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1. Severe COPD cases from Korea, Poland, and USA have substantial differences in respiratory symptoms and other respiratory illnesses

Author

Kim WJ, Yim J, Kim DK, Lee MG, Fuhlbrigge AL, Sliwinski P, Hawrylkiewicz I, Wan ES, Cho MH, and Silverman EK

Subjects
COPD, Epidemiology, Respiratory Symptoms, Tuberculosis, Diseases of the respiratory system, RC705-779
Abstract

Woo Jin Kim,1 Jae-Joon Yim,2 Deog Kyeom Kim,3 Myung Goo Lee,4 Anne L Fuhlbrigge,5 Pawel Sliwinski,6 Iwona Hawrylkiewicz,6 Emily S Wan,7,8 Michael H Cho,7,8 Edwin K Silverman7,8 1Department of Internal Medicine and Environmental Health Center, Kangwon National University Hospital, Chuncheon, 2Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University College of Medicine, Seoul, 3Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, 4Division of Pulmonary, Allergy and Critical Care Medicine, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon, Korea; 5Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA; 62nd Department of Respiratory Medicine, Institute of Tuberculosis and Lung Diseases, Warsaw, Poland; 7Channing Division of Network Medicine, 8Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA Purpose: Chronic obstructive pulmonary disease (COPD), characterized by irreversible airflow obstruction, is a major cause of morbidity and mortality worldwide. However, geographic differences in the clinical characteristics of severe COPD patients have not been widely studied. Methods: We recruited a total of 828 severe COPD cases from three continents. Subjects in Poland were enrolled by the Institute of Tuberculosis and Lung Diseases in Warsaw; subjects in Korea participated at several university hospitals in Korea; and subjects in USA were enrolled at two clinics affiliated with academic medical centers. All subjects were over the age of 30 with at least 10 pack-years of cigarette smoking history. Cases manifested severe to very severe airflow obstruction with post-bronchodilator forced expiratory volume in 1 second (FEV1)

Published
2017

2. Characteristics of stable chronic obstructive pulmonary disease patients in the pulmonology clinics of seven Asian cities

Author

Oh YM, Bhome AB, Boonsawat W, Gunasekera KD, Madegedara D, Idolor L, Roa C, Kim WJ, Kuo HP, Wang CH, Lan LT, Loh LC, Ong CK, Ng A, Nishimura M, Makita H, Silverman EK, Lee JS, Yang T, Lin Y, Wang C, and Lee SD

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Yeon-Mok Oh,1 Arvind B Bhome,2 Watchara Boonsawat,3 Kirthi Dias Gunasekera,4 Dushantha Madegedara,5 Luisito Idolor,6 Camilo Roa,6 Woo Jin Kim,7 Han-Pin Kuo,8 Chun-Hua Wang,8 Le Thi Tuyet Lan,9 Li-Cher Loh,10 Choo-Khoon Ong,10 Alan Ng,11 Masaharu Nishimura,12 Hironi Makita,12 Edwin K Silverman,13 Jae Seung Lee,1 Ting Yang,14 Yingxiang Lin,14 Chen Wang,14 Sang-Do Lee1 1Department of Pulmonary and Critical Care Medicine and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 2Department of Pulmonary and Critical Care, "Friends of the Breathless" Foundation, Pune, India; 3Department of Medicine, Khon Kaen University, Khon Kaen, Thailand; 4Central Chest Clinic, Colombo and National Hospital of Sri Lanka; 5Respiratory Disease Treatment Unit and Teaching Hospital Kandy, Sri Lanka; 6Section of Respiratory Services and Physical Therapy and Rehabilitation Lung Center of the Philippines, Quezon City, Philippines; 7Department of Internal Medicine, Kangwon National University, Kang Won, Korea; 8Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan; 9Respiratory Care Center, University Medical Center Ho Chi Minh City, Vietnam; 10Department of Medicine, Penang Medical College, Penang, Malaysia; 11Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore; 12Division of Respiratory Medicine, Department of Internal Medicine, Hokkaido University Hospital, Sapporo, Japan; 13Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; 14Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, ChinaAll authors made an equal contribution to this studyBackground and objectives: Chronic obstructive pulmonary disease (COPD) is responsible for significant morbidity and mortality worldwide. We evaluated the characteristics of stable COPD patients in the pulmonology clinics of seven Asian cities and also evaluated whether the exposure to biomass fuels and dusty jobs were related to respiratory symptoms, airflow limitation, and quality of life in the COPD patients.Methods: This cross-sectional observational study recruited 922 COPD patients from seven cities of Asia. The patients underwent spirometry and were administered questionnaires about their exposure to cigarette smoking, biomass fuels, and dusty jobs in addition to respiratory symptoms and health related quality of life.Results: Of the patients, there appeared to be variations from city to city in the history of exposure to biomass fuels and dusty jobs and also in respiratory symptoms of cough, phlegm, wheeze, and dyspnea. These symptoms were more frequent in those COPD patients with a history of exposure to biomass fuels than without and those with a history of exposure to dusty jobs than without (P < 0.01 for all comparisons). Airflow limitation was more severe in those COPD patients with a history of exposure to biomass fuels than without (52.2% predicted versus 55.9% of post-bronchodilator forced expiratory volume in 1 second [FEV1], P = 0.009); quality of life was poorer in those with exposure to biomass fuels than without (40.4 versus 36.2 of the St George's Respiratory Questionnaire [SGRQ] total score, P = 0.001). Airflow limitation was more severe in those COPD patients with a history of exposure to dusty jobs than without (51.2% predicted versus 57.3% of post-bronchodilator FEV1, P < 0.001); quality of life was poorer in those with dusty jobs than without (41.0 versus 34.6 of SGRQ score, P = 0.006).Conclusion: In Asian cities, the characteristics of COPD patients vary and the history of exposure to biomass fuels or dusty jobs was related to frequency of symptoms, severe airflow limitation, and poor quality of life.Keywords: COPD, Asia, biomass, dust

Published
2013

3. Effect of polymorphism of the beta(2)-adrenergic receptor on response to regular use of albuterol in asthma.

Author

Israel, E, Drazen, JM, Liggett, SB, Boushey, HA, Cherniack, RM, Chinchilli, VM, Cooper, DM, Fahy, JV, Fish, JE, Ford, JG, Kraft, M, Kunselman, S, Lazarus, SC, Lemanske, RF, Martin, RJ, McLean, DE, Peters, SP, Silverman, EK, Sorkness, CA, Szefler, SJ, Weiss, ST, Yandava, CN, and National Heart, Lung, and Blood Institute's Asthma Clinical Research Network

Subjects
National Heart, Lung, and Blood Institute's Asthma Clinical Research Network, Humans, Asthma, Albuterol, Receptors, Adrenergic, beta-2, Adrenergic beta-Agonists, Peak Expiratory Flow Rate, Cohort Studies, Genotype, Polymorphism, Genetic, Time Factors, Adolescent, Adult, Child, Female, Male, Clinical Research, Genetics, Lung, Respiratory, asthma, beta(2)-adrenergic agonists, beta(2)-adrenergic receptor, albuterol, Immunology, Allergy
Abstract

BackgroundRegular use of inhaled beta-adrenergic agonists may have adverse effects in some asthma patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect its regulation; however, results of smaller studies of the effects of such polymorphisms on response to beta-agonist therapy have been inconsistent.MethodsWe examined the possible effects of polymorphisms at codons 16 (beta(2)-AR-16) and 27 (beta(2)-AR-27) on response to albuterol by genotyping 190 asthmatics who had participated in a trial of regular versus as-needed albuterol use.ResultsDuring the 16-week treatment period, patients homozygous for arginine (Arg/Arg) at beta(2)-AR-16 who used albuterol regularly had a small decline in morning peak expiratory flow (AM PEF). This effect was magnified during a 4-week run-out period, when all patients returned to as-needed albuterol only. By the end of the study, Arg/Arg subjects who had used albuterol regularly had an AM PEF 30.5 +/- 12.1 liters/min lower (p = 0.012) than Arg/Arg patients who had used albuterol as needed only. Subjects homozygous for glycine at beta(2)-AR-16 showed no such decline. Evening PEF also declined in the Arg/Arg regular but not in as-need albuterol users. No significant differences between regular and as-needed treatment were associated with polymorphisms at beta(2)-AR-27.ConclusionsPolymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Published
2001

