Background: Two risk variants in the apolipoprotein L1 gene (APOL1) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether APOL1 high-risk genotypes are associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease.
Methods: A retrospective cohort study of 2242 Black patients hospitalized with infections. We assessed whether carriage of APOL1 high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality, and organ failure related to sepsis.
Results: Of 2242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk APOL1 genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00-1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR = 1.14 [95% CI, 0.88-1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR = 0.99 [95% CI, 0.70-1.39; p=0.95]). APOL1 high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR = 1.64 [95% CI, 1.21-2.22; p=0.001]), but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk APOL1 genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR = 1.36 [95% CI, 1.00-1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR = 1.16 [95% CI, 0.74-1.81; p=0.52]).
Conclusions: APOL1 high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease.
Funding: This study was supported by R01GM120523 (QF), R01HL163854 (QF), R35GM131770 (CMS), HL133786 (WQW), and Vanderbilt Faculty Research Scholar Fund (QF). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Keywords: APOL1; African ancestry; electronic health records; genetics; genomics; human; medicine; sepsis.
When the body is fighting off an infection, the processes it uses to protect itself can sometimes overreact. This results in a condition known as sepsis which can cause life-threatening damage to multiple organs. In the United States, Black patients are 60-80% more likely to develop sepsis compared to individuals who identify as White; differences remain even after accounting for socio-economic status and presence of other illnesses. Recent work has suggested that two variants of the APOL1 gene which are almost exclusively found in people with African ancestry may be a contributing factor to this disparity. These ‘high-risk’ genetic variants have also been shown to increase the likelihood of kidney diseases. It is therefore possible that the elevated chance of sepsis is not directly linked to these variations of APOL1, but rather is the result of patients already having reduced kidney function. To understand the relationship between APOL1 and sepsis, Jiang et al. analyzed data from patients admitted to Vanderbilt University Medical Centre in the United States between 2000 and 2020. This included 2,242 patients who identified as Black and had been hospitalized with an infection. The analyses showed that 16% of these individuals were carriers of the APOL1 high-risk variants. The high-risk patients were more likely to experience sepsis and demonstrate kidney damage. But other organs commonly damaged by sepsis were not affected more in these individuals compared to the other 84% of patients who did not have these variants. Furthermore, when individuals with pre-existing kidney diseases were removed from this high-risk group, the increased likelihood of sepsis was no longer prominent. These findings suggest that the APOL1 variants do not directly increase the risk of sepsis, and this association is primarily due to patients with these genetic variations being more susceptible to kidney diseases. There are new drugs under development targeting the APOL1 variants. While these may provide protection against kidney diseases, they are unlikely to be successful at preventing or treating sepsis once a patient has been hospitalized with an infection.
© 2023, Jiang et al.