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Genetics, Environment & Respiratory Disease Group

Genetic Susceptibility & the Environment

Stephanie J. London, M.D., Dr.P.H.
Stephanie J. London, M.D., Dr.P.H.
Deputy Chief, Epidemiology Branch and Senior Investigator
Tel 919-541-5772
Fax 301-480-3290
london2@niehs.nih.gov
P.O. Box 12233
Mail Drop A3-05
Durham, N.C. 27709

Research Summary

The Genetics, Environment & Respiratory Disease Group, in the Epidemiology Branch, headed by Stephanie J. London, M.D, Dr.P.H., focuses on environmental, genetic, and epigenetic factors, and their interactions, in relation to respiratory health and illness across the life-course. Outcomes of interest include asthma, allergies, pulmonary function and chronic obstructive pulmonary disease.

London began work on genetic susceptibility to respiratory disease in 1990 with a population-based case-control study of lung cancer in African-Americans and Caucasians in Los Angeles County. With collaborators on a cohort of Shanghai men she published the first example of gene-diet interaction based on a dietary biomarker; isothiocyanates, a chemopreventive substance in Brassica vegetables, were protective for lung cancer only among individuals with genetically reduced ability to eliminate these compounds. This finding has been widely replicated.

London now focuses on nonmalignant respiratory outcomes. In the early 1990s, she was part of the small group of investigators at the University of Southern California that established the landmark Children's Health Study, a school-based cohort study of health effects of air pollution. After coming to NIEHS in 1995, she developed a case-parent triad study of genetics of childhood asthma in Mexico City (MCCAS). Beginning in 2008, London’s genetic work shifted to genome-wide approaches. She publishedone of the first genome wide association studies (GWAS) of asthma in MCCAS. She has integrated MCCAS into various consortia to better understand the genetic architecture of asthma.

London collaborates extensively with the Atherosclerosis Risk in Communities Study. Through this collaboration, she established the Pulmonary Working Group within the CHARGE Consortium to study pulmonary function and related phenotypes in adults using GWAS meta-analysis. This work has led to the discovery of numerous novel loci related to pulmonary function. The CHARGE group continues to make discoveries on the genetic of pulmonary traits in collaboration with investigators around the world. London led the first study of any pulmonary phenotype to include interaction with an environmental factor (smoking) in the genome wide setting. London also leads the Genetic Epidemiology Group in the Inflammation Immunity and Disease Laboratory to follow up her GWAS findings using mouse models.

London collaborates with Norwegian investigators to study early life factors in relation to asthma and allergies within the Norwegian Mother and Child (MoBa) pregnancy cohort. London received funding for a seven-year questionnaire in MoBa to identify asthma and allergies at this age when are more reliably ascertained. To extend her asthma findings in MoBa London developed a substudy of genome wide methylation in newborns using the Illumina 450K platform. Her group published the first study of the effects of any in utero exposure using this platform. This study, now widely replicated, identified numerous novel loci differentially methylated in response to maternal smoking in pregnancy. Motivated by this finding, as proof of principle for the use of methylation signatures in newborns to identify effects of other in utero exposures and to study potential epigenetic underpinnings of asthma and other childhood diseases, London formed an international consortium of birth and childhood cohorts, the Pregnancy and Childhood Epigenetics Consortium (PACE) .The first PACE publication combined data on maternal smoking and DNA methylation in offspring from 16 cohorts identifying 6,000 differentially methylated CpGs in newborns, half of them novel and many persisting into childhood. There are numerous PACE projects underway and the consortium continues to expand.

London and colleagues completed a nested case-control study of adult asthma (The Agricultural Lung Health Study, ALHS) in over 3,000 subjects within the Agricultural Health Study (AHS), a US cohort of farmers and spouses. The study was motivated by questionnaire-based findings from the AHS of associations between farming exposures and asthma and allergies. ALHS included home visits with measurement of pulmonary function, allergic status (specific IgE), exhaled nitric oxide, detailed questionnaire information on respiratory and allergic outcomes and farm exposures across the life-course. Early life farm exposures in this study were related to reduced atopy in adults and early life raw milk consumption was related to better adult pulmonary function.  House dust endotoxin measurement were related to asthma and reduced pulmonary in asthmatics, but not with atopy. Dust microbiome has been measured in a subset. Genome wide genotyping has been completed to enable the study of gene by environment interactions and measurement of genome wide methylation with the Illumina EPIC chip is underway. Stored samples on these subjects will enable many future analyses.

London earned a B.A. from Harvard College, an M.D. from Harvard Medical School, an M.P.H in Occupational Health and Dr.P.H. in Epidemiology from the Harvard School of Public Health. She is Board Certified in Internal Medicine and in Occupational Medicine. London was an Assistant Professor in the Department of Preventive Medicine at the University of Southern California School of Medicine before coming to NIEHS in 1995. She is currently a Principal Investigator at NIEHS and holds a dual appointment in the Inflammation, Immunity and Disease Laboratory where she leads the Genetic Epidemiology Group.

