TITLE: Pathways to Disease: The Biological Consequences of Social Adversity on Asthma in Minority Youth

Transcription

1 AWARD NUMBER: W81XWH TITLE: Pathways t Disease: The Bilgical Cnsequences f Scial Adversity n Asthma in Minrity Yuth PRINCIPAL INVESTIGATOR: Neeta Thakur, MD CONTRACTING ORGANIZATION: University f Califrnia San Francisc San Francisc, CA REPORT DATE: OCT 2017 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel Cmmand Frt Detrick, Maryland DISTRIBUTION STATEMENT: Apprved fr public release; distributin unlimited The views, pinins and/r findings cntained in this reprt are thse f the authr(s) and shuld nt be cnstrued as an fficial Department f the Army psitin, plicy r decisin unless s designated by ther dcumentatin.

2 REPORT DOCUMENTATION PAGE Frm Apprved OMB N Public reprting burden fr this cllectin f infrmatin is estimated t average 1 hur per respnse, including the time f r reviewing instructins, searching existing data surces, gathering and maintaining the data needed, and cmpleting and reviewing this cllectin f infrmatin. Send cmments regarding this burden estimate r an y ther aspect f this cllectin f infrmatin, including suggestins fr reducing this burden t Department f Defense, Washingtn Headquarters Services, Directrate fr Infrmatin Operatins and Reprts ( ), 1215 Jeffersn Davis Highway, Suite 1204, Arlingtn, VA Respndents shuld be aware that ntwithstanding any ther prvisin f law, n persn shall be subject t any penalty fr failing t cmply with a cllectin f infrmatin if it des nt display a curren tly valid OMB cntrl number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE Octber TITLE AND SUBTITLE 2. REPORT TYPE Annual Pathways t Disease: The bilgical Cnsequences f Scial Adversity n Asthma in Minrity Yuth 3. DATES COVERED 30Sep Sep2017 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Neeta Thakur, MD 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER Neeta.Thakur@ucsf.edu 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER University f Califrnia San Francisc 1855 Flsm, Ste 425 San Francisc, CA SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR S ACRONYM(S) U.S. Army Medical Research and Materiel Cmmand Frt Detrick, Maryland SPONSOR/MONITOR S REPORT NUMBER(S) 12. DISTRIBUTION / AVAILABILITY STATEMENT Apprved fr Public Release; Distributin Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Asthma incidence is increasing wrldwide and disprprtinately affects disadvantaged and minrity ppulatins. There is verrepresentatin in the Active Duty military f lw incme and minrity ppulatins, including African Americans and Latins. These ppulatins experience the greatest scial adversities and have significant asthma burden. The etilgy f asthma-related disparities is multifactrial and knwn t be affected by pverty and its assciated expsures. Chrnic expsure t scial adversities may trigger a stress respnse resulting in mdulatin f immune and hrmnal respnses and disruptin f the bdy s micrbime. This txic stress respnse is likely t be unique in each racial/ethnic grup and depend n genetic susceptibility, the envirnment, and persnal upbringing. The current prpsal will address the cause, treatment, and preventin f asthma in high-risk ppulatins. Aim 1 will fcus n the immune system and hypthalamus-pituitary-adrenal axis respnse t scial adversities and the effect n asthma utcmes (n=1000). Aim 2 will fcus n the effect f scial adversities n the micrbime and if the differences bserved are assciated with asthma (n=200). The prpsal will allw fr us t delineat e the pathways by which scial adversities impart their effects and identify pints fr interventin t imprve asthma related utcmes. 15. SUBJECT TERMS Nthing listed 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT a. REPORT Unclassified b. ABSTRACT Unclassified c. THIS PAGE Unclassified 18. NUMBER OF PAGES Unclassified 10 19a. NAME OF RESPONSIBLE PERSON USAMRMC 19b. TELEPHONE NUMBER (include area cde) Standard Frm 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18

3 Table f Cntents Page 1. Intrductin Keywrds Accmplishments Impact Changes/Prblems Prducts Participants & Other Cllabrating Organizatins Special Reprting Requirements Appendix...7

