A BAFF polymorphism is associated with asthma exacerbations and serum BAFF levels. BAFF expression in vivo increases in natural rhinovirus infection. BAFF may play a role in airway antiviral immunity and impact asthma exacerbation rates

Avila, Pedro C

Beckman, Kenneth

Boushey, Homer A

Burchard, Esteban G

Favoreto, Silvio

Favro, David

Grammer, Leslie

Hulse, Katie

Kato, Atsushi

Kumar, Rajesh

Lanfear, David E

LeNoir, Michael

Levin, Albert M

Meade, Kelley

Peterson, Edward L

Schleimer, Robert

Thyne, Shannon

Wang, Deli

Weiss, Kevin

Williams, L Keoki

Yang, James J

eScholarship - University of California

UCSFUC San Francisco Previously Published WorksTitleGenetic variation in B cell–activating factor of the TNF family (BAFF) and asthma exacerbations among African American subjectsPermalinkhttps://escholarship.org/uc/item/4d08m6nhJournalJournal of Allergy and Clinical Immunology, 130(4)ISSN0091-6749AuthorsKumar, RajeshWilliams, L KeokiKato, Atsushiet al.Publication Date2012-10-01DOI10.1016/j.jaci.2012.04.047 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaGenetic variation in BAFF and asthma exacerbations amongAfrican American individualsRajesh Kumar, MD, MS(1),*, L. Keoki Williams, MD, MPH(2),(3),*, Atsushi Kato, PhD(4),Edward L. Peterson, PhD(5), Silvio Favoreto Jr., DDS, PhD(4), Katie Hulse, PhD(4), DeliWang, PhD(6), Kenneth Beckman, PhD(7), Shannon Thyne, MD(8), Michael LeNoir, MD(9),Kelley Meade, MD(10), David E. Lanfear, MD, MS(2),(3), Albert M. Levin, PhD(11), David Favro,BS(2), James J. Yang, PhD(5), Kevin Weiss, MD, MPH(11), Homer A. Boushey, MD(12), LeslieGrammer, MD(4), Pedro C Avila, MD(4), Esteban G. Burchard, MD, MPH(12),(13), and RobertSchleimer, PhD(4)(1)Division of Allergy and Immunology, Children's Memorial Hospital,Chicago, IL(2)Center for Health Services Research, Henry Ford Health System, Detroit, MI(3)Department of Internal Medicine, Henry Ford Health System, Detroit, MI(4)Division of Allergy and Immunology; Department of Medicine, Northwestern University FeinbergSchool of Medicine, Chicago, IL(5)Department of Public Health Sciences, Henry Ford Health System, Detroit, MI(6)Biostatistics Research Core, Children’s Memorial Hospital and Children’s Memorial ResearchCenter, Chicago IL(7)Biomedical Genomics Center, University of Minnesota, Minneapolis, MN(8)Department of Pediatrics, University of California San Francisco, San Francisco GeneralHospital, San Francisco, CA(9)Bay Area Pediatrics, Oakland, CA(10)Children's Hospital Oakland Research Institute, Oakland, CA(11)Division of General Internal Medicine, Department of Medicine, Northwestern UniversityFeinberg School of Medicine, Chicago, IL(12)Department of Medicine, University of California San Francisco, San Francisco GeneralHospital, San Francisco, CA(13)Department of Bioengineering and Therapeutic Sciences, University of California SanFrancisco, San Francisco, CACapsule Summary© 2012 American Academy of Allergy, Asthma and Immunology. Published by Mosby, Inc. All rights reserved.Corresponding author: Rajesh Kumar MD, Division of Allergy and Immunology, 2300 Children’s Plaza #60, Children's MemorialHospital, Chicago, IL 60614.*These individuals contributed equally to the manuscript.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to ourcustomers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review ofthe resulting proof before it is published in its final citable form. Please note that during the production process errors may bediscovered which could affect the content, and all legal disclaimers that apply to the journal pertain.NIH Public AccessAuthor ManuscriptJ Allergy Clin Immunol. Author manuscript; available in PMC 2013 October 01.Published in final edited form as:J Allergy Clin Immunol. 