Association between lymphotoxin-alpha (tumor necrosis factor-beta) intron polymorphism and predisposition to severe sepsis is modified by gender and age

• Type of Material: Article
• Authors: Eizo Watanabe, Washington University; Timothy Buchman, Emory University; Hiroyuki Hirasawa, Chiba University; Barbara Zehnbauer, Emory University
• Language: English
• Date: 2010-01-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.
• Final Published Version (URL): http://dx.doi.org/10.1097/CCM.0b013e3181bc805d
• Title of Journal or Parent Work: Critical Care Medicine
• ISSN: 0090-3493
• Volume: 38
• Issue: 1
• Start Page: 181
• End Page: 193
• Grant/Funding Information: This research was supported by NIH/GM (062809) and the Uehara Memorial Foundation.
• Keywords: Life Sciences & Biomedicine; Critical Care Medicine; GENOTYPIC DIFFERENCES; Science & Technology; lymphotoxin-alpha; SEPTIC SHOCK SUSCEPTIBILITY; genetic predisposition to disease; gender; General & Internal Medicine; sepsis; aging
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

Objective: To investigate the significance of functional polymorphisms of inflammatory response genes by analysis of a large population of patients, both with and without severe sepsis, and representative of the diverse populations (geographic diversity, physician diversity, clinical treatment diversity) that would be encountered in critical care clinical practice. Design: Collaborative case-control study conducted from July 2001 to December 2005. Setting: A heterogeneous population of patients from 12 USA intensive care units (ICUs) represented by the Genetic Predisposition to Severe Sepsis (GenPSS) archive. Patients: Eight hundred and fifty-four patients with severe sepsis and an equal number of mortality, age, gender, and race-matched patients also admitted to the ICU without evidence of any infection (matched nonseptic controls). Measurements and Main Results: We developed assays for six functional single nucleotide polymorphisms (SNPs) present before the first codon of TNF at −308, IL1B at −511, IL6 at −174, IL10 at −819, and CD14 at −159, and in the first intron of LTA (also known as TNF-β) at +252 (LTA(+252)). The Project IMPACT™ critical care clinical database information management system developed by the Society of Critical Care Medicine and managed by Tri-Analytics, Inc. and Cerner Corporation was utilized. Template-directed dye-terminator incorporation assay with fluorescence polarization detection was used as a high-throughput genotyping strategy. Fifty-three percent of the patients were male with 87.3 % and 6.4 % of Caucasian and African American racial types, respectively. Overall mortality was 35.1 % in both severe sepsis (SS) and matched nonseptic control (MC) patients group. Average ages (SD) of the SS and MC patients were 63.0 (16.05) and 65.0 (15.58) years old, respectively. Among the 6 SNPs, LTA(+252) was most over-represented in the septic patient group (% severe sepsis; AA 45.6: AG 51.1: GG 56.7, P = .005). Moreover, the genetic risk effect was most pronounced in males, age > 60 yrs (P = .005). Conclusions: LTA(+252) may influence predisposition to severe sepsis, a predisposition that is modulated by gender and age. Although the genetic influences can be overwhelmed by both comorbid factors and acute illness in individual cases, population studies suggest that this is an influential biological pathway modulating risk of critical illnesses.