Dr. London’s former trainees have gone on to positions in academia, research institutes, contract research organizations, and extramural funding agencies.

Relevance to the NIEHS Mission

Dr. London’s work takes a life-course approach to studying environmental exposures from the prenatal period onwards, genetic and epigenetic factors, and their interactions, in the etiology of respiratory and allergic disease in children and adults. Her work in birth cohorts examines the impact of in utero and early-life exposures on child health and illness. She has delineated clear methylation changes in newborns from maternal smoking in pregnancy, confirmed that these require sustained exposure across pregnancy, and established their usefulness as biomarkers in offspring of exposure during pregnancy. Her maternal smoking work provides a proof of principle for the use of genome-wide methylation data to capture signals of other prenatal exposures that may have more subtle effects. Her founding of the Pregnancy and Childhood Epigenetics (PACE) Consortium enables well-powered studies of effects of in utero exposures on methylation and of the relationship of methylation patterns at birth with child development and disease. Her work in adults, extends her focus on the interplay of early exposures and genomics to adults. In the Agricultural Lung Health Study, she found that protective effects of early exposures to the farm environment, identified previously for childhood allergic and respiratory outcomes, extend into older adulthood. Her epigenetic studies of smoking and other exposures in adults complement her work in children. Identifying methylation signatures of exposure and disease across the life-course is relevant to the NIEHS strategic goal of characterizing the exposome, and could enhance the discovery of the full range of health impacts of various environmental exposures. Her continuing discovery of novel genetic loci for pulmonary function highlights the importance of fundamental developmental pathways in respiratory health and disease in adults. Her use of mouse models to help identify the specific genes underlying our human GWAS findings and begin to explore mechanisms underlying variability in maximal attained lung growth could lead to new avenues for preventing COPD and maximizing lung health across the entire population.