4 1. Intrductin Asthma incidence is increasing wrldwide and disprprtinately affects disadvantaged and minrity ppulatins. The etilgy f asthma-related disparities is multifactrial and knwn t be affected by pverty and its assciated expsures. There is verrepresentatin in the Active Duty military f lw incme and minrity ppulatins, including African Americans and Latins. These ppulatins experience the greatest scial adversities and have significant asthma burden, including higher asthma mrtality. Chrnic expsure t scial adversities may trigger a txic stress respnse resulting in mdulatin f the immune and hrmnal respnse and disruptin f the bdy s micrbime, bth f which have been shwn t negatively affect disease utcmes. This txic stress respnse is likely t be unique in each racial/ethnic grup and depend n genetic susceptibility, the envirnment, and persnal upbringing. The current prpsal will address the cause, treatment, and preventin f asthma in high-risk ppulatins. This will be achieved by delineating the pathways by which scial adversities impart their effects n asthma susceptibility and mrbidity in minrity ppulatins. Aim 1 fcused n the immune system and hypthalamus-pituitary-adrenal axis respnse t scial adversities and their effect n asthma susceptibility and mrbidity. We have measured 1000 f the prpsed ttal f 1000 samples. Aim 2 will fcus n the effect f scial adversities n the micrbime and if the differences bserved are assciated with asthma. The measurement f the micrbime (n=200) has been cmpleted. The prpsal will allw fr better identificatin f high-risk ppulatins and develpment f interventins that target the mdifiable aspects f scial adversities t effectively imprve asthma utcmes. 2. Keywrds Asthma, Adlescents, Yung Adults, Chrnic Stress, Sciecnmic Stress, Txic Stress, Minrity Health, Health Disparities, Prtein-based Bimarkers, Micrbime, Allstatic Lad. 3. Accmplishments What were the majr gals f the prject? There are tw majr gals fr the study that align with the Specific Aims. The first majr gal is t measure bimarkers related t the immune and neurendcrine system. We have measured immune- and neurendcrine-related bimarkers n 1000 participants. The secnd majr gal is t measure and examine the ral micrbime in relatin t measures f psychscial and sciecnmic stress and asthma. Using PCR, we have amplified the V4 16S rrna hypervariable regin in 188 individuals. What was accmplished under these gals? Under the first majr gal, t measure bimarkers related t the immune and neurendcrine system, we measured immune- and neurendcrine-related bimarkers n 1000 participants. The bimarkers were measured in ur labratry using immunassays r sent t ur clinical labratry. As part f a preliminary study fr this prpsal, we measured TNF-alpha, a pr-inflammatry cytkine assciated with bth asthma and psychscial stress, in ur African American participants with asthma (n=576). As part f this prpsal, we have cmpleted an analysis