2012 October ; 130(4): 996–9.e6. doi:10.1016/j.jaci.2012.04.047.$watermark-text$watermark-text$watermark-textA BAFF polymorphism is associated with asthma exacerbations and serum BAFF levels. BAFFexpression in vivo increases in natural rhinovirus infection. BAFF may play a role in airwayantiviral immunity and impact asthma exacerbation rates.KeywordsBAFF; B-cell activating factor; tumor necrosis factor ligand superfamily; asthma; asthmaexacerbations; geneticsTo the EditorAfrican American individuals are disproportionately affected by asthma morbidity andmortality,1 and socioeconomic factors alone do not completely account for thesedisparities.2 Viral illnesses, particularly from rhinovirus, are considered to be the mostfrequent triggers of asthma exacerbations.3 As previous studies have shown that the geneticpredictors of asthma may differ between African American and white individuals,4 it standsto reason that the predictors of asthma exacerbation may also differ by race-ethnicity. Weevaluated whether single nucleotide polymorphisms (SNPs) in genes thought to modulateinnate immune response to respiratory viruses (primarily the RIG-I and MDA5 pathwaysand BAFF related genes)5 were associated with exacerbations among African Americanindividuals with asthma.Complete methods are outlined in the online supplement. Self-identified African Americanparticipants with asthma from three independent study cohorts were included in thisanalysis. This included a discovery cohort, the Chicago Initiative to Raise Asthma HealthEquity (CHIRAH) study (n=321), and two replication cohorts, the Study of AfricanAmericans, Asthma, Genes & Environments (SAGE) (n=264) and the Study of AsthmaPhenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) (n=468)(Table E1). A subset (n=63) of unrelated African American subjects from the SAPPHIREstudy also provided serum to determine levels of BAFF by an ELISA kit which specificallyrecognized BAFF (R&D systems, Minneapolis, MN). To assess whether rhinovirus inducesBAFF expression in airways in vivo, we utilized samples from a separate study of thecommon cold in which asthmatic adults were evaluated within 3 days of onset of arhinovirus upper respiratory tract infection (proven by Virochip6 in nasal lavage), and againwhen asymptomatic at baseline (i.e., at least 42 days following cold symptom onset).6 BAFFmRNA was quantified in nasal mucosal samples through a 2-step quantitative real-time RT-PCR.We used multivariate, negative binomial regression to assess the relationship betweengenotype and risk of exacerbation in all 3 cohorts. In SAPPHIRE, Cox proportional hazardsmodels were also used to assess the relationship between genotype and the time toexacerbation. Analysis of variance was used to assess differences in the mean serum levelsof BAFF by rs17564816 genotype. Analyses of RV induced BAFF expression in vivocompared levels at a point during the acute illness (1–3 days after onset of URI) to baselinelevels (42 days after the onset of the URI) using the Wilcoxon signed rank sum test for non-parametric data. All analyses were performed using SAS v9.1 (SAS Institute Inc., Cary,NC).Of these 16 genes evaluated (see Table E2), only BAFF had an intronic SNP, rs17564816,which neared our criterion for a nominal level of significance in our discovery cohort(meeting bonferroni level of significance for the SNPs typed within a gene) with a relativerate [RR]: −2.96 (p=0.003). This borderline protective finding in the CHIRAH cohort was inKumar et al. Page 2J Allergy Clin Immunol. Author manuscript; available in PMC 2013 October 01.