide, Signal Transduction}, issn = {1460-2083}, doi = {10.1093/hmg/ddv378}, author = {Gharib, Sina A and Loth, Daan W and Soler Artigas, Maria and Birkland, Timothy P and Wilk, Jemma B and Wain, Louise V and Brody, Jennifer A and Obeidat, Ma{\textquoteright}en and Hancock, Dana B and Tang, Wenbo and Rawal, Rajesh and Boezen, H Marike and Imboden, Medea and Huffman, Jennifer E and Lahousse, Lies and Alves, Alexessander C and Manichaikul, Ani and Hui, Jennie and Morrison, Alanna C and Ramasamy, Adaikalavan and Smith, Albert Vernon and Gudnason, Vilmundur and Surakka, Ida and Vitart, Veronique and Evans, David M and Strachan, David P and Deary, Ian J and Hofman, Albert and Gl{\"a}ser, Sven and Wilson, James F and North, Kari E and Zhao, Jing Hua and Heckbert, Susan R and Jarvis, Deborah L and Probst-Hensch, Nicole and Schulz, Holger and Barr, R Graham and Jarvelin, Marjo-Riitta and O{\textquoteright}Connor, George T and K{\"a}h{\"o}nen, Mika and Cassano, Patricia A and Hysi, Pirro G and Dupuis, Jos{\'e}e and Hayward, Caroline and Psaty, Bruce M and Hall, Ian P and Parks, William C and Tobin, Martin D and London, Stephanie J} } @article {8042, title = {Harmonization of Respiratory Data From 9 US Population-Based Cohorts: The NHLBI Pooled Cohorts Study.}, journal = {Am J Epidemiol}, volume = {187}, year = {2018}, month = {2018 Nov 01}, pages = {2265-2278}, abstract = {

Chronic lower respiratory diseases (CLRDs) are the fourth leading cause of death in the United States. To support investigations into CLRD risk determinants and new approaches to primary prevention, we aimed to harmonize and pool respiratory data from US general population-based cohorts. Data were obtained from prospective cohorts that performed prebronchodilator spirometry and were harmonized following 2005 ATS/ERS standards. In cohorts conducting follow-up for noncardiovascular events, CLRD events were defined as hospitalizations/deaths adjudicated as CLRD-related or assigned relevant administrative codes. Coding and variable names were applied uniformly. The pooled sample included 65,251 adults in 9 cohorts followed-up for CLRD-related mortality over 653,380 person-years during 1983-2016. Average baseline age was 52 years; 56\% were female; 49\% were never-smokers; and racial/ethnic composition was 44\% white, 22\% black, 28\% Hispanic/Latino, and 5\% American Indian. Over 96\% had complete data on smoking, clinical CLRD diagnoses, and dyspnea. After excluding invalid spirometry examinations (13\%), there were 105,696 valid examinations (median, 2 per participant). Of 29,351 participants followed for CLRD hospitalizations, median follow-up was 14 years; only 5\% were lost to follow-up at 10 years. The NHLBI Pooled Cohorts Study provides a harmonization standard applied to a large, US population-based sample that may be used to advance epidemiologic research on CLRD.

}, issn = {1476-6256}, doi = {10.1093/aje/kwy139}, author = {Oelsner, Elizabeth C and Balte, Pallavi P and Cassano, Patricia A and Couper, David and Enright, Paul L and Folsom, Aaron R and Hankinson, John and Jacobs, David R and Kalhan, Ravi and Kaplan, Robert and Kronmal, Richard and Lange, Leslie and Loehr, Laura R and London, Stephanie J and Navas Acien, Ana and Newman, Anne B and O{\textquoteright}Connor, George T and Schwartz, Joseph E and Smith, Lewis J and Yeh, Fawn and Zhang, Yiyi and Moran, Andrew E and Mwasongwe, Stanford and White, Wendy B and Yende, Sachin and Barr, R Graham} } @article {7775, title = {Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function.}, journal = {Br J Nutr}, year = {2018}, month = {2018 Sep 12}, pages = {1-12}, abstract = {

