Genetics, Environment & Respiratory Disease Group
Genetic Susceptibility & the Environment
Stephanie J. London, M.D., Dr.P.H.
The Genetics, Environment & Respiratory Disease Group, headed by Stephanie J. London, M.D, Dr.P.H., focuses on genetic susceptibility and interactions between genetics and the environment in relation to respiratory endpoints, including asthma, pulmonary function and chronic obstructive pulmonary disease.
London began work on genetic susceptibility to respiratory disease in 1990 with a study of lung cancer. This population-based case-control study of African-Americans and Caucasians in Los Angeles County investigated candidate genes. Later, working with her collaborators in a cohort of Shanghai men, she reported the first example of a gene-diet interaction based on a dietary biomarker. She found that the protective effect of higher intake of isothiocyanates, a chemopreventive substance in Brassica vegetables, was predominantly seen among individuals with genetically impaired ability to eliminate these compounds (GSTM1 null genotype). This finding has been widely replicated.
London now focuses on environmental causes, genetic susceptibility and interactions in relation to nonmalignant respiratory conditions. In the early 1990s, she was part of the small group of investigators at the University of Southern California who established the landmark Children's Health Study, a school-based cohort study of health effects of air pollution among Southern California children. After coming to NIEHS in 1995, she pioneered the genetic component of this study with collection of buccal cells. This addition to the study became the basis for extensive extramural funding for the investigators who succeeded her at USC.
London established a collaboration to study the role of diet, genetics and the environment in relation to asthma and chronic bronchitis in a cohort of adults of Chinese ethnicity in Singapore. She added assessment and validation of respiratory outcomes to this study. These data have shown a protective effect of dietary fiber on the development of chronic bronchitis symptoms. She and her collaborators corroborated these findings in relation to pulmonary function in the Atherosclerosis Risk in Communities (ARIC) Study. To better understand the complex interplay between correlated intakes of foods and nutrients, London and colleagues studied dietary patterns in relation to chronic bronchitis symptoms in the Singapore study. This work indicated that independent of fiber intake, high intake of a diet high in fresh and preserved red meat, refined carbohydrates, and sodium was associated with increased risk. This was the first examination of dietary patterns in relation to nonmalignant respiratory disease.
London collaborates with investigators in Norway to study early life factors in relation to asthma and allergies within the Norwegian Mother and Child (MoBa) pregnancy cohort. London received funding to follow the MoBa cohort at age seven by questionnaire to identify asthma and allergies at an age when they can be more reliably ascertained. This follow-up is ongoing. In the past two years, London has developed a study of epigenetic mechanisms for effects of in utero exposures in MoBa. Using a genome-wide platform (Illumina Methyl450K) to measure methylation in the cord blood DNA of newborns, London’s group identified methylation differences in a number of genes related to maternal smoking during pregnancy, measured objectively by cotinine levels in plasma. These findings replicated in an independent US birth cohort (Joubert et al., Environ Health Perspect 2012). London’s group is following up these findings with additional studies. Her group is also examining genome-wide methylation in relation to other in utero exposures as well as asthma, allergies and other early outcomes.
London, in collaboration with Jane Hoppin, established the Lung Health Study, a nested case-control study of adult asthma within the Agricultural Health Study (AHS), a cohort of license pesticide applicators, mostly farmers, and their spouses. The study is designed to follow up questionnaire-based findings from the AHS indicating that exposure to pesticides, especially organophosphates, are related to wheezing phenotypes. The study will also investigate exposure to pathogen associated molecules (PAMPs), such as endotoxin, in relation to asthma. Another goal is to study gene-by-environment interactions. The study staff enroll cases and controls in their homes and do measurements of pulmonary function, bronchodilator response, and exhaled nitric oxide. They also collect blood samples and house dust. Enrollment will be complete in September 2013. To date, over 2,700 subjects have been enrolled.
Since 2008, London’s genetic work has focused on genome-wide association approaches (GWAS). She published a GWAS of asthma within her case-parent triad study of childhood asthma in Mexico City (MCCAS). The study is now part of the EVE consortium of NIH-funded asthma GWASes. She has also collaborated with the Atherosclerosis Risk in Communities Study and the larger CHARGE consortium to do GWASes of pulmonary function and related phenotypes in adults. She leads the CHARGE pulmonary group which continues to analyze this rich GWAS dataset in collaboration with the SpiroMeta consortium in the UK and other European collaborators. The group has identified over 27 novel loci related to pulmonary function and the related trait of airflow obstruction (Hancock et al., Nat Genet 2010; Soler-Artigas et al., Nat Genet 2011; Wilk et al., AJRCCM 2012). The CHARGE pulmonary group has also employed genome-wide approaches to studying interaction with an environmental exposure, cigarette smoking, to identify novel findings that would have been missed by studying genetic main effects alone (Hancock et al., PLoS Genet 2012). The CHARGE pulmonary group is pursuing analyses of rare variants using exome chip, 1,000 genome imputation and sequencing data.