4. The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.

Author

Israel, E, Drazen, JM, Liggett, SB, Boushey, HA, Cherniack, RM, Chinchilli, VM, Cooper, DM, Fahy, JV, Fish, JE, Ford, JG, Kraft, M, Kunselman, S, Lazarus, SC, Lemanske, RF, Martin, RJ, McLean, DE, Peters, SP, Silverman, EK, Sorkness, CA, Szefler, SJ, Weiss, ST, and Yandava, CN

Subjects
Humans, Asthma, Albuterol, Receptors, Adrenergic, beta-2, Bronchodilator Agents, Double-Blind Method, Genotype, Polymorphism, Genetic, Adolescent, Child, Female, Male, Lung, Genetics, Respiratory, Medical and Health Sciences, Respiratory System
Abstract

Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Published
2000

5. Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Author

Moll, M, Sakornsakolpat, P, Shrine, N, Hobbs, BD, DeMeo, DL, John, C, Guyatt, AL, McGeachie, MJ, Gharib, SA, Obeidat, M, Lahousse, L, Wijnant, SRA, Brusselle, G, Meyers, DA, Bleecker, ER, Li, X, Tal-Singer, R, Manichaikul, A, Rich, SS, Won, S, Kim, WJ, Do, AR, Washko, GR, Barr, RG, Psaty, BM, Bartz, TM, Hansel, NN, Barnes, K, Hokanson, JE, Crapo, JD, Lynch, D, Bakke, P, Gulsvik, A, Hall, IP, Wain, L, Weiss, ST, Silverman, EK, Dudbridge, F, Tobin, MD, Cho, MH, Moll, M, Sakornsakolpat, P, Shrine, N, Hobbs, BD, DeMeo, DL, John, C, Guyatt, AL, McGeachie, MJ, Gharib, SA, Obeidat, M, Lahousse, L, Wijnant, SRA, Brusselle, G, Meyers, DA, Bleecker, ER, Li, X, Tal-Singer, R, Manichaikul, A, Rich, SS, Won, S, Kim, WJ, Do, AR, Washko, GR, Barr, RG, Psaty, BM, Bartz, TM, Hansel, NN, Barnes, K, Hokanson, JE, Crapo, JD, Lynch, D, Bakke, P, Gulsvik, A, Hall, IP, Wain, L, Weiss, ST, Silverman, EK, Dudbridge, F, Tobin, MD, and Cho, MH

Abstract

BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a red

Published
2020

7. Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region

Author

Kelly, M, Park, M, Mihalek, I, Rochtus, A, Gramm, M, Perez-Palma, E, Axeen, ET, Hung, CY, Olson, H, Swanson, L, Anselm, I, Briere, LC, High, FA, Sweetser, DA, Kayani, S, Snyder, M, Calvert, S, Scheffer, IE, Yang, E, Waugh, JL, Lal, D, Bodamer, O, Poduri, A, Adams, DR, Aday, A, Alejandro, ME, Allard, P, Ashley, EA, Azamian, MS, Bacino, CA, Baker, E, Balasubramanyam, A, Barseghyan, H, Batzli, GF, Beggs, AH, Behnam, B, Bellen, HJ, Bernstein, JA, Bican, A, Bick, DP, Birch, CL, Bonner, D, Boone, BE, Bostwick, BL, Brokamp, E, Brown, DM, Brush, M, Burke, EA, Burrage, LC, Butte, MJ, Chen, S, Clark, GD, Coakley, TR, Cogan, JD, Colley, HA, Cooper, CM, Cope, H, Craigen, WJ, D'Souza, P, Davids, M, Davidson, JM, Dayal, JG, Dell'Angelica, EC, Dhar, SU, Dipple, KM, Donnell-Fink, LA, Dorrani, N, Dorset, DC, Douine, ED, Draper, DD, Dries, AM, Eckstein, DJ, Emrick, LT, Eng, CM, Enns, G-GM, Eskin, A, Esteves, C, Estwick, T, Fairbrother, L, Fernandez, L, Ferreira, C, Fieg, EL, Fisher, PG, Fogel, BL, Friedman, ND, Gahl, WA, Glanton, E, Godfrey, RA, Goldman, AM, Goldstein, DB, Gould, SE, Gourdine, J-PF, Groden, CA, Gropman, AL, Haendel, M, Hamid, R, Hanchard, NA, High, F, Holm, IA, Horn, J, Howerton, EM, Huang, Y, Jamal, F, Jiang, Y-H, Johnston, JM, Jones, AL, Karaviti, L, Koeller, DM, Kohane, IS, Kohler, JN, Konick, S, Koziura, M, Krasnewich, DM, Krier, JB, Kyle, JE, Lalani, SR, Lau, CC, Lazar, J, LeBlanc, K, Lee, BH, Lee, H, Levy, SE, Lewis, RA, Lincoln, SA, Loo, SK, Loscalzo, J, Maas, RL, Macnamara, EF, MacRae, CA, Maduro, VV, Majch-erska, MM, Malicdan, MC, Mamounas, LA, Manolio, TA, Markello, TC, Marom, R, Martin, MG, Martinez-Agosto, JA, Mar-waha, S, May, T, McConkie-Rosell, A, McCormack, CE, McCray, AF, Merker, JD, Metz, TO, Might, M, Moretti, PM, Morimoto, M, Mulvihill, JJ, Murdock, DR, Murphy, JL, Muzny, DM, Nehrebecky, ME, Nelson, SF, Newberry, JS, Newman, JH, Nicholas, SK, Novacic, D, Orange, JS, Orengo, JP, Pallais, JC, Palmer, CGS, Papp, JC, Parker, NH, Pena, LDM, Phillips, JA, Posey, JE, Postlethwait, JH, Potocki, L, Pusey, BN, Reuter, CM, Rives, L, Robertson, AK, Rodan, LH, Rosenfeld, JA, Sampson, JB, Samson, SL, Schoch, K, Scott, DA, Shakachite, L, Sharma, P, Shashi, V, Signer, R, Silverman, EK, Sinsheimer, JS, Smith, KS, Spillmann, RC, Stoler, JM, Stong, N, Sullivan, JA, Tan, QK-G, Tifft, CJ, Toro, C, Tran, AA, Urv, TK, Vilain, E, Vogel, TP, Waggott, DM, Wahl, CE, Walker, M, Walley, NM, Walsh, CA, Wan, J, Wangler, MF, Ward, PA, Waters, KM, Webb-Robertson, B-JM, Westerfield, M, Wheeler, MT, Wise, AL, Wolfe, LA, Worthey, EA, Yamamoto, S, Yang, Y, Yoon, AJ, Yu, G, Zastrow, DB, Zhao, C, Zheng, A, Kelly, M, Park, M, Mihalek, I, Rochtus, A, Gramm, M, Perez-Palma, E, Axeen, ET, Hung, CY, Olson, H, Swanson, L, Anselm, I, Briere, LC, High, FA, Sweetser, DA, Kayani, S, Snyder, M, Calvert, S, Scheffer, IE, Yang, E, Waugh, JL, Lal, D, Bodamer, O, Poduri, A, Adams, DR, Aday, A, Alejandro, ME, Allard, P, Ashley, EA, Azamian, MS, Bacino, CA, Baker, E, Balasubramanyam, A, Barseghyan, H, Batzli, GF, Beggs, AH, Behnam, B, Bellen, HJ, Bernstein, JA, Bican, A, Bick, DP, Birch, CL, Bonner, D, Boone, BE, Bostwick, BL, Brokamp, E, Brown, DM, Brush, M, Burke, EA, Burrage, LC, Butte, MJ, Chen, S, Clark, GD, Coakley, TR, Cogan, JD, Colley, HA, Cooper, CM, Cope, H, Craigen, WJ, D'Souza, P, Davids, M, Davidson, JM, Dayal, JG, Dell'Angelica, EC, Dhar, SU, Dipple, KM, Donnell-Fink, LA, Dorrani, N, Dorset, DC, Douine, ED, Draper, DD, Dries, AM, Eckstein, DJ, Emrick, LT, Eng, CM, Enns, G-GM, Eskin, A, Esteves, C, Estwick, T, Fairbrother, L, Fernandez, L, Ferreira, C, Fieg, EL, Fisher, PG, Fogel, BL, Friedman, ND, Gahl, WA, Glanton, E, Godfrey, RA, Goldman, AM, Goldstein, DB, Gould, SE, Gourdine, J-PF, Groden, CA, Gropman, AL, Haendel, M, Hamid, R, Hanchard, NA, High, F, Holm, IA, Horn, J, Howerton, EM, Huang, Y, Jamal, F, Jiang, Y-H, Johnston, JM, Jones, AL, Karaviti, L, Koeller, DM, Kohane, IS, Kohler, JN, Konick, S, Koziura, M, Krasnewich, DM, Krier, JB, Kyle, JE, Lalani, SR, Lau, CC, Lazar, J, LeBlanc, K, Lee, BH, Lee, H, Levy, SE, Lewis, RA, Lincoln, SA, Loo, SK, Loscalzo, J, Maas, RL, Macnamara, EF, MacRae, CA, Maduro, VV, Majch-erska, MM, Malicdan, MC, Mamounas, LA, Manolio, TA, Markello, TC, Marom, R, Martin, MG, Martinez-Agosto, JA, Mar-waha, S, May, T, McConkie-Rosell, A, McCormack, CE, McCray, AF, Merker, JD, Metz, TO, Might, M, Moretti, PM, Morimoto, M, Mulvihill, JJ, Murdock, DR, Murphy, JL, Muzny, DM, Nehrebecky, ME, Nelson, SF, Newberry, JS, Newman, JH, Nicholas, SK, Novacic, D, Orange, JS, Orengo, JP, Pallais, JC, Palmer, CGS, Papp, JC, Parker, NH, Pena, LDM, Phillips, JA, Posey, JE, Postlethwait, JH, Potocki, L, Pusey, BN, Reuter, CM, Rives, L, Robertson, AK, Rodan, LH, Rosenfeld, JA, Sampson, JB, Samson, SL, Schoch, K, Scott, DA, Shakachite, L, Sharma, P, Shashi, V, Signer, R, Silverman, EK, Sinsheimer, JS, Smith, KS, Spillmann, RC, Stoler, JM, Stong, N, Sullivan, JA, Tan, QK-G, Tifft, CJ, Toro, C, Tran, AA, Urv, TK, Vilain, E, Vogel, TP, Waggott, DM, Wahl, CE, Walker, M, Walley, NM, Walsh, CA, Wan, J, Wangler, MF, Ward, PA, Waters, KM, Webb-Robertson, B-JM, Westerfield, M, Wheeler, MT, Wise, AL, Wolfe, LA, Worthey, EA, Yamamoto, S, Yang, Y, Yoon, AJ, Yu, G, Zastrow, DB, Zhao, C, and Zheng, A

