Evidence for an Inherited Contribution to Sepsis Susceptibility Among a Cohort of U.S. Veterans.

• Type of Material: Article
• Authors: Jordan Kempker, Emory University; Gregory Martin, Emory University; Matthew T. Rondina, University of Utah; Lisa A. Cannon-Albright, University of Utah
• Language: English
• Date: 2022-01
• Publisher: Society of Critical Care Medicine
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1097/CCE.0000000000000603
• Title of Journal or Parent Work: Crit Care Explor
• Volume: 4
• Issue: 1
• Start Page: e0603
• End Page: e0603
• Grant/Funding Information: Dr. Cannon-Albright is partially supported by the Huntsman Cancer Institute Cancer Center Support grant P30 CA42014 from the National Cancer Institute. Dr. Rondina received support from the National Institutes of Health (R01HL142804, R35HL145237, and R01 HL130541) and the Veterans Affairs (VA) Clinical Science Research and Development (I01 CX001696). Dr. Kempker received support from the Agency for Healthcare Quality and Research (K08HS025240) and has received consulting fees from Grifols. Dr. Martin received research support from the National Institutes of Health’s National Center for Advancing Translational Science (UL1 TR-002378), National Institute of Biomedical Imaging and Bioengineering (U54 EB-027690), the Office of the Director (OT2 OD-025285), and the Marcus Foundation, and has served as a consultant for Grifols, Regeneron, Apellis, Beckman Coulter, and Genentech.; Supported, in part, by the Department of Veterans Affairs (VA), Veterans Health Administration, and Office of Health Services Research and Development Service (HSR&D); and in part by the VA HSR&D Informatics, Decision-Enhancement, and Analytic Sciences Center of Innovation (13-414).
• Keywords: genealogy; relative risk; Veteran’s Health Affairs genealogy resource; Veteran Health; infection; high-risk pedigree; sepsis; familial clustering
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

Analyze a unique clinical and genealogical resource for evidence of familial clustering of sepsis to test for an inherited contribution to sepsis predisposition. DESIGN: Observational study. SETTING: Veteran's Health Affairs (VHA) Genealogy/Phenotype resource, a U.S. genealogy database with veterans individually linked to VHA electronic health records. PATIENTS: Sepsis was identified using International Classification of Disease, 9th Edition and 10th Edition codes. There were two comparison groups: one composed of the all veterans with linked data and deep genealogy and the other included 1,000 sets of controls, each set randomly sampled from the entire cohort after matching on sex and 10-year birth year range on a 1:1 ratio with cases. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 4,666 cases of sepsis from 2001 to 2018, of which 96% were male and 80% greater than or equal to 65 years old. Utilizing the Genealogical Index of Familiality, there was a significant excess of pairwise relatedness among sepsis cases over that in the control sets sampled from VHA population (p = 0.03). The relative risk (RR) of sepsis among identified relatives compared with the larger linked VHA cohort demonstrated an excess of sepsis cases in the first-degree (RR, 1.39; 95% CI, 1.03-1.92; p = 0.05) and second-degree (RR, 1.50; 95% CI, 1.07-2.17; p = 0.04) relatives that were not demonstrated in higher degree relatives. The sepsis cases clustered into 1,876 pedigrees of which 628 had a significant excess of sepsis cases among the descendants (p < 0.05). CONCLUSIONS: The data from this cohort of nearly all male U.S. veterans demonstrate evidence for contribution of an inherited predisposition to sepsis and the existence of pedigrees with a significant excess of diagnoses that provide a valuable resource for identification of the predisposition genes and variants responsible. This complements studies on individual genetic variants toward estimating the heritability patterns and clinical relevance of genetic sepsis predisposition.