London earned a B.A. from Harvard College, an M.D. and an M.P.H in occupational health from Harvard Medical School, and a Dr.P.H. in epidemiology from the Harvard School of Public Health. She is licensed in California, and is Board Certified in Internal Medicine and Preventive Medicine, with Specialty in Occupational and Environmental Medicine. London was Assistant Professor, Department of Preventive Medicine at the University of Southern California School of Medicine, Los Angeles, before coming to NIEHS in 1995. She is currently a Principal Investigator at NIEHS and holds a dual appointment in the Laboratory of Respiratory Biology.
CHARGE Consortium Pulmonary Group
LA Lung Study
The LA Lung study was one of the first studies of genetic susceptibility to lung cancer using population controls and including large numbers of African-Americans. Recently, the study has been included in a number of pooled analyses from the Collaborative Studies on the Genetics of Cancer.
Mexico Childhood Asthma Study
The Mexico Childhood Asthma Study is a case-parent triad study of childhood allergic asthma in Mexico City. This study is now part of the EVE consortium of NIH-funded asthma GWAS.
The OBOZ Study will investigate whether obesity affects respiratory response to ozone. It is a collaborative effort between London’s and investigators from the Center for Environmental Medicine and Lung Biology (CEMALB) at the University of North Carolina at Chapel Hill.
Singapore Chinese Health Study
The Singapore Chinese Health Study examines the environmental, dietary and genetic risk factors for respiratory disease.
Lung Health Study
The Lung Health Study is an ongoing nested case-control study of adult asthma within the Agricultural Health Study (AHS).
- London SJ, Daly AK, Cooper J, Navidi WC, Carpenter CL, Idle JR. Polymorphism of glutathione S-transferase M1 (GSTM1) and lung cancer risk among African-Americans and Caucasians in Los Angeles County. J Natl Cancer Inst 1995;87:1246-1253. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/7563171) ]
- London SJ, Lehman TA, Taylor JA. Myeloperoxidase genetic polymorphism and lung cancer risk. Cancer Res 1997;57:5001-5003. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/9371491) ]
- London SJ, Idle JR, Daly AK, Coetzee GA. Genetic variation of CYP2A6, smoking and risk of cancer. Lancet 1999;353:898-899. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/10093988) ]
- London SJ, Yuan J-M, Chung FL, Gao YT, Coetzee GA, Yu MC, Ross RK. Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms and lung cancer risk: a prospective study of men in Shanghai, China. Lancet 2000;356:724-729. [Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11085692&query_hl=4&itool=pubmed_docsum) ]
- London SJ, Yuan J-M, Travlos G, Gao Y-T, Wilson R, Ross RK, Yu MC. Insulin-like growth factor 1, IGF-binding protein 3, and lung cancer risk in a prospective study of men in China. J. Natl Cancer Inst 2002;15:749-754. [Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12011225&query_hl=4&itool=pubmed_docsum) ]
- Romieu I, Sienra-Monge JJ, Ramirez M, Moreno-Macias H, Reyes-Ruiz NI, del Rio-Navarro BE, Hernandez-Avila M, London SJ. Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure among Mexico City children. Thorax 2004;59:8-10. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/14694237) ] [Full Text (http://thorax.bmj.com/content/59/1/8.full) ] [download the PDF (http://thorax.bmjjournals.com/cgi/reprint/59/1/8) ]
- Butler LM, Koh W-P, Lee H-P, Tseng M, Yu MC, London SJ. Prospective study of dietary patterns and persistent cough with phlegm among Chinese Singaporeans. Am J Respir Crit Care Med 2005;173:264-270, 2006. Epub Oct 20, 2005. [Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16239624&query_hl=19&itool=pubmed_docsum) ]