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1{\textperiodcentered}1 ml in EA (95 \% CI 0{\textperiodcentered}9, 1{\textperiodcentered}3; P<0{\textperiodcentered}0001) and 1{\textperiodcentered}8 ml (95 \% CI 1{\textperiodcentered}1, 2{\textperiodcentered}5; P<0{\textperiodcentered}0001) in AA (P race difference=0{\textperiodcentered}06), and forced vital capacity (FVC) was higher by 1{\textperiodcentered}3 ml in EA (95 \% CI 1{\textperiodcentered}0, 1{\textperiodcentered}6; P<0{\textperiodcentered}0001) and 1{\textperiodcentered}5 ml (95 \% CI 0{\textperiodcentered}8, 2{\textperiodcentered}3; P=0{\textperiodcentered}0001) in AA (P race difference=0{\textperiodcentered}56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1{\textperiodcentered}7 ml (95 \% CI 1{\textperiodcentered}1, 2{\textperiodcentered}3) for current smokers and 1{\textperiodcentered}7 ml (95 \% CI 1{\textperiodcentered}2, 2{\textperiodcentered}1) for former smokers, compared with 0{\textperiodcentered}8 ml (95 \% CI 0{\textperiodcentered}4, 1{\textperiodcentered}2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

}, issn = {1475-2662}, doi = {10.1017/S0007114518002180}, author = {Xu, Jiayi and Bartz, Traci M and Chittoor, Geetha and Eiriksdottir, Gudny and Manichaikul, Ani W and Sun, Fangui and Terzikhan, Natalie and Zhou, Xia and Booth, Sarah L and Brusselle, Guy G and de Boer, Ian H and Fornage, Myriam and Frazier-Wood, Alexis C and Graff, Mariaelisa and Gudnason, Vilmundur and Harris, Tamara B and Hofman, Albert and Hou, Ruixue and Houston, Denise K and Jacobs, David R and Kritchevsky, Stephen B and Latourelle, Jeanne and Lemaitre, Rozenn N and Lutsey, Pamela L and O{\textquoteright}Connor, George and Oelsner, Elizabeth C and Pankow, James S and Psaty, Bruce M and Rohde, Rebecca R and Rich, Stephen S and Rotter, Jerome I and Smith, Lewis J and Stricker, Bruno H and Voruganti, V Saroja and Wang, Thomas J and Zillikens, M Carola and Barr, R Graham and Dupuis, Jos{\'e}e and Gharib, Sina A and Lahousse, Lies and London, Stephanie J and North, Kari E and Smith, Albert V and Steffen, Lyn M and Hancock, Dana B and Cassano, Patricia A} } @article {7795, title = {Meta-analysis of exome array data identifies six novel genetic loci for lung function.}, journal = {Wellcome Open Res}, volume = {3}, year = {2018}, month = {2018}, pages = {4}, abstract = {

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2{\textperiodcentered}8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

}, issn = {2398-502X}, doi = {10.12688/wellcomeopenres.12583.3}, author = {Jackson, Victoria E and Latourelle, Jeanne C and Wain, Louise V and Smith, Albert V and Grove, Megan L and Bartz, Traci M and Obeidat, Ma{\textquoteright}en and Province, Michael A and Gao, Wei and Qaiser, Beenish and Porteous, David J and Cassano, Patricia A and Ahluwalia, Tarunveer S and Grarup, Niels and Li, Jin and Altmaier, Elisabeth and Marten, Jonathan and Harris, Sarah E and Manichaikul, Ani and Pottinger, Tess D and Li-Gao, Ruifang and Lind-Thomsen, Allan and Mahajan, Anubha and Lahousse, Lies and Imboden, Medea and Teumer, Alexander and Prins, Bram and Lyytik{\"a}inen, Leo-Pekka and Eiriksdottir, Gudny and Franceschini, Nora and Sitlani, Colleen M and Brody, Jennifer A and Boss{\'e}, Yohan and Timens, Wim and Kraja, Aldi and Loukola, Anu and Tang, Wenbo and Liu, Yongmei and Bork-Jensen, Jette and Justesen, Johanne M and Linneberg, Allan and Lange, Leslie A and Rawal, Rajesh and Karrasch, Stefan and Huffman, Jennifer E and Smith, Blair H and Davies, Gail and Burkart, Kristin M and Mychaleckyj, Josyf C and Bonten, Tobias N and Enroth, Stefan and Lind, Lars and Brusselle, Guy G and Kumar, Ashish and Stubbe, Beate and K{\"a}h{\"o}nen, Mika and Wyss, Annah B and Psaty, Bruce M and Heckbert, Susan R and Hao, Ke and Rantanen, Taina and Kritchevsky, Stephen B and Lohman, Kurt and Skaaby, Tea and Pisinger, Charlotta and Hansen, Torben and Schulz, Holger and Polasek, Ozren and Campbell, Archie and Starr, John M and Rich, Stephen S and Mook-Kanamori, Dennis O and Johansson, Asa and Ingelsson, Erik and Uitterlinden, Andr{\'e} G and Weiss, Stefan and Raitakari, Olli T and Gudnason, Vilmundur and North, Kari E and Gharib, Sina A and Sin, Don D and Taylor, Kent D and O{\textquoteright}Connor, George T and Kaprio, Jaakko and Harris, Tamara B and Pederson, Oluf and Vestergaard, Henrik and Wilson, James G and Strauch, Konstantin and Hayward, Caroline and Kerr, Shona and Deary, Ian J and Barr, R Graham and de Mutsert, Ren{\'e}e and Gyllensten, Ulf and Morris, Andrew P and Ikram, M Arfan and Probst-Hensch, Nicole and Gl{\"a}ser, Sven and Zeggini, Eleftheria and Lehtim{\"a}ki, Terho and Strachan, David P and Dupuis, Jos{\'e}e and Morrison, Alanna C and Hall, Ian P and Tobin, Martin D and London, Stephanie J} } @article {7819, title = {Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Jul 30}, pages = {2976}, abstract = {