$watermark-text$watermark-text$watermark-textcontrast to the associations observed in the two other cohorts (Table 1). Specifically, theminor (A) allele of this SNP was associated with an increase in exacerbation rates in SAGE(RR 1.36, p=0.015). In SAPPHIRE, the A allele was also associated with an increase in EDvisits (RR 2.32, p=0.001), oral steroid courses (RR 1.68, p=0.034), and overall exacerbationrates (RR 1.96, p=0.001). Similarly, in SAPPHIRE, the A allele was associated with ashorter time to both oral steroid prescriptions (hazard ratio [HR] 2.37, p=0.001) and EDvisits (HR 2.70, p=0.001), as well as for exacerbations overall (HR 2.54, p=0.001). In arandom subset of SAPPHIRE study participants, serum levels of BAFF varied by BAFFgenotype (Online Figure E2). Those with the AA and AG genotypes had higher levels thanthose with the GG (homozygous wild type) genotypes (AA=859.3 ± 204.5 pg/ml standarddeviation [SD]; AG=821.0 ± 242.5 pg/ml SD; GG=725.6 ± 253.8 pg/ml SD; Jonckheere-Terpstra test for trend p=0.022).In a separate sample of 15 adult asthmatics with a community-acquired upper respiratorytract infection, the copy number for BAFF mRNA was almost five fold higher in nasalepithelial cell samples taken at the time of an active rhinovirus upper respiratory tractinfection (i.e., 1–3 days from the onset of symptoms mean gene copy number was 1.52x107)when compared with the post-convalescence baseline sample (i.e., at least 6 weeks aftersymptom onset the mean gene copy number was 3.09x106) (p<0.003, Wilcoxon signed ranktest) (Figure 1A). Similarly, nasal lavage samples assayed for BAFF protein showed thatBAFF was indeed induced by natural rhinovirus infection in these subjects (Figure 1B) (77.2± 107.3 pg/ml) when compared with the post convalescent sample (4.6 ± 6.3 pg/ml)(p=0.05, Mann Whitney test).In summary, an intronic SNP in the BAFF gene, rs17564816 (A allele), was associated withasthma exacerbations in two African American asthmatic cohorts, time to first exacerbation,and higher serum levels of BAFF. BAFF was also up-regulated in response to communityacquired rhinovirus infection, the most common viral infection associated withexacerbations in children and adults.7, 8 BAFF has been shown to be induced by viruses,9and be present in elevated levels in the airway epithelium of children with RSV.10 Theability of the local tissue to mount a rapid and effective local immunoglobulin responseagainst viruses is likely to be important in limiting of the extent and severity of virus-induced tissue damage. Our group has previously shown that dsRNA (a TLR3 ligand andactivator produced by RSV and rhinovirus) potently and effectively induces BAFFproduction in airway epithelial cells, and that expression of BAFF is regulated by TLR3-and IFN-β-dependent signaling.11 We hypothesize that higher serum levels of BAFF areassociated with a more aggressive immune response to virus, and this may be particularlyimportant since the interaction of innate and adaptive immune responses may provokeasthma exacerbations.12This study has limitations. Namely, there were only 5 subjects in CHIRAH with the minorallele and the allelic relationship in this cohort was in the opposite direction to the other twocohorts. Therefore the findings in CHIRAH may have been spurious. Nevertheless, the Aallele of rs17564816 was consistently and robustly associated with asthma exacerbations inboth SAPPHIRE and SAGE. Given the low frequency of this allele, we did not evaluate theinfluence of genotype on BAFF induction by rhinovirus, and further studies will be needed.In conclusion, we evaluated polymorphisms in viral response genes and found an intronicSNP in the BAFF gene associated with asthma exacerbations in African American subjectsin two of three cohorts of patients. This SNP was also associated with higher levels of BAFFcompared to individuals homozygous for the G allele. Given the importance of asthmaexacerbations in minority urban populations, further studies are needed to determine thegenetic and environmental contributors to this complex outcome.Kumar et al. Page 3J Allergy Clin Immunol. Author manuscript; available in PMC 2013 October 01.