Abstract

OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. METHODS: We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. RESULTS: The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes. SIGNIFICANCE: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment.

Published
2019

8. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Author

Hobbs, BD, de Jong, K, Lamontagne, M, Bossé, Y, Shrine, N, Artigas, MS, Wain, LV, Hall, IP, Jackson, VE, Wyss, AB, London, SJ, North, KE, Franceschini, N, Strachan, DP, Beaty, TH, Hokanson, JE, Crapo, JD, Castaldi, PJ, Chase, RP, Bartz, TM, Heckbert, SR, Psaty, BM, Gharib, SA, Zanen, P, Lammers, JW, Oudkerk, M, Groen, HJ, Locantore, N, Tal-Singer, R, Rennard, SI, Vestbo, J, Timens, W, Paré, PD, Latourelle, JC, Dupuis, J, O'Connor, GT, Wilk, JB, Kim, WJ, Lee, MK, Oh, Y-M, Vonk, JM, de Koning, HJ, Leng, S, Belinsky, SA, Tesfaigzi, Y, Manichaikul, A, Wang, X-Q, Rich, SS, Barr, RG, Sparrow, D, Litonjua, AA, Bakke, P, Gulsvik, A, Lahousse, L, Brusselle, GG, Stricker, BH, Uitterlinden, AG, Ampleford, EJ, Bleecker, ER, Woodruff, PG, Meyers, DA, Qiao, D, Lomas, DA, Yim, J-J, Kim, DK, Hawrylkiewicz, I, Sliwinski, P, Hardin, M, Fingerlin, TE, Schwartz, DA, Postma, DS, MacNee, W, Tobin, MD, Silverman, EK, Boezen, HM, Cho, MH, COPDGene Investigators, ECLIPSE Investigators, LifeLines Investigators, SPIROMICS Research Group, International COPD Genetics Network Investigators, UK BiLEVE Investigators, and International COPD Genetics Consortium

Subjects
respiratory tract diseases
Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Published
2017

9. Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma

Author

Farahi, N, Paige, E, Balla, J, Prudence, E, Ferreira, RC, Southwood, M, Appleby, SL, Bakke, P, Gulsvik, A, Litonjua, AA, Sparrow, D, Silverman, EK, Cho, MH, Danesh, J, Paul, DS, Freitag, DF, Chilvers, ER, Danesh, John [0000-0003-1158-6791], Paul, Dirk [0000-0002-8230-0116], Chilvers, Edwin [0000-0002-4230-9677], and Apollo - University of Cambridge Repository

Subjects
SOLUBLE RECEPTOR, Male, Biochemistry & Molecular Biology, ADAM PROTEASES, in vitro study, AIRWAY INFLAMMATION, Neutrophils, monocyte chemoattractant protein-1, chronic obstructive airway disease, lung, DOUBLE-BLIND, Pulmonary Disease, Chronic Obstructive, respiration disorders, tocilizumab, pulmonary artery, Humans, PRO-INFLAMMATORY ACTIVITIES, genes, interleukin 6 receptor, METAANALYSIS, Genetic Association Studies, squamous intraepithelial lesion, Genetics & Heredity, Science & Technology, interleukin-6, neutrophil, 11 Medical And Health Sciences, 06 Biological Sciences, asthma, Receptors, Interleukin-6, endothelial cells, respiratory tract diseases, RHEUMATOID-ARTHRITIS, LUNG-FUNCTION, homozygote, INTERLEUKIN-6 RECEPTOR, alleles, pmel17, biobanks, Female, LEUKOCYTE RECRUITMENT, Life Sciences & Biomedicine, signal transduction, extrinsic asthma
Abstract

The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.