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-05369-0}, author = {Wyss, Annah B and Sofer, Tamar and Lee, Mi Kyeong and Terzikhan, Natalie and Nguyen, Jennifer N and Lahousse, Lies and Latourelle, Jeanne C and Smith, Albert Vernon and Bartz, Traci M and Feitosa, Mary F and Gao, Wei and Ahluwalia, Tarunveer S and Tang, Wenbo and Oldmeadow, Christopher and Duan, Qing and de Jong, Kim and Wojczynski, Mary K and Wang, Xin-Qun and Noordam, Raymond and Hartwig, Fernando Pires and Jackson, Victoria E and Wang, Tianyuan and Obeidat, Ma{\textquoteright}en and Hobbs, Brian D and Huan, Tianxiao and Gui, Hongsheng and Parker, Margaret M and Hu, Donglei and Mogil, Lauren S and Kichaev, Gleb and Jin, Jianping and Graff, Mariaelisa and Harris, Tamara B and Kalhan, Ravi and Heckbert, Susan R and Paternoster, Lavinia and Burkart, Kristin M and Liu, Yongmei and Holliday, Elizabeth G and Wilson, James G and Vonk, Judith M and Sanders, Jason L and Barr, R Graham and de Mutsert, Ren{\'e}e and Menezes, Ana Maria Baptista and Adams, Hieab H H and van den Berge, Maarten and Joehanes, Roby and Levin, Albert M and Liberto, Jennifer and Launer, Lenore J and Morrison, Alanna C and Sitlani, Colleen M and Celed{\'o}n, Juan C and Kritchevsky, Stephen B and Scott, Rodney J and Christensen, Kaare and Rotter, Jerome I and Bonten, Tobias N and Wehrmeister, Fernando C{\'e}sar and Boss{\'e}, Yohan and Xiao, Shujie and Oh, Sam and Franceschini, Nora and Brody, Jennifer A and Kaplan, Robert C and Lohman, Kurt and McEvoy, Mark and Province, Michael A and Rosendaal, Frits R and Taylor, Kent D and Nickle, David C and Williams, L Keoki and Burchard, Esteban G and Wheeler, Heather E and Sin, Don D and Gudnason, Vilmundur and North, Kari E and Fornage, Myriam and Psaty, Bruce M and Myers, Richard H and O{\textquoteright}Connor, George and Hansen, Torben and Laurie, Cathy C and Cassano, Patricia A and Sung, Joohon and Kim, Woo Jin and Attia, John R and Lange, Leslie and Boezen, H Marike and Thyagarajan, Bharat and Rich, Stephen S and Mook-Kanamori, Dennis O and Horta, Bernardo Lessa and Uitterlinden, Andr{\'e} G and Im, Hae Kyung and Cho, Michael H and Brusselle, Guy G and Gharib, Sina A and Dupuis, Jos{\'e}e and Manichaikul, Ani and London, Stephanie J} } @article {7776, title = {Omega-3 Fatty Acids and Genome-wide Interaction Analyses Reveal DPP10-Pulmonary Function Association.}, journal = {Am J Respir Crit Care Med}, year = {2018}, month = {2018 Sep 10}, abstract = {

RATIONALE: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.

OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.

METHODS: Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV], forced vital capacity [FVC], and [FEV/FVC]) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs.

RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P<0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P=9.4{\texttimes}10 across discovery and replication cohorts). The rs11693320-A allele (frequency~80\%) was associated with lower FVC (P=2.1{\texttimes}10; β= -161.0mL), and the association was attenuated by higher DHA levels (P=2.1{\texttimes}10; β=36.2mL).

CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.

}, issn = {1535-4970}, doi = {10.1164/rccm.201802-0304OC}, author = {Xu, Jiayi and Gaddis, Nathan C and Bartz, Traci M and Hou, Ruixue and Manichaikul, Ani W and Pankratz, Nathan and Smith, Albert V and Sun, Fangui and Terzikhan, Natalie and Markunas, Christina A and Patchen, Bonnie K and Schu, Matthew and Beydoun, May A and Brusselle, Guy G and Eiriksdottir, Gudny and Zhou, Xia and Wood, Alexis C and Graff, Mariaelisa and Harris, Tamara B and Ikram, M Arfan and Jacobs, David R and Launer, Lenore J and Lemaitre, Rozenn N and O{\textquoteright}Connor, George and Oelsner, Elizabeth C and Psaty, Bruce M and Ramachandran, Vasan S and Rohde, Rebecca R and Rich, Stephen S and Rotter, Jerome I and Seshadri, Sudha and Smith, Lewis J and Tiemeier, Henning and Tsai, Michael Y and Uitterlinden, Andr{\'e} G and Voruganti, V Saroja and Xu, Hanfei and Zilh{\~a}o, Nuno R and Fornage, Myriam and Zillikens, M Carola and London, Stephanie J and Barr, R Graham and Dupuis, Jos{\'e}e and Gharib, Sina A and Gudnason, Vilmundur and Lahousse, Lies and North, Kari E and Steffen, Lyn M and Cassano, Patricia A and Hancock, Dana B} } @article {7980, title = {Albuminuria, Lung Function Decline, and Risk of Incident Chronic Obstructive Pulmonary Disease. The NHLBI Pooled Cohorts Study.}, journal = {Am J Respir Crit Care Med}, volume = {199}, year = {2019}, month = {2019 Feb 01}, pages = {321-332}, abstract = {

RATIONALE: Chronic lower respiratory diseases (CLRDs), including chronic obstructive pulmonary disease (COPD) and asthma, are the fourth leading cause of death. Prior studies suggest that albuminuria, a biomarker of endothelial injury, is increased in patients with COPD.

OBJECTIVES: To test whether albuminuria was associated with lung function decline and incident CLRDs.

METHODS: Six U.S. population-based cohorts were harmonized and pooled. Participants with prevalent clinical lung disease were excluded. Albuminuria (urine albumin-to-creatinine ratio) was measured in spot samples. Lung function was assessed by spirometry. Incident CLRD-related hospitalizations and deaths were classified via adjudication and/or administrative criteria. Mixed and proportional hazards models were used to test individual-level associations adjusted for age, height, weight, sex, race/ethnicity, education, birth year, cohort, smoking status, pack-years of smoking, renal function, hypertension, diabetes, and medications.

MEASUREMENTS AND MAIN RESULTS: Among 10,961 participants with preserved lung function, mean age at albuminuria measurement was 60 years, 51\% were never-smokers, median albuminuria was 5.6 mg/g, and mean FEV decline was 31.5 ml/yr. For each SD increase in log-transformed albuminuria, there was 2.81\% greater FEV decline (95\% confidence interval [CI], 0.86-4.76\%; P = 0.0047), 11.02\% greater FEV/FVC decline (95\% CI, 4.43-17.62\%; P = 0.0011), and 15\% increased hazard of incident spirometry-defined moderate-to-severe COPD (95\% CI, 2-31\%, P = 0.0021). Each SD log-transformed albuminuria increased hazards of incident COPD-related hospitalization/mortality by 26\% (95\% CI, 18-34\%, P < 0.0001) among 14,213 participants followed for events. Asthma events were not significantly associated. Associations persisted in participants without current smoking, diabetes, hypertension, or cardiovascular disease.