$watermark-text$watermark-text$watermark-textAcknowledgmentsThe authors would like to acknowledge Zhenling Huang MS for her contribution to this paper including analyses ofthe CHIRAH cohort.Funding: This work was funded in part through grant support from the following institutes of the NationalInstitutes of Health: the National Heart Lung and Blood Institute (NHLBI), the National Institute of Allergy andInfectious Diseases (NIAID), the National Institute of Environmental Health Sciences (NIEHS), and the NationalInstitute of Diabetes and Digestive and Kidney Disease (NIDDK). Individual grant support was as follows: Dr.Kumar received support from the NHBLI (K23HL093023); Dr. Williams received support from the NIAID(R01AI079139, R01AI61774), NHLBI (R01HL079055), NIDDK (R01DK064695), the American AsthmaFoundation, and the Fund for Henry Ford Hospital; Dr. Burchard received support from the NHLBI(R01HL078885, R01HL088133), the NIEHS (R01ES015794), the Robert Wood Johnson Foundation AmosMedical Faculty Development Program, and the Flight Attendant Medical Research Institute; Dr. Weiss receivedsupport from the NHLBI (U01HL072478), and Dr. Schleimer received support from the NIAID (R01AI072570),the NHLBI (R37HL068546) and the Ernest Bazley Grant; Dr. Boushey received support from the NIAID (P01AI50496, R21AI057506); Dr. Avila received support from the NIAID (U01AI082984).References1. Akinbami LJ, Schoendorf KC. Trends in childhood asthma: prevalence, health care utilization, andmortality. Pediatrics. 2002; 110:315–22. [PubMed: 12165584]2. Shalowitz MU, Sadowski LM, Kumar R, Weiss KB, Shannon JJ. Asthma burden in a citywide,diverse sample of elementary schoolchildren in Chicago. Ambul Pediatr. 2007; 7:271–7. [PubMed:17660097]3. Friedlander SL, Busse WW. The role of rhinovirus in asthma exacerbations. J Allergy ClinImmunol. 2005; 116:267–73. [PubMed: 16083778]4. Sleiman PM, Flory J, Imielinski M, Bradfield JP, Annaiah K, Willis-Owen SA, et al. Variants ofDENND1B associated with asthma in children. N Engl J Med. 2010; 362:36–44. [PubMed:20032318]5. Mackay F, Figgett WA, Saulep D, Lepage M, Hibbs ML. B-cell stage and context-dependentrequirements for survival signals from BAFF and the B-cell receptor. Immunol Rev. 2010;237:205–25. [PubMed: 20727038]6. Kistler A, Avila PC, Rouskin S, Wang D, Ward T, Yagi S, et al. Pan-viral screening of respiratorytract infections in adults with and without asthma reveals unexpected human coronavirus andhuman rhinovirus diversity. Journal of Infectious Diseases. 2007; 196:817–25. [PubMed:17703411]7. Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL, Pappas TE, et al. Wheezingrhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir CritCare Med. 2008; 178:667–72. [PubMed: 18565953]8. Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacerbations of asthma in adults. Bmj.1993; 307:982–6. [PubMed: 8241910]9. Ittah M, Miceli-Richard C, Gottenberg JE, Sellam J, Eid P, Lebon P, et al. Viruses induce highexpression of BAFF by salivary gland epithelial cells through TLR- and type-I IFN-dependent and -independent pathways. Eur J Immunol. 2008; 38:1058–64. [PubMed: 18350548]10. Reed JL, Welliver TP, Sims GP, McKinney L, Velozo L, Avendano L, et al. Innate immunesignals modulate antiviral and polyreactive antibody responses during severe respiratory syncytialvirus infection. J Infect Dis. 2009; 199:1128–38. [PubMed: 19278337]11. Kato A, Truong-Tran AQ, Scott AL, Matsumoto K, Schleimer RP. Airway epithelial cells produceB cell-activating factor of TNF family by an IFN-beta-dependent mechanism. J Immunol. 