Research Summary

The Integrative Genomic Epidemiology group, headed by Stephanie J. London, M.D, Dr.P.H., focuses on environmental, genetic, and epigenetic factors, and their interactions, in relation to health outcomes across the life-course. Outcomes of primary interest include asthma, allergies, pulmonary function and chronic obstructive pulmonary disease. The group follows up selected human findings using mouse models.

London began work on genetic susceptibility to respiratory disease in 1990 with a pioneering 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 subsequently focussed 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. London published one of the first genome wide association studies (GWAS) of asthma using MCCAS and integrated it into consortia to better understand the multi-ancestry genetic architecture of asthma.

London has collaborated extensively with the Atherosclerosis Risk in Communities Study (ARIC). 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 led to the discovery of numerous novel loci related to pulmonary function and COPD. Under London's direction, the CHARGE Pulmonary Group went on to identify over 50 new lung function loci in the first large multi-ethnic meta-analysis of these traits. London led the first study of any pulmonary phenotype to include interaction with an environmental factor (smoking) in the genome-wide setting.

London has explored other ‘omic platforms in relation to respiratory and other health outcomes. She led the first meta-analysis of multi-ethnic population based studies examining metabolomics in relation to pulmonary function. Her group led a meta-analysis of Epigenome Wide Association Studies (EWAS) of pulmonary function within the CHARGE consortium. London has examined the exposome in a birth cohort setting. London’s group recently identified circulating proteomic markers of adult asthma.

London has collaborated for many years 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, and 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 childhood health and disease, 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.

In addition to examining methylation signature of smoking exposure in newborns in PACE, London also led a larger meta-analysis of personal smoking in adults and methylation in the CHARGE consortium. Her group compared methylation signatures from these two meta-analyses and identified genes uniquely differentially methylated in relation to the newborn exposure. Subsequent PACE publications have examined newborn methylation in relation to maternal body mass index during pregnancy, maternal alcohol intake, birthweight, gestational age at birth, and prenatal air pollution (NO2 and particulate matter) and other exposures. PACE also has investigated newborn and childhood methylation in relation to various child health outcomes including childhood asthma. There are numerous PACE projects underway and the consortium continues to grow with over 50 birth and child cohorts around the world.

The Agricultural Lung Health Study, ALHS, is a study of current asthma in over 3,000 individuals nested 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. In ALHS, early life farm exposures were related to reduced allergy in adults and early life raw milk consumption was related to better adult pulmonary function. House dust endotoxin was related to asthma and to reduced pulmonary function in asthmatics. Wood burning is common in this population and was also related to reduced pulmonary function in asthmatics. Prior use of carbofuran was associated with development of sleep apnea. Based on 16s sequencing analyses of the microbiota in dust samples from participant bedrooms, her group found specific microbial signatures of current farming exposures including work with crops and farm animals and of atopy and asthma. More recently, London has employed metagenomics to more thoroughly investigate microbial composition of house dust. ALHS has also contributed to CHARGE Consortium genome wide association study (GWAS) and EWAS meta-analyses. ALHS now includes circulating proteome data.

London follows up findings from her epidemiologic studies using mouse models. She has followed up loci identified in her human GWAS studies of pulmonary function, including HTR4 and LRP1, in mouse models and is currently investigating the ADAM19 locus. London’s group is also following up her extensive investigation of methylation signatures of smoking using a mouse exposure model.

London hosted a postdoctoral fellow, Musa Kana, M.D., Ph.D., in the inaugural class of the NIH African Postdoctoral Training Initiative.

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 and Environmental 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 a tenured Senior Investigator at NIEHS.

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

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 develop objective biomarkers of smoking and 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.


