BEPPLER, JAQUELINE

Clarice Sampaio Alho

DAL-PIZZOL, FELIPE

DIAS, FERNANDO S.

GRAEBIN, PIETRA

JOBIM, LUIZ FERNANDO

JOBIM, MARIANA

MERZONI, JOICE

OLIVEIRA, LUCIANA M.

PORTELA, PAMELA

Rafael Roesler

Schwartsmann, Gilberto

Clinical Immunology

Repositório Institucional da PUCRS

Contents lists available at ScienceDirectClinical Immunologyjournal homepage: www.elsevier.com/locate/yclimLetter to the EditorKIR gene haplotype A is associated with hospital mortality in patients with sepsisDear Editor,Natural killer (NK) cell activity represents a potential prognosticmarker in sepsis, although its pathophysiological role is complex andremains poorly understood [1]. NK cell function is regulated by a set ofactivating and inhibitory cell surface receptors named killer im-munoglobulin-like receptors (KIR). The number and type of KIR genesshow considerable variability among individuals, but haplotypes fallwithin two broad types. Haplotype A is defined by the predominance ofinhibitory genes and a single activating gene, whereas haplotype B canshow multiple stimulatory genes in combination with inhibitory ones.Haplotype B has been recently associated with better clinical outcomesin diseases including myelodysplastic syndromes [2], acute myeloidleukemia after hematopoietic stem cell transplantation [3], and type 1diabetes [4]. We have previously reported a reduced frequency of twoactivating KIR genes, 2DS1 and 3DS1, in patients with sepsis comparedwith critical patients with no sepsis [5]. Here we report a follow-upanalysis of the impact of KIR gene haplotypes on clinical outcomes inthe same patient cohort.Patients and methods were described previously [5]. The study wasapproved by the institutional Research Ethics Committee (CAEE10555212.6.0000.5327, protocol number 13-0038). To determine KIRhaplotypes, DNA was genotyped using the polymerase chain reactionmethod with sequence-specific oligonucleotide (PCR-SSO kit, OneLambda® Inc., Woodland Hills, USA) for 16 KIR genes (2DL1, 2DL2,2DL3, 2DL4, 2DL5, 3DL1, 3DL2, 3DL3, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5,2DP1, 3DP1 and 3DS1). Haplotype A was identified by the presence of asingle activating gene KIR2DS4 combined with inhibitory genes. Thepresence of more than one activating gene defined haplotype B. Com-parison of the KIR haplotype between groups was done with Pearsonchi-square. To evaluate the influence of individual genotypes on out-comes, Cox multivariate logistic regression analysis was used. Ka-plan–Meier survival analysis was performed for survival curves. Ap≤ .05 after correction was considered to indicate a statistically sig-nificant difference.Forty-three different KIR gene combinations were found [5]. Hap-lotype A was identified in 28.41%, and haplotype B in 71.59% samples.Haplotype A was identified in 29.38% septic patients and 8.33% con-trols, whereas haplotype B was identified in 70.62% septic patients and91.67% controls (non-significant). Haplotype B was significantly asso-ciated with increased hospital survival (p= .035) and was more fre-quent in ICU survivors compared to non-survivors, although this lattercomparison fell just short of significance (p= .055). Logistic regressionrevealed that haplotype A was associated with a hospital mortality riskof about 50% (HR=1.501; IC 95%: 1.036–2.175; p= .032, adjustedfor APACHE II; Fig. 1A). Among patients with sepsis, haplotype A wasassociated with a hospital mortality risk of about 56% (HR=1.556; IC95%: 1.057–2.28; p= .025, adjusted for APACHE II; Fig. 1B).In conclusion, KIR haplotype A may be a marker of higher prob-ability of hospital mortality in septic patients. These early findings, ifconfirmed by larger studies, might have implications for the develop-ment of therapies based on NK cell function in sepsis.These findings might implicate on NK cell-based therapies in sepsis.Compliance with ethical standardsThe study was approved by the Institutional Research EthicsCommittee (CAEE 10555212.6.0000.5327, protocol number 13-0038)and was conducted in accordance with the Declaration of Helsinki;confidentiality was observed for all