2006;177:7164–72. [PubMed: 17082634]12. Subrata LS, Bizzintino J, Mamessier E, Bosco A, McKenna KL, Wikstrom ME, et al. Interactionsbetween innate antiviral and atopic immunoinflammatory pathways precipitate and sustain asthmaexacerbations in children. J Immunol. 2009; 183:2793–800. [PubMed: 19620293]Kumar et al. Page 4J Allergy Clin Immunol. Author manuscript; available in PMC 2013 October 01.$watermark-text$watermark-text$watermark-textFigure 1. BAFF expression in vivo following Natural Rhinovirus Upper Respiratory TractInfectionsFigure 1A displays the RT-PCR results for BAFF gene copy number in naturally acquiredinfections. The y-axis represents the BAFF gene copy number. The x-axis represents thetiming of the sample in days after cold onset. Figure 1B displays the concentration of BAFFprotein in nasal lavage fluids in naturally acquired infections. The y-axis represents theBAFF concentration in pg/ml. The x-axis represents the timing of the sample in days aftercold onset.Kumar et al. Page 5J Allergy Clin Immunol. Author manuscript; available in PMC 2013 October 01.$watermark-text$watermark-text$watermark-text$watermark-text$watermark-text$watermark-textKumar et al. Page 6Table 1Relationship between BAFF polymorphism, rs17564816, and asthma exacerbations in the SAGE and SAPPHIRE cohorts.*Study cohortOutcome†Genetic Model‡Time-to-event analysis§Rate of events analysis||HRP-valueRRP-valueSAGEComposite outcomeAdditive----1.360.015Dominant1.400.013Recessive1.270.40SAPPHIREOral corticosteroid useAdditive2.370.0011.680.034Dominant2.120.0031.620.075Recessive77.410.0016.800.058Asthma-related ED visitsAdditive2.700.0012.320.001Dominant2.750.0012.670.002Recessive11.280.0324.290.258Composite outcomeAdditive2.540.0011.960.005Dominant2.360.0012.010.007Recessive38.930.0015.060.124BAFF denotes the gene B-cell activating factor; SAGE, Study of African Americans, Asthma, Genes & Environments; SAPPHIRE, the Study of Asthma Phenotypes and Pharmacogenomic Interactions byRace-Ethnicity; ED, emergency department, HR, hazard ratio; and RR, relative rate.* Analyses in SAGE were adjusted for patient age, sex, African ancestry, estimated socioeconomic status based on geocoded home address, current smoking status, passive smoke exposure, total serum IgElevel, and use of an inhaled corticosteroid. Analyses in SAPPHIRE adjusted for age, sex, African ancestry, educational level, household income, percent of predicted forced expiratory volume at onesecond, asthma duration, current smoking status, passive smoking exposure, allergic sensitization (defined as =1 allergen-specific IgE value), and baseline corticosteroid use.† Composite outcome for an asthma exacerbation includes oral corticosteroid use, an asthma-related emergency room visit, or an asthma-related hospitalization.‡ The additive genetic model for rs17564816 was coded as GG=0, AG=1, and AA=2, where A is the minor allele. The dominant model was coded as GG=0 and both AG and AA=1. The Recessive modelswas coded as both GG and AG=0 and AA=1.§ Time-to-event analyses analyzed with Cox proportional hazard regression models.|| Rate of event analyses analyzed with negative binomial regression models.J Allergy Clin Immunol. Author manuscript; available in PMC 2013 October 01.

English

Genetic variation in B cell–activating factor of the TNF family (BAFF) and asthma exacerbations among African American subjects

Genetic variation in B cell-activating factor of the TNF family (BAFF) and asthma exacerbations among African American subjects.

Genetic variation in B cell-activating factor of the TNF family (BAFF) and asthma exacerbations among African American subjects.

Abstract

Similar works

Full text

Available Versions

eScholarship - University of California