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

Abstract

OBJECTIVES: 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.