samples. All subjects or their sur-Fig. 1. Survival curves for A critical care patientspopulation with and without sepsis (n=271) and Bseptic patients (n=211). Lines in grey representhaplotype A; lines in black represent haplotype B. Incritical care patients, logistic regression adjusted forAPACHE II shows a significant association betweenhaplotype A and hospital mortality (HR=1.501; IC95%: 1.036–2.175; p= .032). In patients with sepsis,haplotype A was associated with higher hospitalmortality (HR=1.556; IC 95%: 1.057–2.28;p= .025).https://doi.org/10.1016/j.clim.2019.01.008Received 28 January 2019; Accepted 29 January 2019Clinical Immunology 200 (2019) 37–38Available online 30 January 20191521-6616/ © 2019 Elsevier Inc. All rights reserved.Trogates received detailed explanations and provided written consentprior to inclusion in this investigation.Conflicts of interestThe authors declare no competing interests.FundingThis research was supported by the National Institute forTranslational Medicine (INCT-TM); the Immunology Service andInstitutional Research Fund (FIPE), Porto Alegre Clinical Hospital(HCPA); and the National Council for Scientific and TechnologicalDevelopment (CNPq).References[1] Y. Guo, N.K. Patil, L. Luan, J.K. Bohannon, E.R. Sherwood, The biology of naturalkiller cells during sepsis, Immunology 153 (2018) 190–202.[2] K. Stringaris, D. Marin, A.J. Barrett, R. Hills, C. Sobieski, K. Cao, J.G. Saltarrelli,M. Daher, H. Shaim, N. Smith, D. Linch, R. Gale, C. Allen, T. Sekine, R. Mehta,R. Champlin, E.J. Shpall, H. Kantarjian, G. Garcia-Manero, K. Rezvani, KIR genehaplotype: an independent predictor of clinical outcome in MDS patients, Blood 128(2016) 2819–2823.[3] U. Impola, H. Turpeinen, N. Alakulppi, T. Linjama, L. Volin, R. Niittyvuopio,J. Partanen, S. Koskela, Donor haplotype B of NK KIR receptor reduces the relapserisk in HLA-identical sibling hematopoietic stem cell transplantation of AML patients,Front. Immunol. 5 (2014) 405.[4] J.A. Traherne, W. Jiang, A.M. Valdes, J.A. Hollenbach, J. Jayaraman, J.A. Lane,C. Johnson, J. Trowsdale, J.A. Noble, KIR haplotypes are associated with late-onsettype 1 diabetes in European-American families, Genes Immun. 17 (2016) 8–12.[5] L.M. Oliveira, P. Portela, J. Merzoni, J.D. Lindenau, F.S. Dias, J. Beppler, P. Graebin,C.S. Alho, G. Schwartsmann, F. Dal-Pizzol, L.F. Jobim, M. Jobim, R. Roesler, Reducedfrequency of two activating KIR genes in patients with sepsis, Hum. Immunol. 78(2017) 363–369.Luciana M. Oliveiraa,b,⁎, Pamela Portelab, Joice Merzonib,Jaqueline Bepplerb, Fernando S. Diasc, Pietra Graebind, Clarice S. Alhod,Gilberto Schwartsmanna,e, Felipe Dal-Pizzolf,g, Luiz Fernando Jobimb,e,Mariana Jobimb, Rafael Roeslera,ha Cancer and Neurobiology Laboratory, Experimental Research Center,Porto Alegre Clinical Hospital, Federal University of Rio Grande do Sul,Porto Alegre, Brazilb Immunology Service, Porto Alegre Clinical Hospital, Federal University ofRio Grande do Sul, Porto Alegre, Brazilc Intensive Care Unit, Pompéia Hospital, Caxias do Sul, Brazild Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul,Porto Alegre, BrazileDepartment of Internal Medicine, Faculty of Medicine, Federal Universityof Rio Grande do Sul, Porto Alegre, Brazilf Experimental Physiopathology Laboratory, Graduate Program in HealthSciences, Universidade do Extremo Sul Catarinense, Criciúma, Brazilg Intensive Care Unit, São José Hospital, Criciúma, BrazilhDepartment of Pharmacology, Institute for Basic Health Sciences, FederalUniversity of Rio Grande do Sul, Porto Alegre, BrazilE-mail address: oliveiralm@gmail.com (L.M. Oliveira).⁎ Corresponding author at: Cancer and Neurobiology Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (CPE-HCPA), Rua RamiroBarcelos, 2350, 90035-003 Porto Alegre, RS, Brazil.Letter to the Editor Clinical Immunology 200 (2019) 37–3838

KIR gene haplotype A is associated with hospital mortality in patients with sepsis

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KIR gene haplotype A is associated with hospital mortality in patients with sepsis

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