5 examining the effect f perceived racial discriminatin n brnchdilatr respnse (a measure f airway cntractility) t albuterl (the mainstay rescue drug fr asthma) amng African American yuth with asthma. We knw that asthma is a multifactrial disease with varying risk prfiles and utcmes, and thus, phentypes. Hwever, it is unknwn which f these asthma phentypes are vulnerable t psychscial stress, the main expsure f interest fr this prpsal and a well described independent cntributr t asthma mrbidity. Almst half f participants (48.8%) reprted experiencing racial discriminatin. Thse reprting discriminatin were lder (median age 15.4 versus 12.1 years, p<0.001), had a histry f in uter smke expsure (22.1 versus 15.3%, p=0.036), and had prly cntrlled asthma (50.2 versus 33.9%; p<0.001). In the adjusted analysis, the mean BDR difference between participants reprting discriminatin and thse wh did nt was 1.70% (95%CI: %). Hwever, this difference varied with TNF- status (p=0.040). Amng individuals with TNF- high asthma, we bserved a 2.78% greater mean BDR amng thse reprting perceived discriminatin than thse nt reprting discriminatin (95%CI: %). This difference was nt seen in the TNF- lw asthma grup (0.66%, 95%CI: %; Table). This is clinically imprtant, as thse wh are at risk f pr asthma utcmes and were previusly thught t be unrespnsive t asthma medicatins may actually be respnsive and may benefit frm adjunct behaviral r envirnmental interventins. These results supprt screening fr psychscial stress in thse with mderatesevere asthma as it may reclassify asthma type and delineate a treatment path. These results were presented as an ral abstract at the 2016 UCSF Health Disparities Frum (San Francisc, CA), the 2017 American Thracic Sciety meeting (Washingtn, D.C.) and published in PLOS One as a scientific manuscript (Carlsn PLOS One 2017). Table: Mean Difference in Brnchdilatr Respnse^ and 95% CI fr Reprts f Racial Discriminatin and accrding t TNF- status fr SAGE II Participants with Asthma ( ) TNF- Status 2 Racial Discriminatin Never Any Adjusted 1 Lw 1 High 1 Reference 1.70 (0.36, 3.03) Reference 0.78 (-1.07, 2.63) Reference 2.78 (0.79, 4.77) ^ Brnchdilatr respnse: mean percentage change in measured FEV1 befre and after albuterl administratin, using the pst-albuterl spirmetry with the maximal change. 1 adjusted fr sex, age, maternal educatin, recruitment center, in uter smke expsure, daycare attendance, baseline lung functin, cntrller medicatin use, African ancestry, TNF- mean, and bimarker strage time. 2 p-interactin = 0.04 Amng the 1000 participants with measured bimarkers, 689 had cmplete data fr sciecnmic status, experiences f discriminatin, and early-life NO 2 expsure (a marker fr traffic-related air pllutin). These three variables represent different aspects f adversity: sciecnmic, psychscial, and envirnmental stress. Frm these three expsure variables, a cmpsite adversity variable was develped. Participants with 2 r mre expsures were cnsider t have high adversity expsure and thse with 1 r less expsure were cnsidered t have lw adversity expsure. CCL17 (thymus and activatin regulated chemkine- TARC) is prduced in the thymus by dendritic cells and binds t a regin n Th2 lymphcytes and induce an allergic respnse (elevated in Th2 high asthma a well-defined atpic endtype f asthma). Amng children withut asthma, participants with the high adversity were mre likely t have elevated CCL17/TARC cmpared with thse with lw adversity (94.0 pg vs 71.8 pg,

6 p=0.06); n difference in CCL17/TARC levels were nted amng kids with asthma by adversity expsure. Similarly, we fund that CHI3L1 (YKL-40), a cytkine elevated in asthma, was elevated in healthy cntrls with adversity expsure in cmparisn with children withut adversity p=0.03) and n difference was bserved amng children with asthma. These findings suggest that adversity expsures are assciated with increased atpy respnse in children withut asthma. We may nt bserve a similar respnse in children with asthma due t an verall increase due t the underlying disease state versus a differential based n case/cntrl status. Our findings will be further explred by examining ther cytkines by adversity expsure and examining skin-prick testing t evaluate fr allergen sensitizatin status by adversity expsure (gld standard fr cnfirming psitive atpy respnse). The secnd majr gal is t measure and examine the ral micrbime in relatin t measures f psychscial and sciecnmic stress and asthma. We deep sequence the 16s rrna gene frm the DNA in 188 saliva samples frm participants. DNA was extracted n all samples and the V4 16S rrna hypervariable regin was amplified. Samples were sequenced by pair-end 300 base pair reads in a MiSeq sequencer. We will nw cmpare the measured V4 regin frm ur samples t recrded libraries t define the ral micrbime in terms f richness, diversity and bacterial taxnmy. This will then be examined as it relates t stress expsures and asthma. What pprtunities fr training and prfessinal develpment has the prject prvided? Nthing t Reprt Hw were the results disseminated t cmmunities f interest? The participants included in this study are frm clinics that serve predminantly under-insured minrity cmmunities that experience an excess f scial adversities and chrnic stress. The results f the study examining the rle f perceived discriminatin n drug respnse amng African American yuth with lw and high TNF-alpha were shared with clinical prviders and utreach crdinatrs frm the Center f Yuth Wellness (Bayview neighbrhd, San Francisc, CA) and UCSF Children s Hspital Oakland (Oakland, CA) in the frmat f a jurnal club. We were able t discuss the ptential clinical implicatins and the necessary next steps t cnfirm ur findings. What d yu plan t d during the next reprting perid t accmplish the gals? Fr prject gal 1, we have cmpleted measurement f the inflammatry and neurendcrine bimarkers n 1000 participants. We are 1) examining hw the bimarkers differ by asthma diagnsis (case/cntrl study), and 2) determining if these bimarkers differ by stress expsure in thse with and withut asthma (stratified analysis). These analyses will be cmpleted in the next six mnths. Fr prject gal 2 we have measured the ral micrbime by sequencing the 16S rrna regin. Currently, we are perfrming quality cntrl. We will then define the diversity, richness, and abundance f the micrbime in the next 6 mnths. 4. Impact What was the impact n the develpment f the principal discipline(s) f the prject?