CONCLUSIONS: Albuminuria was associated with greater lung function decline, incident spirometry-defined COPD, and incident COPD-related events in a U.S. population-based sample.

}, issn = {1535-4970}, doi = {10.1164/rccm.201803-0402OC}, author = {Oelsner, Elizabeth C and Balte, Pallavi P and Grams, Morgan E and Cassano, Patricia A and Jacobs, David R and Barr, R Graham and Burkart, Kristin M and Kalhan, Ravi and Kronmal, Richard and Loehr, Laura R and O{\textquoteright}Connor, George T and Schwartz, Joseph E and Shlipak, Michael and Tracy, Russell P and Tsai, Michael Y and White, Wendy and Yende, Sachin} } @article {8097, title = {Discriminative Accuracy of FEV1:FVC Thresholds for COPD-Related Hospitalization and Mortality.}, journal = {JAMA}, volume = {321}, year = {2019}, month = {2019 06 25}, pages = {2438-2447}, abstract = {

Importance: According to numerous current guidelines, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of the forced expiratory volume in the first second to the forced vital capacity (FEV1:FVC) of less than 0.70, yet this fixed threshold is based on expert opinion and remains controversial.

Objective: To determine the discriminative accuracy of various FEV1:FVC fixed thresholds for predicting COPD-related hospitalization and mortality.

Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 4 US general population-based cohorts (Atherosclerosis Risk in Communities Study; Cardiovascular Health Study; Health, Aging, and Body Composition Study; and Multi-Ethnic Study of Atherosclerosis). Participants aged 45 to 102 years were enrolled from 1987 to 2000 and received follow-up longitudinally through 2016.

Exposures: Presence of airflow obstruction, which was defined by a baseline FEV1:FVC less than a range of fixed thresholds (0.75 to 0.65) or less than the lower limit of normal as defined by Global Lung Initiative reference equations (LLN).

Main Outcomes and Measures: The primary outcome was a composite of COPD hospitalization and COPD-related mortality, defined by adjudication or administrative criteria. The optimal fixed FEV1:FVC threshold was defined by the best discrimination for these COPD-related events as indexed using the Harrell C statistic from unadjusted Cox proportional hazards models. Differences in C statistics were compared with respect to less than 0.70 and less than LLN thresholds using a nonparametric approach.

Results: Among 24 207 adults in the pooled cohort (mean [SD] age at enrollment, 63 [10.5] years; 12 990 [54\%] women; 16 794 [69\%] non-Hispanic white; 15 181 [63\%] ever smokers), complete follow-up was available for 11 077 (77\%) at 15 years. During a median follow-up of 15 years, 3925 participants experienced COPD-related events over 340 757 person-years of follow-up (incidence density rate, 11.5 per 1000 person-years), including 3563 COPD-related hospitalizations and 447 COPD-related deaths. With respect to discrimination of COPD-related events, the optimal fixed threshold (0.71; C statistic for optimal fixed threshold, 0.696) was not significantly different from the 0.70 threshold (difference, 0.001 [95\% CI, -0.002 to 0.004]) but was more accurate than the LLN threshold (difference, 0.034 [95\% CI, 0.028 to 0.041]). The 0.70 threshold provided optimal discrimination in the subgroup analysis of ever smokers and in adjusted models.

Conclusions and Relevance: Defining airflow obstruction as FEV1:FVC less than 0.70 provided discrimination of COPD-related hospitalization and mortality that was not significantly different or was more accurate than other fixed thresholds and the LLN. These results support the use of FEV1:FVC less than 0.70 to identify individuals at risk of clinically significant COPD.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Female, Forced Expiratory Volume, Hospitalization, Humans, Male, Middle Aged, Prognosis, Proportional Hazards Models, Pulmonary Disease, Chronic Obstructive, Risk Assessment, Vital Capacity}, issn = {1538-3598}, doi = {10.1001/jama.2019.7233}, author = {Bhatt, Surya P and Balte, Pallavi P and Schwartz, Joseph E and Cassano, Patricia A and Couper, David and Jacobs, David R and Kalhan, Ravi and O{\textquoteright}Connor, George T and Yende, Sachin and Sanders, Jason L and Umans, Jason G and Dransfield, Mark T and Chaves, Paulo H and White, Wendy B and Oelsner, Elizabeth C} } @article {8623, title = {A Dyadic Growth Modeling Approach for Examining Associations Between Weight Gain and Lung Function Decline.}, journal = {Am J Epidemiol}, volume = {189}, year = {2020}, month = {2020 10 01}, pages = {1173-1184}, abstract = {

