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Increased Genomic Copy Number of DEFA1/DEFA3 Is Associated with Susceptibility to Severe Sepsis in Chinese Han Population

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Increased Genomic Copy Number of DEFA1/DEFA3 Is Associated with Susceptibility to Severe Sepsis in Chinese Han Population CRITICAL CARE MEDICINE Anesthesiology 2010; 112:1428–34 Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins Increased Genomic Copy Number of DEFA1/DEFA3 Is Associated with Susceptibility to Severe Sepsis in Chinese Han Population QiXing Chen, M.D.,* Matthew Hakimi, M.Sc.,† ShuiJing Wu, M.D.,‡ Yue Jin, M.Sc.,§ ʈ ʈ BaoLi Cheng, M.D., Ph.D., HaiHong Wang, M.D., Ph.D., GuoHao Xie, M.D.,‡ Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/112/6/1428/251619/0000542-201006000-00022.pdf by guest on 24 September 2021 Tomas Ganz, M.D., Ph.D.,# Rose M. Linzmeier, Ph.D.,** XiangMing Fang, M.D.†† Ϫ ABSTRACT with an increased risk of severe sepsis (P ϭ 2.25 ϫ 10 5, odds Background: Human neutrophil peptides 1–3 are endoge- ratio 2.66, 95% confidence interval 1.69–4.19). This estab- nous cationic antimicrobial peptides implicated in host defense lished association was replicated in a second age- and gender- against microbes. The genes encoding human neutrophil pep- matched case–control cohort (P ϭ 0.02, odds ratio 1.90, 95% tides 1–3 (DEFA1/DEFA3) exhibit copy number variations. confidence interval 1.11–3.27). Furthermore, compared with This study was designed to determine whether DEFA1/DEFA3 those with fewer copies, the patients carrying more than eight copy number variations conferred susceptibility to infection- copies of DEFA1/DEFA3 presented significantly lower plasma induced complications such as severe sepsis. levels of human neutrophil peptides 1–3, tumor necrosis fac- Methods: This case–control study was performed in 179 pa- tor-␣, interleukin-6, and interleukin-10 (P ϭ 0.039, 0.017, tients with severe sepsis and 233 healthy blood donors and was 0.030, and 0.029, respectively). replicated in an independent cohort of 112 cases and 118 Conclusions: DEFA1/DEFA3 is an important genetic com- controls. Plasma levels of human neutrophil peptides 1–3, ponent participating in host immune response to severe sep- tumor necrosis factor-␣, interleukin-6, and interleukin-10 sis. A higher copy number of DEFA1/DEFA3 (Ͼ8 copies) is were detected. significantly associated with the risk of severe sepsis. Results: The genotype of DEFA1/DEFA3 with more than eight copies was more frequent in patients with severe sepsis Ϫ than in controls (55.9% vs. 31.3%; P ϭ 1.13 ϫ 10 6, odds What We Already Know about This Topic ratio 2.77, 95% confidence interval 1.85–4.16). After ad- ❖ Human neutrophil peptides (HNP) 1–3 are antimicrobial pep- justment for age and gender, logistic regression analysis con- tides produced by leukocytes and important to host defense ❖ There is considerable genetic variability in the copy number for firmed the association of the genotype of more than eight copies HNP 1–3 and presumably in their expression and effects dur- ing severe infection and sepsis * Senior Research Assistant, ‡ Resident, § Research Assistant, ʈ Research Assistant and Senior Resident, Department of Anesthe- What This Article Tells Us That Is New siology, the First Affiliated Hospital, School of Medicine, Zhejiang ❖ In a case–control series of more than 200 patients, a high University, Hangzhou, China. †† Professor, Department of Anesthe- copy number for the defensin neutrophil peptides 1–3 siology, the First Affiliated Hospital, School of Medicine, and State (DEFA1/DEFA3) was associated with more than two-fold in- Key Laboratory for Diagnosis and Treatment of Infectious Disease, creased risk of severe sepsis Zhejiang University. † Research Assistant, # Professor, ** Senior Research Assistant, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California. EPSIS is a systemic inflammatory reaction syndrome Received from Department of Anesthesiology, the First Affiliated Sthat occurs during infection and is considered severe Hospital, School of Medicine, Zhejiang University, Hangzhou, when associated with acute organ dysfunction. Sepsis has China. Submitted for publication June 29, 2009. Accepted for pub- 1 lication February 5, 2010. Supported by National Science Fund for become the leading cause of death in critically ill patients. Distinguished Young Scholars (No. 30825037) from National Natural Science Foundation of China, Beijing, China, and sponsored by Zhejiang Provincial Program for the Cultivation of High-level Inno- ᭛ This article is featured in “This Month in Anesthesiology.” vative Health talents, Hangzhou, China. Drs. Linzmeier and Fang are Please see this issue of ANESTHESIOLOGY, page 9A. co-corresponding authors. ᭜ This article is accompanied by an Editorial View. Please see: Address correspondence