Published
2017

10. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study

Author

Haycock, PC, Burgess, S, Nounu, A, Zheng, J, Okoli, GN, Bowden, J, Wade, KH, Timpson, NJ, Evans, DM, Willeit, P, Aviv, A, Gaunt, T, Hemani, G, Mangino, M, Ellis, HP, Kurian, KM, Pooley, KA, Eeles, RA, Lee, JE, Fang, SY, Chen, WV, Law, MH, Bowdler, LM, Iles, MM, Yang, Q, Worrall, BB, Markus, HS, Hung, RJ, Amos, CI, Spurdle, AB, Thompson, DJ, O'Mara, TA, Wolpin, B, Amundadottir, L, Stolzenberg-Solomon, R, Trichopoulou, A, Onland-Moret, C, Lund, E, Duell, EJ, Canzian, F, Severi, G, Overvad, K, Gunter, MJ, Tumino, R, Svenson, U, van Rij, A, Baas, AF, Bown, MJ, Samani, NJ, van t'Hof, FNG, Tromp, G, Jones, GT, Kuivaniemi, H, Elmore, JR, Johansson, M, Mckay, J, Scelo, G, Carreras-Torres, R, Gaborieau, V, Brennan, P, Bracci, PM, Neale, RE, Olson, SH, Gallinger, S, Li, DH, Petersen, GM, Risch, HA, Klein, AP, Han, JL, Abnet, CC, Freedman, N D, Taylor, PR, Maris, JM, Aben, KK, Kiemeney, LA, Vermeulen, SH, Wiencke, JK, Walsh, KM, Wrensch, M, Rice, T, Turnbull, C, Litchfield, K, Paternoster, L, Standl, M, Abecasis, GR, SanGiovanni, JP, Li, Y, Mijatovic, V, Sapkota, Y, Low, SK, Zondervan, KT, Montgomery, GW, Nyholt, DR, van Heel, D A, Hunt, K, Arking, DE, Ashar, FN, Sotoodehnia, N, Woo, D, Rosand, J, Comeau, ME, Brown, W M, Silverman, EK, Hokanson, JE, Cho, MH, Hui, J, Ferreira, MA, Thompson, PJ, Morrison, AC, Felix, Janine, Smith, NL, Christiano, AM, Petukhova, L, Betz, RC, Fan, X, Zhang, XJ, Zhu, CH, Langefeld, CD, Thompson, SD, Wang, FJ, Lin, X, Schwartz, DA, Fingerlin, T, Rotter, JI, Cotch, MF, Jensen, RA, Munz, M, Dommisch, H, Schaefer, AS, Han, F, Ollila, HM, Hillary, RP, Albagha, O, Ralston, SH, Zeng, CJ, Zheng, W, Shu, XO, Reis, A, Uebe, S, Huffmeier, U, Kawamura, Y, Otowa, T, Sasaki, T, Hibberd, ML, Davila, S, Xie, G, Siminovitch, K, Bei, JX, Zeng, YX, Forsti, A, Chen, B (Bowang), Landi, S, Franke, A, Fischer, A, Ellinghaus, D, Flores, C, Noth, I, Ma, SF, Foo, JN, Liu, JJ, Kim, JW, Cox, DG, Delattre, O, Mirabeau, O, Skibola, CF, Tang, CS, Garcia-Barcelo, M, Chang, KP, Su, WH, Chang, YS, Martin, NG, Gordon, S, Wade, TD, Lee, C, Kubo, M, Cha, PC, Nakamura, Y, Levy, D, Kimura, M, Hwang, SJ, Hunt, S, Spector, T, Soranzo, N, Manichaikul, A, Barr, G, Kahali, B, Speliotes, E, Yerges-Armstrong, L, Cheng, CY (Ching-Yu), Jonas, JB, Wong, TY, Fogh, I, Lin, K, Powell, JF, Rice, K, Relton, CL, Martin, RM, Smith, GD, Haycock, PC, Burgess, S, Nounu, A, Zheng, J, Okoli, GN, Bowden, J, Wade, KH, Timpson, NJ, Evans, DM, Willeit, P, Aviv, A, Gaunt, T, Hemani, G, Mangino, M, Ellis, HP, Kurian, KM, Pooley, KA, Eeles, RA, Lee, JE, Fang, SY, Chen, WV, Law, MH, Bowdler, LM, Iles, MM, Yang, Q, Worrall, BB, Markus, HS, Hung, RJ, Amos, CI, Spurdle, AB, Thompson, DJ, O'Mara, TA, Wolpin, B, Amundadottir, L, Stolzenberg-Solomon, R, Trichopoulou, A, Onland-Moret, C, Lund, E, Duell, EJ, Canzian, F, Severi, G, Overvad, K, Gunter, MJ, Tumino, R, Svenson, U, van Rij, A, Baas, AF, Bown, MJ, Samani, NJ, van t'Hof, FNG, Tromp, G, Jones, GT, Kuivaniemi, H, Elmore, JR, Johansson, M, Mckay, J, Scelo, G, Carreras-Torres, R, Gaborieau, V, Brennan, P, Bracci, PM, Neale, RE, Olson, SH, Gallinger, S, Li, DH, Petersen, GM, Risch, HA, Klein, AP, Han, JL, Abnet, CC, Freedman, N D, Taylor, PR, Maris, JM, Aben, KK, Kiemeney, LA, Vermeulen, SH, Wiencke, JK, Walsh, KM, Wrensch, M, Rice, T, Turnbull, C, Litchfield, K, Paternoster, L, Standl, M, Abecasis, GR, SanGiovanni, JP, Li, Y, Mijatovic, V, Sapkota, Y, Low, SK, Zondervan, KT, Montgomery, GW, Nyholt, DR, van Heel, D A, Hunt, K, Arking, DE, Ashar, FN, Sotoodehnia, N, Woo, D, Rosand, J, Comeau, ME, Brown, W M, Silverman, EK, Hokanson, JE, Cho, MH, Hui, J, Ferreira, MA, Thompson, PJ, Morrison, AC, Felix, Janine, Smith, NL, Christiano, AM, Petukhova, L, Betz, RC, Fan, X, Zhang, XJ, Zhu, CH, Langefeld, CD, Thompson, SD, Wang, FJ, Lin, X, Schwartz, DA, Fingerlin, T, Rotter, JI, Cotch, MF, Jensen, RA, Munz, M, Dommisch, H, Schaefer, AS, Han, F, Ollila, HM, Hillary, RP, Albagha, O, Ralston, SH, Zeng, CJ, Zheng, W, Shu, XO, Reis, A, Uebe, S, Huffmeier, U, Kawamura, Y, Otowa, T, Sasaki, T, Hibberd, ML, Davila, S, Xie, G, Siminovitch, K, Bei, JX, Zeng, YX, Forsti, A, Chen, B (Bowang), Landi, S, Franke, A, Fischer, A, Ellinghaus, D, Flores, C, Noth, I, Ma, SF, Foo, JN, Liu, JJ, Kim, JW, Cox, DG, Delattre, O, Mirabeau, O, Skibola, CF, Tang, CS, Garcia-Barcelo, M, Chang, KP, Su, WH, Chang, YS, Martin, NG, Gordon, S, Wade, TD, Lee, C, Kubo, M, Cha, PC, Nakamura, Y, Levy, D, Kimura, M, Hwang, SJ, Hunt, S, Spector, T, Soranzo, N, Manichaikul, A, Barr, G, Kahali, B, Speliotes, E, Yerges-Armstrong, L, Cheng, CY (Ching-Yu), Jonas, JB, Wong, TY, Fogh, I, Lin, K, Powell, JF, Rice, K, Relton, CL, Martin, RM, and Smith, GD

Published
2017

11. Clinical and radiologic disease in smokers with normal spirometry

Author

Regan, EA, Lynch, DA, Curran-Everett, D, Curtis, JL, Austin, JHM, Grenier, PA, Kauczor, HU, Bailey, WC, De Meo, DL, Casaburi, RH, Friedman, P, Van Beek, EJR, Hokanson, JE, Bowler, RP, Beaty, TH, Washko, GR, Han, MK, Kim, V, Kim, SS, Yagihashi, K, Washington, L, McEvoy, CE, Tanner, C, Mannino, DM, Make, BJ, Silverman, EK, Crapo, JD, Martinez, C, Pernicano, PG, Hanania, N, Alapat, P, Bandi, V, Atik, M, Boriek, A, Guntupalli, K, Guy, E, Parulekar, A, Nachiappan, A, Hersh, C, Jacobson, F, Barr, RG, Thomashow, B, D'Souza, B, Pearson, GDN, Rozenshtein, A, MacIntyre, N, McAdams, HP, Tashjian, J, Wise, R, Hansel, N, Brown, R, Horton, K, Putcha, N, Adami, A, Porszasz, J, Fischer, H, Budoff, M, Cannon, D, Rossiter, H, Sharafkhaneh, A, Lan, C, Wendt, C, Bell, B, Foreman, M, Westney, G, Berkowitz, E, Rosiello, R, Pace, D, Criner, G, Ciccolella, D, Cordova, F, Dass, C, D'Alonzo, R, Desai, P, Jacobs, M, Kelsen, S, Mamary, AJ, Marchetti, N, Satti, A, Shenoy, K, Steiner, RM, Swift, A, Swift, I, Vega-Sanchez, G, Dransfield, M, Wells, JM, Bhatt, S, Nath, H, Ramsdell, J, Soler, X, Yen, A, Cornellas, A, Newell, J, Thompson, B, Kazerooni, E, Martinez, F, Billings, J, and Allen, T

Subjects
respiratory tract diseases
Abstract

Copyright 2015 American Medical Association. All rights reserved. IMPORTANCE: Airflow obstruction on spirometry is universally used to define chronic obstructive pulmonary disease (COPD), and current or former smokers without airflow obstruction may assume that they are disease free. OBJECTIVE: To identify clinical and radiologic evidence of smoking-related disease in a cohort of current and former smokers who did not meet spirometric criteria for COPD, for whom we adopted the discarded label of Global Initiative for Obstructive Lung Disease (GOLD) 0. DESIGN, SETTING, AND PARTICIPANTS: Individuals from the Genetic Epidemiology of COPD (COPDGene) cross-sectional observational study completed spirometry, chest computed tomography (CT) scans, a 6-minute walk, and questionnaires. Participants were recruited from local communities at 21 sites across the United States. The GOLD 0 group (n = 4388) (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity >0.7 and FEV1 >80% predicted) from the COPDGene study was compared with a GOLD 1 group (n = 794), COPD groups (n = 3690), and a group of never smokers (n = 108). Recruitment began in January 2008 and ended in July 2011. MAIN OUTCOMES AND MEASURES: Physical function impairments, respiratory symptoms, CT abnormalities, use of respiratory medications, and reduced respiratory-specific quality of life. RESULTS: One or more respiratory-related impairments were found in 54.1% (2375 of 4388) of the GOLD 0 group. The GOLD 0 group had worse quality of life (mean [SD] St George's Respiratory Questionnaire total score, 17.0 [18.0] vs 3.8 [6.8] for the never smokers; P

Published
2015

12. The genetics of chronic obstructive pulmonary disease

Author

Lomas, DA, Silverman, EK, and Apollo - University of Cambridge Repository

Subjects
lcsh:RC705-779, Genome, Smoking, lcsh:Diseases of the respiratory system, Review, Environment, respiratory tract diseases, chronic obstructive pulmonary disease, Pulmonary Disease, Chronic Obstructive, emphysema, association studies, Risk Factors, Humans, genetics, Genetic Predisposition to Disease, Cloning, Molecular, lungs
Abstract

Chronic obstructive pulmonary disease (COPD) is a significant cause of global morbidity and mortality. Previous studies have shown that COPD aggregates in families, suggesting a genetic predisposition to airflow obstruction. Many candidate genes have been assessed, but the data are often conflicting. We review the genetic factors that predispose smokers to COPD and highlight the future role of genomic scans in identifying novel susceptibility genes.

Published
2001

13. Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

Author

Dijkstra, Akkelies E., Smolonska, J, Van Den Berge, M, Wijmenga, C, Zanen, P, Luinge, MA, Platteel, M, Lammers, JW, Dahlback, M, Tosh, K, Hiemstra, PS, Sterk, PJ, Spira, A, Vestbo, J, Nordestgaard, BG, Benn, M, Nielsen, SF, Dahl, M, Verschuren, WM, Picavet, HSJ, Smit, HA, Owsijewitsch, M, Kauczor, HU, De Koning, HJ, Nizankowska-Mogilnicka, E, Mejza, F, Nastalek, P, Van Diemen, CC, Cho, MH, Silverman, EK, Crapo, JD, Beaty, TH, Lomas, DA, Bakke, Per, Gulsvik, Amund, Bosse, Y, Obeidat, MA, Loth, DW, Lahousse, L, Rivadeneira, F, Uitterlinden, AG, Hofman, A, Stricker, BH, Brusselle, GG, Van Duijn, CM, Brouwer, U, Koppelman, GH, Vonk, JM, Nawijn, MC, Groen, HJM, Timens, W, Boezen, HM, Postma, DS, Alizadeh, BZ, De Boer, RA, Bruinenberg, M, Franke, L, Van Der Harst, P, Hillege, HL, Van Der Klauw, MM, Navis, G, Ormel, J, Rosmalen, J, Slaets, JP, Snieder, H, Stolk, RP, Wolffenbuttel, B, Amsterdam institute for Infection and Immunity, Pulmonology, Clinical Chemistry, Public Health, Otorhinolaryngology and Head and Neck Surgery, Epidemiology, Internal Medicine, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
CHROMATIN, Male, Chronic bronchitis, Pulmonology, Epidemiology, OBSTRUCTIVE PULMONARY-DISEASE CHRONIC-BRONCHITIS GENETIC EPIDEMIOLOGY GENERAL-POPULATION BINDING-PROTEIN RISK-FACTORS COPD CHROMATIN SATB1 EXPRESSION, lcsh:Medicine, Genome-wide association study, Lung/metabolism, Mucus/metabolism, Drug Addiction, Matrix Attachment Region Binding Proteins/genetics, Recreational Drug Addiction, Cohort Studies, Pulmonary Disease, Chronic Obstructive, Medicine and Health Sciences, Psychology, Clinical Epidemiology, lcsh:Science, Lung, Cells, Cultured, GENETIC EPIDEMIOLOGY, GENERAL-POPULATION, Aged, 80 and over, education.field_of_study, Multidisciplinary, Medical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714 [VDP], Genomics, respiratory system, Middle Aged, 3. Good health, Functional Genomics, BINDING-PROTEIN, medicine.anatomical_structure, CHRONIC-BRONCHITIS, Genetic Epidemiology, Medical sciences: 700::Clinical medical sciences: 750::Lung diseases: 777 [VDP], Epidemiological Methods and Statistics, Female, medicine.symptom, Transcriptome Analysis, Medisinske fag: 700::Klinisk medisinske fag: 750::Lungesykdommer: 777 [VDP], Research Article, EXPRESSION, Adult, Chronic Obstructive Pulmonary Disease, Population, Addiction, Single-nucleotide polymorphism, Biology, Environmental and Occupational Lung Diseases, OBSTRUCTIVE PULMONARY-DISEASE, Polymorphism, Single Nucleotide, Environmental Epidemiology, SATB1, SDG 3 - Good Health and Well-being, medicine, Genome-Wide Association Studies, Genetics, SNP, COPD, Humans, education, Lifecourse Epidemiology, Aged, lcsh:R, Biology and Life Sciences, Computational Biology, Correction, Matrix Attachment Region Binding Proteins, Genome Analysis, Pulmonary Disease, Chronic Obstructive/genetics, Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP], Mucus, Genetic epidemiology, Immunology, Respiratory Infections, Chronic Disease, RISK-FACTORS, Sputum, lcsh:Q, Genome Expression Analysis, Genome-Wide Association Study
Abstract

Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and metaanalysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (>= 20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25610(-6), OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3610 29) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH. Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25x10 -6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3x10 -9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.

Published
2013

14. Quantitative CT of the Lungs and Airways in Healthy Non-smoking Adults

Author

Zach, JA, Newell, JD, Schroeder, J, Murphy, JR, Curran-Everett, D, Hoffman, EA, Westgate, PM, Han, MK, Silverman, EK, Crapo, JD, and Lynch, DA

Subjects
Aged, 80 and over, Male, Health Status, Respiratory System, Statistics as Topic, Age Factors, Middle Aged, Article, Respiratory Function Tests, Linear Models, Humans, Female, Tomography, X-Ray Computed, Lung, Aged
Abstract

The purposes of this study were to evaluate the reference range of quantitative computed tomography (QCT) measures of lung attenuation and airway parameter measurements in healthy nonsmoking adults and to identify sources of variation in those measures and possible means to adjust for them.Within the COPDGene study, 92 healthy non-Hispanic white nonsmokers (29 men, 63 women; mean [SD] age, 62.7 [9.0] years; mean [SD] body mass index [BMI], 28.1 [5.1] kg/m(2)) underwent volumetric computed tomography (CT) at full inspiration and at the end of a normal expiration. On QCT analysis (Pulmonary Workstation 2, VIDA Diagnostics), inspiratory low-attenuation areas were defined as lung tissue with attenuation values -950 Hounsfield units or less on inspiratory CT (LAA(I-950)). Expiratory low-attenuation areas were defined as lung tissue -856 Hounsfield units or less on expiratory CT (LAA(E-856)). We used simple linear regression to determine the impact of age and sex on QCT parameters and multiple regression to assess the additional impact of total lung capacity and functional residual capacity measured by CT (TLC(CT) and FRC(CT)), scanner type, and mean tracheal air attenuation. Airways were evaluated using measures of airway wall thickness, inner luminal area, wall area percentage (WA%), and standardized thickness of an airway with inner perimeter of 10 mm (Pi10).Mean (SD) %LAA(I-950) was 2.0% (2.7%), and mean (SD) %LAA(E-856) was 9.2% (6.8%). Mean (SD) %LAA(I-950) was 3.6% (3.2%) in men, compared with 1.3% (2.0%) in women (P0.001). The %LAA(I-950) did not change significantly with age (P = 0.08) or BMI (P = 0.52). %LAA(E-856) did not show any independent relationship with age (P = 0.33), sex (P = 0.70), or BMI (P = 0.32). On multivariate analysis, %LAA(I-950) showed a direct relationship to TLC(CT) (P = 0.002) and an inverse relationship to mean tracheal air attenuation (P = 0.003), and %LAA(E-856) was related to age (P = 0.001), FRC(CT) (P = 0.007), and scanner type (P0.001). Multivariate analysis of segmental airways showed that inner luminal area and WA% were significantly related to TLC(CT) (P0.001) and age (0.006). Moreover, WA% was associated with sex (P = 0.05), axial pixel size (P = 0.03), and slice interval (P = 0.04). Lastly, airway wall thickness was strongly influenced by axial pixel size (P0.001).Although the attenuation characteristics of normal lung differ by age and sex, these differences do not persist on multivariate analysis. Potential sources of variation in measurement of attenuation-based QCT parameters include depth of inspiration/expiration and scanner type. Tracheal air attenuation may partially correct variation because of scanner type. Sources of variation in QCT airway measurements may include age, sex, BMI, depth of inspiration, and spatial resolution.