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]
  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 in asthmatic children in Mexico City. Thorax. 59:8-10, 2004. [Abstract]
  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]
  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]
  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]
  8. Soler Artigas M, Loth D, Wain LV, … 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]
    *Co-corresponding authors with equal contribution (London for the CHARGE Consortium, Tobin for the SpiroMeta Consortium).
  9. Hancock DB, Artigas MS, Gharib SA…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]
  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]
  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]
  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]
  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]
  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]
  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]
  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]
  17. Joehanes R, Just AC, Marioni RE… Fornage M, Levy D, London SJ. Epigenetic Signatures of Cigarette Smoking. Circ Cardiovasc Genet. 2016;9:436-447. PMID: 27651444. [Abstract]
  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]
  19. Lee MK, Carnes MU, Butz N, Azcarate-Peril MA, Richards M, Umbach DM, Thorne PS, Beane Freeman LE, Peddada SD, London SJ. Exposures Related to House Dust Microbiota in a U.S. Farming Population. Environ Health Perspect. 2018 Jun 1;126(6):067001. doi: 10.1289/EHP3145. eCollection 2018 Jun. PMID: 29863827. [Abstract]
  20. Wyss AB, Sofer T, Lee MK…Dupuis J, Manichaikul A, London SJ. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. Nat Commun. 2018 Jul 30;9(1):2976. PMID: 30061609. [Abstract]
  21. Reese SE, Xu CJ, den Dekker HT, Lee MK, Sikdar S…Melén E, Duijts L, Koppelman GH, London SJ. Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma. J Allergy Clin Immunol. 2019 Jun;143(6):2062-2074. doi: 10.1016/j.jaci.2018.11.043. Epub 2018 Dec 21. PMID: 30579849. [Abstract]
  22. Sikdar S, Joehanes R, Joubert BR…Koppelman GH, Bustamante M, Levy D, London SJ. Comparison of Smoking-related DNA Methylation Between Newborns from Prenatal Exposure and Adults from Personal Smoking. Epigenomics. 2019 Oct;11(13):1487-1500. doi: 10.2217/epi-2019-0066. Epub 2019 Sep 19. PMID: 31536415. [Abstract]
  23. Kana MA, Ahmed J, Ashiru AY, Jibrin S, Sunday AD, Shehu K, Safiyan H, Kantiyok C, Yusuf HE, Ibrahim JM, Musa S, Baduku TS, Tabari AM, Barros H, London SJ. 2020. Child Electronic Growth Monitoring System: An innovative and sustainable approach for establishing the Kaduna Infant Development (KID) Study in Nigeria. Paediatr Perinat Epidemiol. 2020 Sep;34(5):532-543. doi: 10.1111/ppe.12641. Epub 2020 Feb 21. PMID: 32083347. [Abstract]
  24. Nichols CE, House JS, Li H, Ward JM, Wyss A, Williams JG, Deterding LJ, Bradbury JA, Miller L, Zeldin DC, London SJ. 2021. Lrp1 regulation of pulmonary function. Follow-up of human GWAS in mice. Am J Respir Cell Mol Biol. 2021 Mar;64(3):368-378. doi: 10.1165/rcmb.2019-0444OC. PMID: 33290178. [Abstract]
  25. Lee MK, Wyss AB, Carnes MU, Richards M, Parks CG, Beane Freeman LE, Thorne PS, Umbach DM, Azcarate-Peril MA, Peddada SD, London SJ. House dust microbiota in relation to adult asthma and atopy in a US farming population. J Allergy Clin Immunol. 2021 Mar;147(3):910-920. doi: 10.1016/j.jaci.2020.06.013. Epub 2020 Jun 29. PMID: 32615170. [Abstract]
  26. White JD, Wyss AB, Hoang TT, Lee M, Richards M, Parks CG, Beane-Freeman LE, Hankinson JL, Umbach DM, London SJ. 2022. Residential wood burning and pulmonary function in the Agricultural Lung Health Study. Environ Health Perspect. 2022 Aug;130(8):87008. doi: 10.1289/EHP10734. Epub 2022 Aug 25. PMID: 36006053. [Abstract]
  27. Lee M, Huan T, McCartney DL…. Dupuis J, Breeze CE, Manichaikul A, London SJ. 2022. Pulmonary function and blood DNA methylation: A multiancestry epigenome-wide association meta-analysis. m J Respir Crit Care Med. 2022 Aug 1;206(3):321-336. doi: 10.1164/rccm.202108-1907OC. PMID: 35536696. [Abstract]
  28. Chen M, Guan Y, Huang R, Duan J, Zhou J, Chen T, Wang X, Xia Y, London SJ. 2022. Associations between the maternal exposome and metabolome during pregnancy. Environ Health Perspect 130(3):37003. [Abstract]
  29. Bakulski KM, Blostein F, London SJ. Linking Prenatal Environmental Exposures to Lifetime Health with Epigenome-Wide Association Studies: State-of-the-Science Review and Future Recommendations. Environ Health Perspect. 2023 Dec;131(12):126001. doi: 10.1289/EHP12956. Epub 2023 Dec 4. PMID: 38048101. [Abstract]
  30. Wang Z, Dalton KR, Lee M, Parks CG, Beane Freeman LE, Zhu Q, González A, Knight R, Zhao S, Motsinger-Reif AA, London SJ. Metagenomics reveals novel microbial signatures of farm exposures in house dust. Front Microbiol. 2023 Jun 21;14:1202194. doi: 10.3389/fmicb.2023.1202194. PMID: 37415812. [Abstract]
  31. Smilnak GJ, Lee Y, Chattopadhyay A, Wyss AB, White JD, Sikdar S, Jin J, Grant AJ, Motsinger-Reif AA, Li JL, Lee M, Yu B, London SJ. Plasma protein signatures of adult asthma. Allergy. 2024 Mar;79(3):643-655. doi: 10.1111/all.16000. Epub 2024 Jan 23. PMID: 38263798. [Abstract]
  32. Hoang TT, Lee Y, McCartney DL…Marioni RE, Håberg SE, London SJ. Comprehensive evaluation of smoking exposures and their interactions on DNA methylation. EBioMedicine. 2024 Feb;100:104956. doi: 10.1016/j.ebiom.2023.104956. Epub 2024 Jan 9. PMID: 38199042. [Abstract]
  33. Dalton KR, Lee M, Wang Z, Zhao S, Parks CG, Beane-Freeman LE, Motsinger-Reif AA, London SJ. Occupational farm work activities influence workers' indoor home microbiome. Environ Res. 2024 Feb 15;243:117819. doi: 10.1016/j.envres.2023.117819. Epub 2023 Dec 3. PMID: 38052359. [Abstract]

Complete Publication List
ORCID ID: 0000-0003-4911-5290