The relationship between body weight and lung function is complex. Using a dyadic multilevel linear modeling approach, treating body mass index (BMI; weight (kg)/height (m)2) and lung function as paired, within-person outcomes, we tested the hypothesis that persons with more rapid increase in BMI exhibit more rapid decline in lung function, as measured by forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio (FEV1:FVC). Models included random intercepts and slopes and adjusted for sociodemographic and smoking-related factors. A sample of 9,115 adults with paired measurements of BMI and lung function taken at >=3 visits were selected from a pooled set of 5 US population-based cohort studies (1983-2018; mean age at baseline = 46 years; median follow-up, 19 years). At age 46 years, average annual rates of change in BMI, FEV1, FVC, and FEV1:FVC ratio were 0.22 kg/m2/year, -25.50 mL/year, -21.99 mL/year, and~-0.24\%/year, respectively. Persons with steeper BMI increases had faster declines in FEV1 (r~=~-0.16) and FVC (r~=~-0.26) and slower declines in FEV1:FVC ratio (r~=~0.11) (all P~values <~0.0001). Results were similar in subgroup analyses. Residual correlations were negative (P~<~0.0001), suggesting additional interdependence between BMI and lung function. Results show that greater rates of weight gain are associated with greater rates of lung function loss.

}, keywords = {Adult, Aged, Body Mass Index, Cohort Studies, Humans, Linear Models, Lung, Middle Aged, Respiratory Function Tests, Weight Gain}, issn = {1476-6256}, doi = {10.1093/aje/kwaa059}, author = {Cornelius, Talea and Schwartz, Joseph E and Balte, Pallavi and Bhatt, Surya P and Cassano, Patricia A and Currow, David and Jacobs, David R and Johnson, Miriam and Kalhan, Ravi and Kronmal, Richard and Loehr, Laura and O{\textquoteright}Connor, George T and Smith, Benjamin and White, Wendy B and Yende, Sachin and Oelsner, Elizabeth C} } @article {8402, title = {Lung function decline in former smokers and low-intensity current smokers: a secondary data analysis of the NHLBI Pooled Cohorts Study.}, journal = {Lancet Respir Med}, volume = {8}, year = {2020}, month = {2020 01}, pages = {34-44}, abstract = {

BACKGROUND: Former smokers now outnumber current smokers in many developed countries, and current smokers are smoking fewer cigarettes per day. Some data suggest that lung function decline normalises with smoking cessation; however, mechanistic studies suggest that lung function decline could continue. We hypothesised that former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers, including among those without prevalent lung disease.

METHODS: We used data on six US population-based cohorts included in the NHLBI Pooled Cohort Study. We restricted the sample to participants with valid spirometry at two or more exams. Two cohorts recruited younger adults (>=17 years), two recruited middle-aged and older adults (>=45 years), and two recruited only elderly adults (>=65 years) with examinations done between 1983 and 2014. FEV decline in sustained former smokers and current smokers was compared to that of never-smokers by use of mixed models adjusted for sociodemographic and anthropometric factors. Differential FEV decline was also evaluated according to duration of smoking cessation and cumulative (number of pack-years) and current (number of cigarettes per day) cigarette consumption.