Published
2012

15. Non-emphysematous chronic obstructive pulmonary disease is associated with diabetes mellitus

Author

Hersh, CP, Make, BJ, Lynch, DA, Barr, RG, Bowler, RP, Calverley, PMA, Castaldi, PJ, Cho, MH, Coxson, HO, DeMeo, DL, Foreman, MG, Han, MLK, Harshfield, BJ, Hokanson, JE, Lutz, S, Ramsdell, JW, Regan, EA, Rennard, SI, Schroeder, JD, Sciurba, FC, Steiner, RM, Tal-Singer, R, van Beek, EJR, Silverman, EK, Crapo, JD, Lantz, R, Stepp, L, Melanson, S, Beaty, T, Laird, N, Lange, C, Santorico, S, Hansel, N, McDonald, ML, Zhou, J, Mattheisen, M, Wan, E, Hardin, M, Hetmanski, J, Parker, M, Murray, T, Newell, J, Reilly, J, Judy, P, Hoffman, E, Estepar, RSJ, Ross, J, Al Qaisi, M, Zach, J, Kluiber, A, Sieren, J, Mann, T, Richert, D, McKenzie, A, Akhavan, J, Stinson, D, Jensen, R, Farzadegan, H, Meyerer, S, Chandan, S, Bragan, S, Everett, D, Williams, A, Wilson, C, Forssen, A, Powell, A, Piccoli, J, Sontag, M, Black-Shinn, J, Kinney, G, Curtis, J, Kazerooni, E, Hanania, N, Alapat, P, Bandi, V, Guntupalli, K, Guy, E, Mallampalli, A, Trinh, C, Atik, M, Al-Azzawi, H, Willis, M, Pinero, S, Fahr, L, Nachiappan, A, Bray, C, Frigini, LA, Farinas, C, Katz, D, Freytes, J, Marciel, AM, Washko, G, Jacobson, F, Hatabu, H, Clarke, P, Gill, R, Hunsaker, A, Trotman-Dickenson, B, Madan, R, Thomashow, B, Hersh, CP, Make, BJ, Lynch, DA, Barr, RG, Bowler, RP, Calverley, PMA, Castaldi, PJ, Cho, MH, Coxson, HO, DeMeo, DL, Foreman, MG, Han, MLK, Harshfield, BJ, Hokanson, JE, Lutz, S, Ramsdell, JW, Regan, EA, Rennard, SI, Schroeder, JD, Sciurba, FC, Steiner, RM, Tal-Singer, R, van Beek, EJR, Silverman, EK, Crapo, JD, Lantz, R, Stepp, L, Melanson, S, Beaty, T, Laird, N, Lange, C, Santorico, S, Hansel, N, McDonald, ML, Zhou, J, Mattheisen, M, Wan, E, Hardin, M, Hetmanski, J, Parker, M, Murray, T, Newell, J, Reilly, J, Judy, P, Hoffman, E, Estepar, RSJ, Ross, J, Al Qaisi, M, Zach, J, Kluiber, A, Sieren, J, Mann, T, Richert, D, McKenzie, A, Akhavan, J, Stinson, D, Jensen, R, Farzadegan, H, Meyerer, S, Chandan, S, Bragan, S, Everett, D, Williams, A, Wilson, C, Forssen, A, Powell, A, Piccoli, J, Sontag, M, Black-Shinn, J, Kinney, G, Curtis, J, Kazerooni, E, Hanania, N, Alapat, P, Bandi, V, Guntupalli, K, Guy, E, Mallampalli, A, Trinh, C, Atik, M, Al-Azzawi, H, Willis, M, Pinero, S, Fahr, L, Nachiappan, A, Bray, C, Frigini, LA, Farinas, C, Katz, D, Freytes, J, Marciel, AM, Washko, G, Jacobson, F, Hatabu, H, Clarke, P, Gill, R, Hunsaker, A, Trotman-Dickenson, B, Madan, R, and Thomashow, B

Abstract

Background: Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients. Methods: Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 < 5%). Results: Out of 4197 COPD subjects, 1687 were classified as emphysema-predominant and 1817 as non-emphysematous; 693 had LAA-950 between 5-10% and were not categorized. Subjects with emphysema-predominant COPD were older (65.6 vs 60.6 years, p < 0.0001) with more severe COPD based on airflow obstruction (FEV1 44.5 vs 68.4%, p < 0.0001), greater exercise limitation (6-minute walk distance 1138 vs 1331 ft, p < 0.0001) and reduced quality of life (St. George's Respiratory Questionnaire score 43 vs 31, p < 0.0001). Self-reported diabetes was more frequent in non-emphysematous COPD (OR 2.13, p < 0.001), which was also confirmed using a strict definition of diabetes based on medication use. The association between diabetes and non-emphysematous COPD was replicated in the ECLIPSE study. Conclusions: Non-emphysematous COPD, defined by airflow obstruction with a paucity of emphysema on chest CT scan, is associated with an increased risk of diabetes. COPD patients without emphysema may warrant closer monitoring for diabetes, hypertension, and hyperlipidemia and vice versa.

Published
2014

16. Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

Author

Dijkstra, AE, Smolonska, J, van den Berge, M (Maarten), Wijmenga, C, Zanen, P, Luinge, MA, Platteel, M, Lammers, JW, Dahlback, M, Tosh, K, Hiemstra, PS, Sterk, PJ, Spira, A, Vestbo, J, Nordestgaard, BG, Benn, M, Nielsen, SF, Dahl, M, Verschuren, WM, Picavet, HSJ, Smit, HA, Owsijewitsch, M, Kauczor, HU, de Koning, Harry, Nizankowska-Mogilnicka, E, Mejza, F, Nastalek, P, van Diemen, CC, Cho, MH, Silverman, EK, Crapo, JD, Beaty, TH, Lomas, DA, Bakke, P, Gulsvik, A, Bosse, Y, Obeidat, MA, Loth, Daan, Lahousse, Lies, Rivadeneira, Fernando, Uitterlinden, André, Hofman, Bert, Stricker, Bruno, Brusselle, Guy, Duijn, Cornelia, Brouwer, U, Koppelman, GH, Vonk, JM, Nawijn, MC, Groen, HJM, Timens, W, Boezen, HM, Postma, DS, Dijkstra, AE, Smolonska, J, van den Berge, M (Maarten), Wijmenga, C, Zanen, P, Luinge, MA, Platteel, M, Lammers, JW, Dahlback, M, Tosh, K, Hiemstra, PS, Sterk, PJ, Spira, A, Vestbo, J, Nordestgaard, BG, Benn, M, Nielsen, SF, Dahl, M, Verschuren, WM, Picavet, HSJ, Smit, HA, Owsijewitsch, M, Kauczor, HU, de Koning, Harry, Nizankowska-Mogilnicka, E, Mejza, F, Nastalek, P, van Diemen, CC, Cho, MH, Silverman, EK, Crapo, JD, Beaty, TH, Lomas, DA, Bakke, P, Gulsvik, A, Bosse, Y, Obeidat, MA, Loth, Daan, Lahousse, Lies, Rivadeneira, Fernando, Uitterlinden, André, Hofman, Bert, Stricker, Bruno, Brusselle, Guy, Duijn, Cornelia, Brouwer, U, Koppelman, GH, Vonk, JM, Nawijn, MC, Groen, HJM, Timens, W, Boezen, HM, and Postma, DS

Abstract

Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and metaanalysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (>= 20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25610(-6), OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3610 29) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.

