NETWORK ANALYSIS OF SINGLE-NUCLEOTIDE POLYMORPHISMS ASSOCIATED WITH ABERRANT INFLAMMATION IN TRAUMA PATIENTS SUGGESTS A ROLE FOR VESICLE-ASSOCIATED INFLAMMATORY PROGRAMS INVOLVING CD55.
Fayten El-Dehaibi, Ruben Zamora, Jinling Yin, Rami A Namas, Timothy R Billiar, Yoram Vodovotz
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Abstract
Abstract: Background: Critical illness stemming from severe traumatic injury is a leading cause of morbidity and mortality worldwide and involves the dysfunction of multiple organ systems, driven, at least in part, by dysregulated inflammation. We and others have shown a key role for genetic predisposition to dysregulated inflammation and downstream adverse critical illness outcomes. Recently, we demonstrated an association among genotypes at the single-nucleotide polymorphism (SNP) rs10404939 in LYPD4 , dysregulated systemic inflammation, and adverse clinical outcomes in a broad sample of ~1,000 critically ill patients. Methods: We sought to gain mechanistic insights into the role of LYPD4 in critical illness by bioinformatically analyzing potential interactions among rs10404939 and other SNPs. We analyzed a dataset of common (i.e., not rare) SNPs previously defined to be associated with genotype-specific, significantly dysregulated systemic inflammation trajectories in trauma patients, in comparison to a control dataset of common SNPs determined to exhibit an absence of genotype-specific inflammatory responses. Results: In the control dataset, this analysis implicated SNPs associated with phosphatidylinositol and various membrane transport proteins, but not LYPD4. In the patient subset with genotypically dysregulated inflammation, our analysis suggested the co-localization to lipid rafts of LYPD4 and the complement receptor CD55, as well as the neurally related CNTNAP2 and RIMS4. Segregation of trauma patients based on genotype of the CD55 SNP rs11117564 showed distinct trajectories of organ dysfunction and systemic inflammation despite similar demographics and injury characteristics. Conclusion: These analyses define novel interactions among SNPs that could enhance our understanding of the response to traumatic injury and critical illness.
期刊介绍：
SHOCK®: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches includes studies of novel therapeutic approaches, such as immunomodulation, gene therapy, nutrition, and others. The mission of the Journal is to foster and promote multidisciplinary studies, both experimental and clinical in nature, that critically examine the etiology, mechanisms and novel therapeutics of shock-related pathophysiological conditions. Its purpose is to excel as a vehicle for timely publication in the areas of basic and clinical studies of shock, trauma, sepsis, inflammation, ischemia, and related pathobiological states, with particular emphasis on the biologic mechanisms that determine the response to such injury. Making such information available will ultimately facilitate improved care of the traumatized or septic individual.
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