- Bennett WD , Hazucha MJ, Folinsbee LJ, Bromberg PA, Kissling GE, London SJ. Acute pulmonary function response to ozone(O3) in young adults as a function of body mass index (BMI). Inhalation Toxicology 2007; 19(14):1147-1154. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17987466?dopt=Abstract) ]
- Kan H, Heiss G, Rose KM, Whitsel E, Lurmann F, London SJ. Traffic exposure and lung function in adults: the Atherosclerosis Risk in Communities Study. Thorax 2007;62:873-879. [Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17442705) ]
- Håberg SE, London SJ, Stigum H, Nafstad P, Nystad W. Folic acid supplements in pregnancy and early childhood respiratory health. Archives of disease in childhood 2009;94(3):180-184. [Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=19052032) ]
- Hancock DB, Romieu I, Shi M, Sienra-Monge JJ, Wu H, Chiu GY, Li H, del Rio-Navarro BE, Eng C, Chapela R, Burchard EG, Tang H, Sullivan PF, London SJ. Genome-wide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in Mexican children. PLoS genetics 2009;5(8):e1000623. [Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=19714205) ]
- Wu H, Romieu I, Shi M, Hancock DB, Li H, Sienra-Monge JJ, Chiu GY, del Rio-Navarro BE, London SJ. Evaluation of candidate genes in a genome-wide association study of childhood asthma in Mexicans. The Journal of allergy and clinical immunology. 125(2):321-327, 2010. [Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=19910030) ]
- Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, Franceschini N, van Durme YMTA, Chen T, Barr RG, Schabath MB, Couper DJ, Brusselle GG, Psaty BM, van Duijn CM, Rotter J, Uitterlinden AG, Hofman A, Punjabi NM, Rivadeneira F, Morrison AC, Enright PL, North KE, Heckbert SR, Lumley T, Stricker BHC, O'Connor GT, London SJ. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nature genetics 2010;42:45-52. [Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=20010835) ]
- Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, Graves PE, Himes BE, Levin AM, Mathias RA, Hancock DB, Baurley J, Eng C, Stern DA, Celedón JC, Rafaels N, Capurso D, Conti DV, Roth LA, Soto-Quiros M, Togias A, Li X, Myers RA, Romieu I, Van den Berg DJ, Hu D, Hansel NN, Hernandez RD, Israel E, Salam MT, Galanter J, Avila PC, Avila L, Rodriquez-Santana JR, Chapela R, Rodriguez-Cintron W, Diette GB, Adkinson NF, Abel RA, Ross KD, Shi M, Faruque WMU, Dunston GM, Watson HR, Mantese VJ, Ezurum SC, Liang L, Ruczinski I, Ford JG, Huntsman S, Chung KF, Vora H, Li X, Calhoun WJ, Castro M, Sierra-Monge JJ, del Rio-Navarro B, Deichmann KA, Heinzmann A, Wenzel SE, Busse WW, Gern JE, Lemanske Jr. RF, Beaty TH, Bleecker ER, Raby BA, Meyers DA, London SJ, Gilliland FD, Burchard EG, Martinez FD, Weiss ST, Williams LK, Barnes KD, Ober C, and Nicolae DL. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat Genet 2011;43(9):887-92. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/21804549) ]
- Soler Artigas M‡, Loth D‡, Wain LV‡, Gharib SA‡, Obeidat M‡, Tang W‡, Zhai G, Zhao JH, Smith AV, Huffman JE, Albrecht E, Jackson CM, Evans DM, Cadby G, Fornage M, Manichaikul A, Lopez JM, Johnson T, Aldrich MC, Aspelund T, Barroso I, Campbell H, Cassano PA, Couper DJ, Eiriksdottir G, Franceschini N, Garcia M, Gieger C, Gislason GK, Grkovic I, Hammond CJ, Hancock DB, Harris TB, Ramasamy A, Heckbert SR, Heliövaara M, Homuth G, Hysi PG, James AL, Jankovic S, Joubert BR, Karrasch S, Klopp N, Kritchevsky SB, Koch B, Kritchevsky SB, Launer LJ, Liu Y, Loehr LR, Lohman K, Loos RJP, Lumley T, Balushi A, Ang WQ, Barr GR, Beilby J, Beilin LJ, Blakey JD, Boban M, Boraska V, Brisman J, Britton JR, Brusselle GG, Cooper C, Curjuric I, Dahgam S, Deary IJ, Ebrahim S, Eijgelsheim M, Francks C, Gaysina D, Granell R, Gu X, Hankinson JL, Hardy R, Harris SE, Henderson J, Henry A, Hingorani AD, Hofman A, Holt PG, Hui J, Hunter ML, Imboden M, Jameson