7 The preliminary results, the cntent expertise, and the infrastructure develped frm this prpsal led t the successful funding fr a lngitudinal study f early-life expsure t adversity and health, including asthma. The TARA Health Fundatin awarded $4.8 Millin dllars t establish the Bay Area Research Cnsrtium n Txic Stress and Health; UCSF (Thakur) received $819,415 t examine bimarkers as they relate t scial adversity, stress, and health (study perid: ). This study cmprehensively measures expsure t trauma and adversity in childhd that are cmmnly assciated with pst-traumatic stress disrder in adulthd and will fllw the enrlled children lngitudinally. We are btaining bispecimens at several time pints ver the curse f the study and measure inflammatry and neur-endcrine bimarkers, the micrbime, and telemere length and relate these bimarkers t the measured expsures t adversity and stress. The selectin f and methds t measure the bimarkers were directly infrmed by this study and represent the natural next step frm the current study. In 2016, the Kret Fundatin awarded University f Califrnia, Berkeley t establish the Kret Institute f Precisin Preventin (KIPP) Center. As part f this center, UCSF was awarded a subcntract (PI: Thakur, $331,885) t implement in health study in Richmnd, CA t examine the effect f scial and envirnmental stressrs based n asthma type amng adlescents with and withut asthma. This study will mirrr the abve study, and, tgether, these studies have the pprtunity t change the way we think abut scial and envirnmental adversities and health by prviding a bilgical framewrk and identifying critical pints fr interventin. What was the impact n ther disciplines? Nthing t Reprt What was the impact n technlgy transfer? Nthing t Reprt. What was the impact n sciety beynd science and technlgy? The results f this study have the ptential t have great impact n hw we classify asthma and determine treatment path. The results frm ur TNF-alpha and discriminatin and ur preliminary results suggest that these scial stressrs effect different pathways and may prvide insight n hw t apprach thse with mderate t severe asthma. We may find that thse wh are at risk f pr asthma utcmes and previusly thught t be unrespnsive t asthma medicatins may actually be respnsive and may benefit frm adjunct behaviral r envirnmental interventins. 5. Changes/Prblems Changes in apprach and reasns fr change: Nthing t Reprt. Actual r anticipated prblems r delays and actins r plans t reslve them The prpsed timeline fr ur prject was delayed. We experienced an initial delay f 3 mnths while the Department f Defense s Human Research Prtectin Office cmpleted their review f the prject. This review resulted in a lcal (UCSF) Institutinal Review Bard Amendment f the prject and we were granted apprval frm the HRPO at the end f December After selecting a subset f ur study ppulatin fr evaluatin, we experienced a secnd delay f almst three mnths in setting up ur accunt fr Clinical lab testing. At this time, we have measured the prpsed bimarkers and micrbime and are currently in the analytical stage f the prpsal.