to Dr. Fang: Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Qing- Russell JA: Are copy number variants of defensins a key Chun Road 79, 310003 Hangzhou, China. [email protected]. This source of variation in the orchestrated response to infection? article may be accessed for personal use at no charge through the ANESTHESIOLOGY 2010; 112:1307–8. Journal Web site, www.anesthesiology.org. 1428 Anesthesiology, V 112 • No 6 • June 2010 CRITICAL CARE MEDICINE The pathogenesis of sepsis includes the immune response interleukin (IL)-6 as well as IL-10 in patients with severe and the coagulation–fibrinolysis system as well as elements of sepsis and explored the potential immunomodulating mech- genetic predisposition, which interact mutually in a compli- anisms of DEFA1/DEFA3 CNV in severe sepsis. cated network.2,3 Neutrophils are the first line of host de- fense against infection. They migrate to the site of infection Materials and Methods early and engulf and kill microbes using oxygen-dependent and -independent mechanisms. Oxygen-independent killing Study Design and Subjects mechanisms depend on neutrophil degranulation, which The study was approved by the Ethics Committee of Zhe- leads to the release of antibiotic proteins such as defensins.4,5 jiang University (Hangzhou, China), and written informed Defensins, classified according to their structure as ␣-de- consent was obtained from the subjects or a close relative of fensins and ␤-defensins, are small cysteine-rich endogenous the patient. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/112/6/1428/251619/0000542-201006000-00022.pdf by guest on 24 September 2021 antimicrobial peptides produced by certain leukocytes and Discovery Cohort. From December 1, 2003, to November many epithelial cells. The ␣-defensins, human neutrophil 30, 2005, all patients admitted in the postsurgical intensive peptides (HNP) 1–3, are constitutively expressed in neutro- care units (ICUs) at two University Hospitals of Zhejiang phils and comprise 30–50% of the granule proteins. HNP University for more than 24 h were screened for eligibility. 1–3 differ only in a single N-terminal amino acid, and the The diagnosis of sepsis met the criteria recommended by the HNP-2 peptide lacks this residue and is believed to be a American College of Chest Physicians and the Society of 17 proteolytic product of the other two peptides because no Critical Care Medicine Consensus Conference. Severe sep- separate gene has been identified to encode HNP-2.5–7 In sis was defined by sepsis in combination with sepsis-induced addition to their antimicrobial properties, HNP 1–3 may acute organ dysfunction in at least one organ. Acute organ contribute to host innate defenses against invading patho- dysfunction was defined as Sequential Organ Failure Assess- gens by their capacity to enhance phagocytosis by macro- ment score more than 2 for the organ in question. The Se- phages, to promote neutrophil recruitment, and to regulate quential Organ Failure Assessment score was calculated complement activation.8 It has also been proposed that HNP daily. The maximum Sequential Organ Failure Assessment 1–3 participate in the activation of the host-adaptive im- score was defined as the highest Sequential Organ Failure mune system by chemoattracting immature dendritic cells Assessment score reached during the ICU stay and was used and T cells to sites of inflammation and by functioning as to express the worst organ dysfunction status attained during immunoadjuvants.9,10 Because of neutrophil activation dur- the ICU stay. The Acute Physiology and Chronic Health ing sepsis, the levels of HNP 1–3 peptide are greatly in- Evaluation score II was obtained within 24 h of admission. creased in the blood of patients with sepsis and pulmonary The outcome of patients with severe sepsis referred to 28-day infections.11,12 Thus, HNP 1–3 may play an important role survival. All the patients studied were Han Chinese. Notable in infectious and inflammatory diseases. exclusion criteria included the following: age younger than The genes encoding ␣-defensins and eight members of 18 yr, a life expectancy of less than 24 h, human immuno- the ␤-defensin gene family are located on chromosome deficiency virus positive, treatment with long-term cortico- 8p22–23, which is a site of frequent chromosomal rearrange- steroids within 6 months or short-term corticosteroids ments. In this gene cluster, DEFA1 (encoding HNP-1) and within 4 weeks, chemotherapy or radiation therapy within 4 DEFA3 (encoding HNP-3) display copy number variations weeks, or a history of bone marrow or liver transplantation. (CNV) that are independent of a second set of CNV involv- The control group consisted of 233 ethnic-matched healthy ing several ␤-defensin genes (DEFB4, DEFB103, and blood donors. DEFB104 encoding human ␤-defensin 2, 3,
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