PCSK9 loss-of-function variants and risk of infection and sepsis in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort

BACKGROUND: Elevated proprotein convertase subtilisin/kexin type 9 (PCSK9) levels have been associated with adverse outcomes in patients hospitalized for sepsis. PCSK9 loss-of-function (LOF) variants area associated with lower low-density lipoprotein cholesterol (LDL-C) levels. Decreased LDL-C is a biomarker of acute and chronic infection and sepsis risk. We examined the association between presence of two genetic PCSK9 LOF variants and risk of infection and sepsis in community-dwelling adults. METHODS: We analyzed data from 10,924 Black participants tested for PCSK9 LOF variants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. The primary endpoint was hospitalization for a serious infection. Within serious infection hospitalizations, we defined sepsis as ≥2 system inflammatory response syndrome criteria. Using multivariable Cox and logistic regression, we investigated the association between LOF variants and hospitalization for infection and sepsis events, adjusting for sociodemographics, health behaviors, chronic medical conditions and select biomarkers. RESULTS: Among 10,924 Black participants, PCSK9 LOF variants were present in 244 (2.2%). Serious infection hospitalizations occurred in 779 participants (14 with PCSK9 variants and 765 without). The presence of PCSK9 variants was not associated with infection risk (adjusted HR 0.68; 95% CI: 0.38–1.25). Among participants hospitalized for a serious infection, the presence of PCSK9 variants was not associated with sepsis (adjusted OR 7.31; 95% CI = 0.91–58.7). CONCLUSIONS: PCSK9 LOF variants are not associated with increased risk of hospitalization for a serious infection. Among those hospitalized for a serious infection, PCSK9 LOF variants was not associated with odds of sepsis.