Studies

Selected Publications

  1. 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. 356:724-729, 2000. [Abstract]
  2. David GL, Romieu I, Sienra-Monge JJ, Collins WJ, Ramirez-Aguilar M, del Rio-Navarro BE, Reyes-Ruiz NI, Morris R, Marzec JM, London SJ. Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase and glutathione S-transferase M1 polymorphisms and childhood asthma. Am J Respir Crit Care Med. 168:1199-1204, 2003. [Abstract] [Full Text]
  3. 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. 59:8-10, 2004. [Abstract] [Full Text] [Download the PDF]
  4. 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. 62:873-879, 2007. PMID: 17442705 [Abstract] [Full Text]
  5. 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. 94(3):180-184, 2009. [Abstract]
  6. 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. 5(8):e1000623, 2009. PMID: 19714205. [Abstract] [Full Text]
  7. 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. 42(1):45-52, 2010. PMID: 20010835. [Abstract] [Full Text]
  8. 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*. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nature Genet. 2011;43:1082-90. PMID: 21946350 [Abstract] [Full Text]
    *Co-corresponding authors with equal contribution (London for the CHARGE Consortium, Tobin for the SpiroMeta Consortium).
  9. Hancock DB, Artigas MS, 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…Kraft P, Wareham NJ, Volzke H, Stricker BH, Spector TD, Probst-Hensch NM, Jarvis D, Jarvelin MR, 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 Genet. 2012;8:e1003098. PMID: 23284291. [Abstract] [Full Text]
  10. Joubert BR, Haberg 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. Environ Health Perspect. 2012;120:1425-31. PMID: 22851337. [Abstract] [Full Text]
  11. Bertelsen RJ, Brantsaeter AL, Magnus MC, Haugen M, Myhre R, Jacobsson B, Longnecker MP, Meltzer HM, London SJ. Probiotic milk consumption in pregnancy and infancy and subsequent childhood allergic diseases. J Allergy Clin Immunol. 2014;133:165-71 e1-8. PMID: 24034345. [Abstract] [Full Text]
  12. Loth DW, Artigas MS, Gharib SA, Wain LV, Franceschini N, Koch B, Pottinger TD, Smith AV, Duan Q, Oldmeadow C...Lange LA, Barr RG, Bracke KR, Verhamme FM, Sung J, Hiemstra PS, Cassano PA, Sood A, Hayward C, Dupuis J, Hall IP, Brusselle GG, Tobin MD, London SJ. Genome-wide association analysis identifies six new loci associated with forced vital capacity. Nat Genet. 2014;46:669-77. PMID: 24929828. [Abstract] [Full Text]
  13. House JS, Li H, DeGraff LM, Flake G, Zeldin DC, London SJ. Genetic variation in HTR4 and lung function: GWAS follow-up in mouse. FASEB J. 2015;29:323-35. PMID: 25342126. [Abstract] [Full Text]
  14. Joubert BR, den Dekker HT, Felix JF, Bohlin J, Ligthart S, Beckett E, Tiemeier H, van Meurs JB, Uitterlinden AG, Hofman A, Håberg SE, Reese SE, Peters M, Kulle Andreassen B, Steegers EAP, Nilsen RM, Vollset SE, Midttun O, Ueland PM, Franco O, Dehghan O, de Jongste J, Wu MC, Wang T, Peddada SD, Jaddoe WWV, Nystad W, Duijts L, London SJ. Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns. Nature Communications. 2016;7:10577. PMID: 26861414. [Abstract] [Full Text]
  15. Joubert BR, Felix JF, Yousefi P, Bakulski KM, Just AC, Breton C, Reese S, Markunas CA, Richmond RC, Xu C-J, Kupers LK, Oh SS, Hoyo C, Gruzieva O, Soderhall C, Salas LA, Baiz N, Zhang H, Lepeule J, Ruiz C, Ligthart S, Wang T, Taylor JA, Duijts L, Sharp GC, Jankipersadsing SA, Nilsen RM, Vaez A, Fallin MD, Hu D, Litonjua AA, Fuemmeler BF, Huen K, Kere J, Kull I, Munthe-Kaas MC, Gehring U, Bustamante M, Saurel-Coubizolles MJ, Quraishi BM, Ren J, Tost J, Gonzalez JR, Peters MJ, Haberg SE, Xu Z, van Meurs JB, Gant TR, Kerkhof M, Corpeleijn E, Feinberg AP, Eng C, Baccarelli AA, Benjamin Neelon SE, Bradman A, Merid SK, Bergstrom A, Herceg Z, Hernandez-Vargas H, Brunekreef B, Pinart M, Heude B, Ewart S, Yao J, Lemonnier N, Franco OH, Wu MC, Hofman A, McArdle W, Van der Vlies P, Falahi F, Gillman MW, Barcellos LF, Kumar A, Wickman M, Guerra S, Charles M-A, Holloway J, Auffray C, Tiemeier HW, Smith GD, Postma D, Hivert M-F, Eskenazi B, Vrijheid M, Arshad H, Anto JM, Dehghan A, Karmaus W, Annesi-Maesano I, Sunyer J, Ghantous A, Pershagen G, Holland N, Murphy SK, DeMeo DL, Burchand EG, Ladd-Acosta C, Snieder H, Nystad W, Koppelman GH, Relton CL, Jaddoe VWV, Wilcox A, Melen E, London SJ. 2016. DNA methylation in newborns and maternal smoking in pregnancy: Genome-wide consortium meta-analysis. Am J Hum Genet. 2016;98:680-96. PMID: 27040690. [Abstract] [Full Text]
  16. Parr CL, Magnus MS, Karlstad Ø, Haugen M, Refsum H, Nafstad P, Håberg SE, Nystad W, London SJ. Maternal Folate Intake During Pregnancy and Childhood Asthma in a Population Based Cohort. Am J Respir Crit Care Med. 2016 Aug 12. [Epub ahead of print]. PMID: 27518161.
    [Abstract] [Full Text]
  17. Joehanes R, Just AC, Marioni RE, Pilling LC, Reynolds LM, Mandaviya PR, Guan W, Xu T, Elks CE, Aslibekyan S, Moreno-Macias H, Smith JA, Brody JA, Dhingra R, Yousefi P, Pankow JS, Kunze S, Shah S, McRae AF, Lohman K, Sha J, Absher DM, Ferrucci L, Zhao W, Demerath EW, Bressler J, Grove ML, Huan T, Liu C, Mendelson MM, Yao C, Kiel DP, Peters A, Wang-Sattler R, Visscher PM, Wray NR, Starr JM, Ding J, Rodriguez CJ, Wareham NJ, Irvin MR, Zhi D, Barrdahl M, Vineis P, Ambatipudi S, Uitterlinden AG, Hofman A, Schwartz J, Colicino E, Hou L, Vokonas PS, Hernandez DG, Singleton AB, Bandinelli S, Turner ST, Ware EB, Smith AK, Klengel T, Binder EB, Psaty BM, Taylor KD, Gharib SA, Swenson BR, Liang L, DeMeo DL, O'Connor GT, Herceg Z, Ressler KJ, Conneely KN, Sotoodehnia N, Kardia SL, Melzer D, Baccarelli AA, van Meurs JB, Romieu I, Arnett DK, Ong KK, Liu Y, Waldenberger M, Deary IJ, Fornage M, Levy D, London SJ. Epigenetic Signatures of Cigarette Smoking. Circ Cardiovasc Genet. 2016;9:436-447. PMID: 27651444.    [Abstract] [Full Text]
  18. House JS, Wyss AB, Hoppin JA, Richards M, Long S, Umbach DM, Henneberger P, Beane Freeman LE, Sandler DP, O’Connell EL, Barker Cumming C, London SJ. Early-life Farm Exposures and Adult Asthma and Atopy in the Agricultural Lung Health Study. J Allergy Clin Immunol. 2017 Jul;140(1):249-256.e14. doi: 10.1016/j.jaci.2016.09.036. Epub 2016 Nov 12. PMID: 27845237 Abstract  Free Full Text(1MB) 

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