Published
2014

17. CT metrics of airway disease and emphysema in severe COPD

Author

Kim, WJ, Silverman, EK, Hoffman, E, Criner, GJ, Mosenifar, Z, Sciurba, FC, Make, BJ, Carey, V, San José Estépar, R, Diaz, A, Reilly, JJ, Martinez, FJ, Washko, GR, Fishman, AP, Bozzarello, BA, Al-Amin, A, Katz, M, Wheeler, C, Baker, E, Barnard, P, Cagle, P, Carter, J, Chatziioannou, S, Conejo-Gonzales, K, Dubose, K, Haddad, J, Hicks, D, Kleiman, N, Milburn-Barnes, M, Nguyen, C, Reardon, M, Reeves-Viets, J, Sax, S, Sharafkhaneh, A, Wilson, O, Young, C, Espada, R, Butanda, R, Ellisor, M, Fox, P, Hale, K, Hood, E, Jahn, A, Jhingran, S, King, K, Miller, C, Nizami, I, Officer, T, Ricketts, J, Rodarte, J, Teague, R, Williams, K, Reilly, J, Sugarbaker, D, Fanning, C, Body, S, Duffy, S, Formanek, V, Fuhlbrigge, A, Hartigan, P, Hooper, S, Hunsaker, A, Jacobson, F, Moy, M, Peterson, S, Russell, R, Saunders, D, Swanson, S, McKenna, R, Mohsenifar, Z, Geaga, C, Biring, M, Clark, S, Cutler, J, Frantz, R, Julien, P, Lewis, M, Minkoff-Rau, J, Yegyan, V, Joyner, M, De-Camp, M, Stoller, J, Meli, Y, Apostolakis, J, Atwell, D, Chapman, J, DeVilliers, P, Dweik, R, Kraenzler, E, Lann, R, Kurokawa, N, Marlow, S, McCarthy, K, McCreight, P, Mehta, A, Meziane, M, Minai, O, and Steiger, M

Subjects
respiratory system, respiratory tract diseases
Abstract

Background: CT scan measures of emphysema and airway disease have been correlated with lung function in cohorts of subjects with a range of COPD severity. The contribution of CT scan-assessed airway disease to objective measures of lung function and respiratory symptoms such as dyspnea in severe emphysema is less clear. Methods: Using data from 338 subjects in the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study, densitometric measures of emphysema using a threshold of -950 Hounsfield units (%LAA-950) and airway wall phenotypes of the wall thickness (WT) and the square root of wall area (SRWA) of a 10-mm luminal perimeter airway were calculated for each subject. Linear regression analysis was performed for outcome variables FEV1and percent predicted value of FEV1with CT scan measures of emphysema and airway disease. Results: In univariate analysis, there were significant negative correlations between %LAA-950 and both the WT (r = -0.28, p = 0.0001) and SRWA (r = -0.19, p = 0.0008). Airway wall thickness was weakly but significantly correlated with postbronchodilator FEV1% predicted (R = -0.12, p = 0.02). Multivariate analysis showed significant associations between either WT or SRWA (β = -5.2, p = 0.009; β = -2.6, p = 0.008, respectively) and %LAA-950 (β = -10.6, p = 0.03) with the postbronchodilator FEV1% predicted. Male subjects exhibited significantly thicker airway wall phenotypes (p = 0.007 for WT and p = 0.0006 for SRWA). Conclusions: Airway disease and emphysema detected by CT scanning are inversely related in patients with severe COPD. Airway wall phenotypes were influenced by gender and associated with lung function in subjects with severe emphysema. © 2009 American College of Chest Physicians.

Published
2009

18. Apolipoprotein E genotype predicts 24-month Bayley scales infant development score

Author

Wright, RO, Hu, H, Silverman, EK, Tsaih, SW, Schwartz, J, Bellinger, D, Palazuelos, E, Weiss, ST, Hernandez-Avila, M, and University of Groningen

Subjects
E-DEFICIENT MICE, ALZHEIMERS-DISEASE, LEAD-EXPOSURE, CHOLESTEROL TRANSPORT, LIPOPROTEIN RECEPTORS, NEURODEGENERATION, AGE 2 YEARS, lipids (amino acids, peptides, and proteins), CHILDREN, BRAIN, DEGENERATION
Abstract

Apolipoprotein E (APOE) regulates cholesterol and fatty acid metabolism, and may mediate synaptogenesis during neurodevelopment. To our knowledge, the effects of APOE4 isoforms on infant development have not been studied. This study was nested within a cohort of mother-infant pairs living in and around Mexico City. A multiple linear regression model was constructed using the 24-mo Mental Development Index (MDI) of the Bayley Scale as the primary outcome and infant APOE genotype as the primary risk factor of interest. Regression models stratified on APOE genotype were constructed to explore effect modification. Of 311 subjects, 53 (17%) carried at least one copy of the APOE4 allele. Mean (SD) MDI scores among carriers with at least one copy of APOE4 Were 94.1 (14.3) and among E3/E2 carriers were 91.2 (14.0). After adjustment for covariates, APOE4 carrier status was associated with a 4.4 point (95% confidence interval: 0.1-8.7; p = 0.04) higher 24-mo MDL. In the stratified regression models, the negative effects for umbilical cord blood lead level on 24-mo MDI score was approximately 4-fold greater among APOE3/APOE2 carriers than among APOE4 carriers. These results suggest that subjects with the E4 isoform of APOE may have advantages over those with the E2 or E3 isoforms with respect to early life neuronal/brain development.

Published
2003

19. Family-based association analysis of beta(2)-adrenergic receptor polymorphisms in the Childhood Asthma Management Program

Author

Silverman, EK, Kwiatkowski, DJ, Sylvia, JS, Lazarus, R, Drazen, JM, Lange, C, Laird, NM, Weiss, ST, and University of Groningen

Subjects
haplotype, ALBUTEROL, bronchodilator, CHILDREN, asthma, SUSCEPTIBILITY, association analysis, GENOTYPE, single nucleotide polymorphism, HYPERRESPONSIVENESS, GENOME-WIDE SEARCH, LINKAGE, genetics, GENETIC POLYMORPHISMS, HAPLOTYPES, POPULATION
Abstract

Background: beta(2)-Adrenergic receptor (B2AR) polymorphisms have been associated with a variety of asthma-related phenotypes, but association results have been inconsistent across different studies. Objective: We sought to apply family-based association methods to individual single nucleotide polymorphisms (SNPs) and haplotypes of SNPs in B2AR to define the relationship of these genetic variants to asthma-related phenotypes. Methods: DNA samples were obtained from 707 Childhood Asthma Management Program participants, representing 650 sibships, as well as their parents. Genotyping was performed at 8 B2AR SNPs. Qualitative asthma-related phenotypes were analyzed with single SNPs and haplotypes by using TRANSMIT; quantitative asthma-related phenotypes were analyzed with the Family-Based Association Test. Results: Several SNPs, including SNP -654 and SNP +46, demonstrated significant associations (P Conclusion: B2AR variants are associated with spirometric values and bronchodilator responsiveness, but different regions of the gene provide evidence for association with these phenotypes.

Published
2003

21. Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three US ethnic groups and exploratory case-control disease association studies

Author

Lazarus, R, Klimecki, WT, Raby, BA, Vercelli, D, Palmer, LJ, Kwiatkowski, DJ, Silverman, EK, Martinez, F, Weiss, ST, and University of Groningen

Subjects
TLR9, haplotype, Toll-like receptor, case-control studies, BACTERIAL-DNA, SNP, POPULATIONS, ethnic groups, linkage disequilibrium
Abstract

TLR9 is a mammalian Toll-like receptor homologue that appears to function as an innate immune pattern recognition protein for motifs that are far more common in bacterial than in mammalian DNA. The gene was sequenced in 71 subjects from three self-identified U.S. ethnic groups to identify single-nucleotide polymorphisms (SNPs). A total of 20 SNPs were found of which only 20% were in the public dbSNP database. Four SNPs were relatively common in all three ethnic samples. Using these four SNPs, seven distinct haplotypes were statistically inferred, of which four accounted for 75% or more chromosomes. These four haplotypes could be distinguished from each other by the alleles of two SNPs (- 1237 and 2848). Five exploratory nested case-control disease-association studies (asthma, DVT, MI, and COPD in European Americans and asthma in African Americans) were performed by genotyping DNA collected from four ongoing cohort studies. There was evidence suggesting increased risk for asthma with a C allele at - 1237 (odds ratio 1.85, 95%Cl 1.05 to 3.25) among European Americans (genotypes available from 67 cases and 152 controls). No other significant disease associations were detected. Replication of this finding in other, larger samples is needed. This study suggests that there is substantial diversity in human TLR9, possibly associated with asthma in Europeans but not African Americans. No association was detected with three other diseases potentially related to innate immunity. (C) 2003 Elsevier Science (USA). All rights reserved.

