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

Watanabe, Eizo MD, PhD; Buchman, Timothy G. MD, PhD, FCCM; Hirasawa, Hiroyuki MD, PhD; Zehnbauer, Barbara A. PhD, FACMG

doi: 10.1097/CCM.0b013e3181bc805d
Clinical Investigations

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 U.S. intensive care units represented by the Genetic Predisposition to Severe Sepsis archive.

Patients: A total of 854 patients with severe sepsis and an equal number of mortality, age, gender, and race-matched patients also admitted to the intensive care unit without evidence of any infection (matched nonseptic controls).

Measurements and Main Results: We developed assays for six functional single nucleotide polymorphisms present before the first codon of tumor necrosis factor 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 tumor necrosis factor-B) 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 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 and matched nonseptic control patients group. Average ages (standard deviation) of the severe sepsis and matched nonseptic control patients were 63.0 (16.05) and 65.0 (15.58) yrs old, respectively. Among the six single nucleotide polymorphisms, LTA (+252) was most overrepresented in the septic patient group (% severe sepsis; AA 45.6: AG 51.1: GG 56.7, p = .005). Furthermore, 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.

From the Department of Surgery (EW, TGB), Section of Acute Critical Care Surgery, Washington University School of Medicine, St. Louis, MO; Center for Critical Care (TGB), Emory University, Atlanta, GA; Department of Emergency and Critical Care Medicine (HH), Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Pathology and Immunology (BAZ), Washington University School of Medicine, St. Louis, MO.

Supported, in part, by Grant 062809 from the National Institutes of Health/GM and the Uehara Memorial Foundation. The funding sources had no role in study design, collection, analysis, or interpretation of data.

The authors have not disclosed any potential conflicts of interest.

Current address for Dr. Zehnbauer: Centers for Disease Control and Prevention, Chief, Laboratory Practice Evaluation and Genomics Branch, Atlanta, GA.

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© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins