A Thrombomodulin Promoter Gene Polymorphism, rs2239562, Influences Both Susceptibility to and Outcome of Sepsis

Eizo Watanabe; Osamu Takasu; Youichi Teratake; Teruo Sakamoto; Toshiaki Ikeda; Joji Kotani; Nobuya Kitamura; Masaaki Ohmori; Ayako Teratani; Goichi Honda; Masahiko Hatano; Benjamin Mayer; E Marion Schneider; Shigeto Oda

doi:10.3389/fmed.2021.762198

A Thrombomodulin Promoter Gene Polymorphism, rs2239562, Influences Both Susceptibility to and Outcome of Sepsis

Front Med (Lausanne). 2022 Jan 10:8:762198. doi: 10.3389/fmed.2021.762198. eCollection 2021.

Authors

Eizo Watanabe^{1

2}, Osamu Takasu³, Youichi Teratake⁴, Teruo Sakamoto³, Toshiaki Ikeda⁵, Joji Kotani⁶, Nobuya Kitamura⁷, Masaaki Ohmori¹, Ayako Teratani¹, Goichi Honda⁸, Masahiko Hatano⁴, Benjamin Mayer⁹, E Marion Schneider¹⁰, Shigeto Oda¹

Affiliations

¹ Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
² General Medical Science, Chiba University Graduate School of Medicine, Chiba, Japan.
³ Department of Emergency and Critical Care Medicine, Kurume University School of Medicine, Kurume, Japan.
⁴ Biomedical Research Center, Chiba University, Chiba, Japan.
⁵ Division of Critical Care and Emergency Medicine, Tokyo Medical University Hachioji Medical Center, Hachioji, Japan.
⁶ Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
⁷ Department of Emergency and Critical Care Medicine, Kimitsu Chuo Hospital, Kisarazu, Japan.
⁸ Medical Affairs Department, Asahi Kasei Pharma Corporation, Tokyo, Japan.
⁹ Institute for Epidemiology and Medical Biometry, Ulm Universtiy, Ulm, Germany.
¹⁰ Division of Experimental Anesthesiology, University Hospital Ulm, Ulm, Germany.

Abstract

Objective: Disseminated intravascular coagulation plays a key role in the pathophysiology of sepsis. Thrombomodulin is essential in the protein C system of coagulation cascade, and functional polymorphisms influence the human thrombomodulin gene (THBD). Therefore, we conducted a multicenter study to evaluate the influence of such polymorphisms on the pathophysiology of sepsis. Methods: A collaborative case-control study in the intensive care unit (ICU) of each of five tertiary emergency centers. The study included 259 patients (of whom 125 displayed severe sepsis), who were admitted to the ICU of Chiba University Hospital, Chiba, Japan between October 2001 and September 2008 (discovery cohort) and 793 patients (of whom 271 patients displayed severe sepsis), who were admitted to the five ICUs between October 2008 and September 2012 (multicenter validation cohort). To assess the susceptibility to severe sepsis, we further selected 222 critically ill patients from the validation cohort matched for age, gender, morbidity, and severity with the patients with severe sepsis, but without any evidence of sepsis. Results: We examined whether the eight THBD single nucleotide polymorphisms (SNPs) were associated with susceptibility to and/or mortality of sepsis. Higher mortality on severe sepsis in the discovery and combined cohorts was significantly associated with the CC genotype in a THBD promoter SNP (-1920^*C/G; rs2239562) [odds ratio [OR] 2.709 (1.067-6.877), P = 0.033 and OR 1.768 (1.060-2.949), P = 0.028]. Furthermore, rs2239562 SNP was associated with susceptibility to severe sepsis [OR 1.593 (1.086-2.338), P = 0.017]. Conclusions: The data demonstrate that rs2239562, the THBD promoter SNP influences both the outcome and susceptibility to severe sepsis.

Keywords: disseminated intravascular coagulation; genetic predisposition to disease; genetic testing; multicenter studies; single nucleotide polymorphisms.