8 Changes that had a significant impact n expenditures While there have nt been any significant changes in the verall cst f the prject, the delays listed abve have shifted the verall timeline f expenditures by six mnths. Significant changes in use r care f human subjects, vertebrate animals, bihazards, and/r select agents: Nthing t Reprt Significant changes in use r care f human subjects: Nthing t Reprt Significant changes in use r care f vertebrate animals N/A Significant changes in use f bihazards and/r select agents N/A 6. Prducts: Publicatins, cnference papers, and presentatins: S Carlsn, LN Brrel, SS Oh, C Eng, A Davis, K Meade, HJ Farber, E Brigin- Buenaventura, S Thyne, S Sen, MA LeNir, N Burke-Harris, EG Burchard, N Thakur. Perceived Discriminatin Affects Brnchdilatr Respnse in African American Yuth with Asthma. UCSF Health Disparities Research Sympsium San Francisc, CA Octber (Accepted fr Oral Presentatin) N Thakur, S Carlsn, LN Brrel, SS Oh, C Eng, A Davis, K Meade, HJ Farber, E Brigin-Buenaventura, S Thyne, S Sen, MA LeNir, N Burke-Harris, EG Burchard. Perceived Discriminatin Affects Brnchdilatr Respnse in African American Yuth with Asthma American Thracic Sciety. Washingtn, D.C. May (Accepted fr Oral Presentatin) Jurnal publicatins. S. Carlsn, Brrell N, Eng C, Nguyen M, Thyne S, LeNir MA, Burke-Harris N, Burchard EG*, Thakur N*. *These authrs cntributed equally t this wrk. Selfreprted racial/ethnic discriminatin and brnchdilatr respnse in African American yuth with asthma. PLS ONE 12(6): e PMID Bks r ther nn-peridical, ne-time publicatins: Nthing t Reprt Other publicatins, cnference papers, and presentatins. Website(s) r ther Internet site(s): Nthing t Reprt Technlgies r techniques: Nthing t Reprt Inventins, patent applicatins, and/r licenses: Nthing t Reprt Other Prducts Database: With this study, we have added plasma-based bimarker measurements and micrbime data t the SAGE II and GALA II datasets. These tw pieces f the infrmatin will

9 allw it t be pssible t perfrm analyses acrss multiple levels f data ranging frm the plasma-based bimarkers t envirnmental data. 7. Participants & Other Cllabrating Organizatins What individuals have wrked n the prject? Name: Prject Rle: Neeta Thakur Principal Investigatr Researcher Identifier (e.g. ORCID ID): Nearest persn mnth wrked: 3 Cntributin t Prject: Funding Supprt: Dr. Thakur versaw the measurement f bimarkers, came up with the research questin and analytical plans fr the preliminary study. NHLBI K23 Career Develpment Award, Parker B. Francis Fellwship Prgram, TARA Health Name: Prject Rle: Sam Oh C-I Researcher Identifier (e.g. ORCID ID): Nearest persn mnth wrked: 1 Cntributin t Prject: Funding Supprt: Dr. Oh NIH/ NIMHD; NIH/NHLBI; NIH/NIEHS; DOD; Harvard Pilgrim Health Care, Inc. Name: Prject Rle: Researcher Identifier (e.g. ORCID ID): Nearest persn mnth wrked: 2 Cntributin t Prject: Funding Supprt: Celeste Eng Research Assciate Ms. Eng INO Therapeutics; NIH/NIMHD; NIH/NHLBI: University f Califrnia Tbacc Related Disease Prgram, Tara Fundatin * Name: DngLei Hu Prject Rle: Bistatistician Researcher Identifier (e.g. ORCID ID): Nearest persn mnth wrked: 1 Cntributin t Prject: Dr. Hu

10 Funding Supprt: INO Therapeutics; NIH/NHLBI; NIH/NCI; DOD; City f Hpe/NIH/NCI; NIH/NIMHD; Harvard Pilgrim Health Care, Inc. Name: Snia Carlsn Prject Rle: Medical Student Researcher Identifier (e.g. ORCID ID): n/a Nearest persn mnth wrked: 4 Cntributin t Prject: Ms. Carlsn Funding Supprt: NIH/NIMHD UCSF PROF-PATH Has there been a change in the active ther supprt f the PD/PI(s) r senir/key persnnel since the last reprting perid? N Change What ther rganizatins were invlved as partners? Organizatin Name: Center fr Yuth Wellness Lcatin f Organizatin: San Francisc, CA Partner's cntributin t the prject In-kind supprt: SAGEII and GALAII include a ttal f 6,500 participants. This prpsal allws fr the measurement f bimarkers in 1000 f these participants. The CYW prvided assays and assciated materials fr the measurement f bimarkers in an additinal 750 individuals frm the SAGEII study. 8. Special Reprting Requirements: NA 9. Appendix: NA