Published
2003

22. Paired inspiratory-expiratory chest CT scans to assess for small airways disease in COPD

Author

Hersh, CP, Washko, GR, Estépar, RSJ, Lutz, S, Friedman, PJ, Han, MLK, Hokanson, JE, Judy, PF, Lynch, DA, Make, BJ, Marchetti, N, Newell, JD, Sciurba, FC, Crapo, JD, Silverman, EK, Hersh, CP, Washko, GR, Estépar, RSJ, Lutz, S, Friedman, PJ, Han, MLK, Hokanson, JE, Judy, PF, Lynch, DA, Make, BJ, Marchetti, N, Newell, JD, Sciurba, FC, Crapo, JD, and Silverman, EK

Abstract

Background: Gas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD. We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease.Methods: Smokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans. Emphysema was quantified by the percent of lung with attenuation < -950HU on inspiratory CT. Four gas trapping measures were defined: (1) Exp-856, the percent of lung < -856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC856-950, the difference between expiratory and inspiratory lung volumes with attenuation between -856 and -950 HU; and (4) Residuals from the regression of Exp-856 on percent emphysema.Results: In 8517 subjects with complete data, Exp-856 was highly correlated with emphysema. The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema. Exp-856, E/I MLA and RVC856-950 were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema. In subjects with severe emphysema, E/I MLA and RVC856-950 showed the highest correlations with clinical variables.Conclusions: Quantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans. © 2013 Hersh et al.; licensee BioMed Central Ltd.

Published
2013

23. Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene

Author

Himes, BE, Sheppard, K, Berndt, A, Leme, AS, Myers, RA, Gignoux, CR, Levin, AM, Gauderman, WJ, Yang, JJ, Mathias, RA, Romieu, I, Torgerson, DG, Roth, LA, Huntsman, S, Eng, C, Klanderman, B, Ziniti, J, Senter-Sylvia, J, Szefler, SJ, Lemanske, RF, Zeiger, RS, Strunk, RC, Martinez, FD, Boushey, H, Chinchilli, VM, Israel, E, Mauger, D, Koppelman, GH, Postma, DS, Nieuwenhuis, MAE, Vonk, JM, Lima, JJ, Irvin, CG, Peters, SP, Kubo, M, Tamari, M, Nakamura, Y, Litonjua, AA, Tantisira, KG, Raby, BA, Bleecker, ER, Meyers, DA, London, SJ, Barnes, KC, Gilliland, FD, Williams, LK, Burchard, EG, Nicolae, DL, Ober, C, DeMeo, DL, Silverman, EK, Paigen, B, Churchill, G, Shapiro, SD, Weiss, ST, Himes, BE, Sheppard, K, Berndt, A, Leme, AS, Myers, RA, Gignoux, CR, Levin, AM, Gauderman, WJ, Yang, JJ, Mathias, RA, Romieu, I, Torgerson, DG, Roth, LA, Huntsman, S, Eng, C, Klanderman, B, Ziniti, J, Senter-Sylvia, J, Szefler, SJ, Lemanske, RF, Zeiger, RS, Strunk, RC, Martinez, FD, Boushey, H, Chinchilli, VM, Israel, E, Mauger, D, Koppelman, GH, Postma, DS, Nieuwenhuis, MAE, Vonk, JM, Lima, JJ, Irvin, CG, Peters, SP, Kubo, M, Tamari, M, Nakamura, Y, Litonjua, AA, Tantisira, KG, Raby, BA, Bleecker, ER, Meyers, DA, London, SJ, Barnes, KC, Gilliland, FD, Williams, LK, Burchard, EG, Nicolae, DL, Ober, C, DeMeo, DL, Silverman, EK, Paigen, B, Churchill, G, Shapiro, SD, and Weiss, ST

Abstract

Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data. © 2013 Himes et al.

Published
2013

24. Peripheral blood gene expression profiles in COPD subjects

Author

Bhattacharya, S, Tyagi, S, Srisuma, S, DeMeo, DL, Shapiro, SD, Bueno, R, Silverman, EK, Reilly, JJ, Mariani, TJ, Bhattacharya, S, Tyagi, S, Srisuma, S, DeMeo, DL, Shapiro, SD, Bueno, R, Silverman, EK, Reilly, JJ, and Mariani, TJ

Abstract

To identify non-invasive gene expression markers for chronic obstructive pulmonary disease (COPD), we performed genome-wide expression profiling of peripheral blood samples from 12 subjects with significant airflow obstruction and an equal number of non-obstructed controls. RNA was isolated from Peripheral Blood Mononuclear Cells (PBMCs) and gene expression was assessed using Affymetrix U133 Plus 2.0 arrays.Tests for gene expression changes that discriminate between COPD cases (FEV1< 70% predicted, FEV1/FVC < 0.7) and controls (FEV1> 80% predicted, FEV1/FVC > 0.7) were performed using Significance Analysis of Microarrays (SAM) and Bayesian Analysis of Differential Gene Expression (BADGE). Using either test at high stringency (SAM median FDR = 0 or BADGE p < 0.01) we identified differential expression for 45 known genes. Correlation of gene expression with lung function measurements (FEV1 & FEV1/FVC), using both Pearson and Spearman correlation coefficients (p < 0.05), identified a set of 86 genes. A total of 16 markers showed evidence of significant correlation (p < 0.05) with quantitative traits and differential expression between cases and controls. We further compared our peripheral gene expression markers with those we previously identified from lung tissue of the same cohort. Two genes, RP9and NAPE-PLD, were identified as decreased in COPD cases compared to controls in both lung tissue and blood. These results contribute to our understanding of gene expression changes in the peripheral blood of patients with COPD and may provide insight into potential mechanisms involved in the disease. © 2011 Bhattacharya et al; licensee BioMed Central Ltd.

Published
2011

26. Development of Predictive Models for Airflow Obstruction in Alpha-1 Antitrypsin Deficiency.

Author

Castaldi, PJ, primary, Demeo, DL, additional, Kent, DM, additional, Campbell, EJ, additional, Barker, AJ, additional, Brantly, ML, additional, Eden, EE, additional, McElvaney, NG, additional, Rennard, SI, additional, Stocks, JM, additional, Stoller, JK, additional, Strange, C, additional, Turino, G, additional, Sandhaus, RA, additional, Griffith, JL, additional, and Silverman, EK, additional

Published
2009
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31. A Functional MMP12 Polymorphism Is Associated with Lung Function throughout Life and Delayed Onset of COPD.

Author

Hunninghake, GM, primary, Cho, MH, additional, Tesfaigzi, Y, additional, Soto-Quiros, ME, additional, Avila, L, additional, Lasky-Su, J, additional, Lange, C, additional, Demeo, DL, additional, Hersh, CP, additional, Klanderman, BJ, additional, Raby, BA, additional, Sparrow, D, additional, Shapiro, SD, additional, Silverman, EK, additional, Litonjua, AA, additional, Weiss, ST, additional, and Celedon, JC, additional

Published
2009
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49. Gene-environment interaction testing in family-based association studies with phenotypically ascertained samples: a causal inference approach.

Author

Fardo DW, Liu J, Demeo DL, Silverman EK, Vansteelandt S, Fardo, David W, Liu, Jinze, Demeo, Dawn L, Silverman, Edwin K, and Vansteelandt, Stijn

Abstract

We propose a method for testing gene-environment (G × E) interactions on a complex trait in family-based studies in which a phenotypic ascertainment criterion has been imposed. This novel approach employs G-estimation, a semiparametric estimation technique from the causal inference literature, to avoid modeling of the association between the environmental exposure and the phenotype, to gain robustness against unmeasured confounding due to population substructure, and to acknowledge the ascertainment conditions. The proposed test allows for incomplete parental genotypes. It is compared by simulation studies to an analogous conditional likelihood-based approach and to the QBAT-I test, which also invokes the G-estimation principle but ignores ascertainment. We apply our approach to a study of chronic obstructive pulmonary disorder. [ABSTRACT FROM AUTHOR]

Published
2012
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50. Genome-wide association study of smoking behaviours in patients with COPD.

Author

Siedlinski M, Cho MH, Bakke P, Gulsvik A, Lomas DA, Anderson W, Kong X, Rennard SI, Beaty TH, Hokanson JE, Crapo JD, Silverman EK, COPDGene Investigators, Siedlinski, Mateusz, Cho, Michael H, Bakke, Per, Gulsvik, Amund, Lomas, David A, Anderson, Wayne, and Kong, Xiangyang

Abstract

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10(-7). No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10(-6). Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78×10(-5) for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD. [ABSTRACT FROM AUTHOR]

Published
2011
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