FINDINGS: 25 352 participants (ages 17-93 years) completed 70 228 valid spirometry exams. Over a median follow-up of 7 years (IQR 3-20), FEV decline at the median age (57 years) was 31{\textperiodcentered}01 mL per year (95\% CI 30{\textperiodcentered}66-31{\textperiodcentered}37) in sustained never-smokers, 34{\textperiodcentered}97 mL per year (34{\textperiodcentered}36-35{\textperiodcentered}57) in former smokers, and 39{\textperiodcentered}92 mL per year (38{\textperiodcentered}92-40{\textperiodcentered}92) in current smokers. With adjustment, former smokers showed an accelerated FEV decline of 1{\textperiodcentered}82 mL per year (95\% CI 1{\textperiodcentered}24-2{\textperiodcentered}40) compared to never-smokers, which was approximately 20\% of the effect estimate for current smokers (9{\textperiodcentered}21 mL per year; 95\% CI 8{\textperiodcentered}35-10{\textperiodcentered}08). Compared to never-smokers, accelerated FEV decline was observed in former smokers for decades after smoking cessation and in current smokers with low cumulative cigarette consumption (<10 pack-years). With respect to current cigarette consumption, the effect estimate for FEV decline in current smokers consuming less than five cigarettes per day (7{\textperiodcentered}65 mL per year; 95\% CI 6{\textperiodcentered}21-9{\textperiodcentered}09) was 68\% of that in current smokers consuming 30 or more cigarettes per day (11{\textperiodcentered}24 mL per year; 9{\textperiodcentered}86-12{\textperiodcentered}62), and around five times greater than in former smokers (1{\textperiodcentered}57 mL per year; 1{\textperiodcentered}00-2{\textperiodcentered}14). Among participants without prevalent lung disease, associations were attenuated but were consistent with the main results.

INTERPRETATION: Former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers. These results suggest that all levels of smoking exposure are likely to be associated with lasting and progressive lung damage.

FUNDING: National Institutes of Health, National Heart Lung and Blood Institute, and US Environmental Protection Agency.

}, keywords = {Adult, Aged, Case-Control Studies, Ex-Smokers, Female, Follow-Up Studies, Humans, Lung, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Non-Smokers, Respiratory Physiological Phenomena, Smokers, Smoking, Spirometry, United States, Young Adult}, issn = {2213-2619}, doi = {10.1016/S2213-2600(19)30276-0}, author = {Oelsner, Elizabeth C and Balte, Pallavi P and Bhatt, Surya P and Cassano, Patricia A and Couper, David and Folsom, Aaron R and Freedman, Neal D and Jacobs, David R and Kalhan, Ravi and Mathew, Amanda R and Kronmal, Richard A and Loehr, Laura R and London, Stephanie J and Newman, Anne B and O{\textquoteright}Connor, George T and Schwartz, Joseph E and Smith, Lewis J and White, Wendy B and Yende, Sachin} } @article {9114, title = {Association Between Preserved Ratio Impaired Spirometry and Clinical Outcomes in US Adults.}, journal = {JAMA}, volume = {326}, year = {2021}, month = {2021 12 14}, pages = {2287-2298}, abstract = {

Importance: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood.

Objective: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults.

Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018).

Exposures: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80\% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80\% predicted.

Main Outcomes and Measures: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities.

Results: Among all participants (mean [SD] age, 53.2 [15.8] years, 56.4\% women, 48.5\% never-smokers), 4582 (8.5\%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3\% vs 31.4\%; prevalence ratio [PR], 1.68 [95\% CI, 1.55-1.82]), underweight (prevalence, 1.4\% vs 1.0\%; PR, 2.20 [95\% CI, 1.72-2.82]), female sex (prevalence, 60.3\% vs 59.0\%; PR, 1.07 [95\% CI, 1.01-1.13]), and current smoking (prevalence, 25.2\% vs 17.5\%; PR, 1.33 [95\% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95\% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95\% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95\% CI, 0.7-1.6]; adjusted HR, 1.95 [95\% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95\% CI, 2.1-3.4]; adjusted HR, 1.55 [95\% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95\% CI, 4.9-7.5]; adjusted HR, 1.90 [95\% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95\% CI, 3.7-5.8]; adjusted HR, 1.30 [95\% CI, 1.18-1.42]).

Conclusions and Relevance: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.

}, keywords = {Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Forced Expiratory Volume, Humans, Lung, Lung Diseases, Male, Middle Aged, Prevalence, Retrospective Studies, Spirometry, United States, Vital Capacity}, issn = {1538-3598}, doi = {10.1001/jama.2021.20939}, author = {Wan, Emily S and Balte, Pallavi and Schwartz, Joseph E and Bhatt, Surya P and Cassano, Patricia A and Couper, David and Daviglus, Martha L and Dransfield, Mark T and Gharib, Sina A and Jacobs, David R and Kalhan, Ravi and London, Stephanie J and Navas-Acien, Ana and O{\textquoteright}Connor, George T and Sanders, Jason L and Smith, Benjamin M and White, Wendy and Yende, Sachin and Oelsner, Elizabeth C} } @article {9160, title = {Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study.}, journal = {Eur Heart J}, volume = {43}, year = {2022}, month = {2022 06 14}, pages = {2196-2208}, abstract = {

AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF).

METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC >=0.70, FVC <80\%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50\%) or preserved EF (HFpEF; EF >=50\%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95\% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95\% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking.

CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.

}, keywords = {Adult, Heart Failure, Hospitalization, Humans, Lung, National Heart, Lung, and Blood Institute (U.S.), Prognosis, Risk Factors, Stroke Volume, United States}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehac205}, author = {Eckhardt, Christina M and Balte, Pallavi P and Barr, Robert Graham and Bertoni, Alain G and Bhatt, Surya P and Cuttica, Michael and Cassano, Patricia A and Chaves, Paolo and Couper, David and Jacobs, David R and Kalhan, Ravi and Kronmal, Richard and Lange, Leslie and Loehr, Laura and London, Stephanie J and O{\textquoteright}Connor, George T and Rosamond, Wayne and Sanders, Jason and Schwartz, Joseph E and Shah, Amil and Shah, Sanjiv J and Smith, Lewis and White, Wendy and Yende, Sachin and Oelsner, Elizabeth C} } @article {9156, title = {Pooled Cohort Probability Score for Subclinical Airflow Obstruction.}, journal = {Ann Am Thorac Soc}, volume = {19}, year = {2022}, month = {2022 08}, pages = {1294-1304}, abstract = {

Early detection of chronic obstructive pulmonary disease (COPD) is a public health priority. Airflow obstruction is the single most important risk factor for adverse COPD outcomes, but spirometry is not routinely recommended for screening. To describe the burden of subclinical airflow obstruction (SAO) and to develop a probability score for SAO to inform potential detection and prevention programs. Lung function and clinical data were harmonized and pooled across nine U.S. general population cohorts. Adults with respiratory symptoms, inhaler use, or prior diagnosis of COPD or asthma were excluded. A probability score for prevalent SAO (forced expiratory volume in 1 second/forced vital capacity < 0.70) was developed via hierarchical group-lasso regularization from clinical variables in strata of sex and smoking status, and its discriminative accuracy for SAO was assessed in the pooled cohort as well as in an external validation cohort (NHANES [National Health and Nutrition Examination Survey] 2011-2012). Incident hospitalizations and deaths due to COPD (respiratory events) were defined by adjudication or administrative criteria in four of nine cohorts. Of 33,546 participants (mean age 52 yr, 54\% female, 44\% non-Hispanic White), 4,424 (13.2\%) had prevalent SAO. The incidence of respiratory events ( = 14,024) was threefold higher in participants with SAO versus those without (152 vs. 39 events/10,000 person-years). The probability score, which was based on six commonly available variables (age, sex, race and/or ethnicity, body mass index, smoking status, and smoking pack-years) was well calibrated and showed excellent discrimination in both the testing sample (C-statistic, 0.81; 95\% confidence interval [CI], 0.80-0.82) and in NHANES (C-statistic, 0.83; 95\% CI, 0.80-0.86). Among participants with predicted probabilities ⩾ 15\%, 3.2 would need to undergo spirometry to detect one case of SAO. Adults with SAO demonstrate excess respiratory hospitalization and mortality. A probability score for SAO using commonly available clinical risk factors may be suitable for targeting screening and primary prevention strategies.

}, keywords = {Adult, Female, Forced Expiratory Volume, Humans, Lung, Male, Middle Aged, Nutrition Surveys, Pulmonary Disease, Chronic Obstructive, Risk Factors, Spirometry, Vital Capacity}, issn = {2325-6621}, doi = {10.1513/AnnalsATS.202109-1020OC}, author = {Bhatt, Surya P and Balte, Pallavi P and Schwartz, Joseph E and Jaeger, Byron C and Cassano, Patricia A and Chaves, Paulo H and Couper, David and Jacobs, David R and Kalhan, Ravi and Kaplan, Robert and Lloyd-Jones, Donald and Newman, Anne B and O{\textquoteright}Connor, George and Sanders, Jason L and Smith, Benjamin M and Sun, Yifei and Umans, Jason G and White, Wendy B and Yende, Sachin and Oelsner, Elizabeth C} }