KA, Kerr SM, Kolcic I, Kronenberg F, Liu JZ, Marchini J, McKeever T, Morris AD, Olin A-C, Porteus D, Postma DS, Rich SS, Ring SM, Rivadeneira F, Rochat T, Sayer AA, Sayers I, Sly PD, Smith GD, Sood A, Starr JM, Uitterlinden AG, Vonk JM, Wannamethee SG, Whincup PH, Wijmenga C, Williams OD, Wong A, Mangino M, Marciante KD, McArdle WL, Meibohm B, Morrison AC, North KE, Omenaas E, Palmer LJ, Pietiläinen KH, Pin I, Polašek O, Pouta A, Psaty BM, Hartikainen A-L, Rantanen T, Ripatti S, Rotter JI, Rudan I, Rudnicka AR, Schulz H, Shin S-Y, Spector TD, Surakka I, Vitart V, Völzke H, Wareham NJ, Warrington NM, Wichmann H-E, Wild SH, Wilk JB, Wjst M, Wright AF, Zgaga L, Zemunik T, Pennell CE, Nyberg F, Kuh D, Holloway JW, Boezen HM, Lawlor DA, Morris RW, Probst-Hensch N, The International Lung Cancer Consortium, GIANT Consortium, Kaprio J, Wilson JF, Hayward C, Kähönen M, Heinrich J, Musk AW, Jarvis DL, Gläser S, Järvelin M-R, Stricker BHC‡, Elliott P‡, O'Connor GT‡, Strachan DP‡, London SJ‡*, Hall IP‡, Gudnason V‡, Tobin MD‡*. [‡ Equal contribution. *Corresponding authors – SJ London for the CHARGE consortium, MD Tobin for the SpiroMeta Consortium]. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.Nature Genet 2011;43:1082-90. [Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=21946350) ]
- Hancock DB, Romieu I, Chiu GY, Sienra-Monge JJ, Li H, Estela del Rio-Navarro B, London SJ. STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children. Journal of Allergy and Clinical Immunology 2012;129(6):1673-6. [Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=22534531) ]
- Joubert BR, Håberg SE, Nilsen RM , Wang X, Vollset SE, Murphy SK, Huang Z, Hoyo C, Midttun O, Cupul-Uicab LA , Ueland PM, Wu MC, Nystad W , Bell DA , Peddada SD , London SJ. 450K Epigenome-Wide Scan Identifies Differential DNA Methylation in Newborns Related to Maternal Smoking during Pregnancy.. Environmental Health Perspectives 2012;120(10):1425-31. [Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=22851337) ]
- Hancock DB*, Soler Artigas M*, Gharib SA*, Henry A*, Manichaikul A*, Ramasamy A*, Loth DW*, Imboden M, Koch B, McArdle WL, Smith AV, Smolonska J, Sood A, Tang W, Wilk JB, Zhai G, Zhao JH, Aschard H, Burkart KM, Curjuric I, Eijgelsheim M, Elliott P, Gu X, Harris TB, Janson C, Homuth G, Hysi PG, Liu JZ, Loehr LR, Lohman K, Loos RJF, Manning AK, Marciante KD, Obeidat M, Postma DS, Aldrich MC, Brusselle GG, Chen T-H, Eiriksdottir G, Franceschini N, Heinrich J, Rotter JI, Wijmenga C, Williams OD, Bentley AR, Hofman A, Laurie CC, Lumley T, Morrison AC, Joubert BR, Rivadeneira F, Couper DJ, Kritchevsky SB, Liu Y, Wjst M, Wain LV, Vonk JM, Uitterlinden AG, Rochat T, Rich SS, Psaty BM, O’Connor GT, North KE, Mirel DB, Meibohm B, Launer LJ, Khaw K-T, Hartikainen A-L, Hammond CJ, Gläser S, Marchini J, Kraft P, Wareham NJ, Völzke H, Stricker BHC, Spector TD, Probst-Hensch NM, Jarvis D, Jarvelin M-R, Heckbert SR, Gudnason V, Boezen HM, Barr RG, Cassano PA†, Strachan DP†, Fornage M†, Hall IP†, Dupuis J†, Tobin MD†, London SJ†. Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. PLoS Genetics. 2012: 8: e1003098 [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/23284291) ]
- 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 Jr, Zeiger RS, Strunk RC, Martinez FD, Boushey H, Chinchilli VM, Israel E, Mauger D, Koppelman GH, Postma DS, Nieuwenhuis MA, 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. Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene. PLOS ONE 2013;8(2):e56179-. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/23457522?dopt=Abstract) ]
- Bertelsen RJ, Longnecker MP, Løvik M, Calafat AM, Carlsen KH, London SJ, Lødrup Carlsen LC. Triclosan Exposure and Allergic Sensitization in Norwegian Children. Allergy 2013 68:84-91. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/23146048) ]