@article {1154, title = {Common coding variants of the HNF1A gene are associated with multiple cardiovascular risk phenotypes in community-based samples of younger and older European-American adults: the Coronary Artery Risk Development in Young Adults Study and The Cardiovascula}, journal = {Circ Cardiovasc Genet}, volume = {2}, year = {2009}, month = {2009 Jun}, pages = {244-54}, abstract = {

BACKGROUND: The transcription factor hepatocyte nuclear factor (HNF)-1 alpha regulates the activity of a number of genes involved in innate immunity, blood coagulation, lipid and glucose transport and metabolism, and cellular detoxification. Common polymorphisms of the HNF-1 alpha gene (HNF1A) were recently associated with plasma C-reactive protein and gamma-glutamyl transferase concentration in middle-aged to older European Americans (EA).

METHODS AND RESULTS: We assessed whether common variants of HNF1A are associated with C-reactive protein, gamma-glutamyl transferase, and other atherosclerotic and metabolic risk factors, in the large, population-based Coronary Artery Risk Development in Young Adults Study of healthy young EA (n=2154) and African American (AA; n=2083) adults. The minor alleles of Ile27Leu (rs1169288) and Ser486Asn (rs2464196) were associated with 0.10 to 0.15 standard deviation units lower C-reactive protein and gamma-glutamyl transferase levels in EA. The same HNF1A coding variants were associated with higher low-density lipoprotein cholesterol, apolipoprotein B, creatinine, and fibrinogen in EA. We replicated the associations between HNF1A coding variants and C-reactive protein, fibrinogen, low-density lipoprotein cholesterol, and renal function in a second population-based sample of EA adults 65 years and older from the Cardiovascular Health Study. The HNF1A Ser486Asn and/or Ile27Leu variants were also associated with increased risk of subclinical coronary atherosclerosis in Coronary Artery Risk Development in Young Adults and with incident coronary heart disease in Cardiovascular Health Study. The Ile27Leu and Ser486Asn variants were 3-fold less common in AA than in EA. There was little evidence of association between HNF1A genotype and atherosclerosis-related phenotypes in AA.

CONCLUSIONS: Common polymorphisms of HNF1A seem to influence multiple phenotypes related to cardiovascular risk in the general population of younger and older EA adults.

}, keywords = {Adolescent, Adult, African Americans, Aged, Aged, 80 and over, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, LDL, Cohort Studies, European Continental Ancestry Group, Female, Fibrinogen, gamma-Glutamyltransferase, Genetic Predisposition to Disease, Genotype, Hepatocyte Nuclear Factor 1-alpha, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.108.839506}, author = {Reiner, Alexander P and Gross, Myron D and Carlson, Christopher S and Bielinski, Suzette J and Lange, Leslie A and Fornage, Myriam and Jenny, Nancy S and Walston, Jeremy and Tracy, Russell P and Williams, O Dale and Jacobs, David R and Nickerson, Deborah A} } @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 {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} }