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

Date Published: February 6, 2019

Publisher: Public Library of Science

Author(s): Kellie A. Mitchell, Justin Xavier Moore, Robert S. Rosenson, Ryan Irvin, Faheem W. Guirgis, Nathan Shapiro, Monika Safford, Henry E. Wang, Tatsuo Shimosawa.

http://doi.org/10.1371/journal.pone.0210808

Abstract

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.

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.

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).

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.

Partial Text

Sepsis is the syndrome of infection complicated by systemic inflammation and organ dysfunction. Low levels of low density lipoprotein cholesterol (LDL-C), a negative acute phase reactant, have been associated with organ failure and mortality in sepsis. Multiple clinical observations have displayed an association linking lower cholesterol levels with higher sepsis severity and mortality.[1–3] Moreover, in a previous study of the population-based REGARDS cohort we found an association between baseline low LDL-C and higher rates of future sepsis events.[4]

Among 12,514 Black participants, 10,934 consented to genetic testing, and 10,924 completed testing. Of these, 190 tested positive for the C679X variant and 54 tested positive for the Y142X variant; the overall prevalence of any PCSK9 LOF variant was 2.2% (Table 1). There were no statistically significant differences in sociodemographic factors or health behaviors (alcohol and smoking) between those with and without PCSK9 variants. Participants with PCSK9 LOF variants were less likely to have dyslipidemia when compared with other participants (26.2% vs 54.3%, P < .001) and had lower total cholesterol levels (mean values 161 vs 194 mg/dL, P < .001). There were no other biomarker differences between participants with and without the PCSK9 variants. Participants with PCSK9 LOF variants were less likely to report statin use. In this study of 10,924 Blacks in the REGARDS cohort, we found no association between PCSK9 LOF variants and the incidence of serious infections. Among first infection hospitalizations, we also did not observe significant associations between the presence of PCSK9 LOF variants and odds of sepsis. We limited the analysis to presence and absence of the Y142X or C679X variants in PCSK9 in Blacks. We did not assess other genomic variants. We did not assess these variants in Whites due to the emphasis of REGARDS on genetic risk in Blacks. REGARDS is not a surveillance study, and thus complete ascertainment of all infection or sepsis events is unlikely. By design, the REGARDS cohort includes only Blacks and Whites, and this study limited further only to Blacks. Therefore, these results may not generalize to other ethnic groups. There is potential for participation bias because some individuals did not consent to genetic testing. Infection events in REGARDS were based upon clinical documentation, not culture, laboratory or diagnostic imaging. We did not consider the causal organism of infection. Among Blacks in the REGARDS cohort, we found no association between PCSK9 LOF variant presence and risk of serious infection hospitalization. Among first serious infection hospitalizations, there was no association between PCSK9 variant presence and the odds of sepsis. Other mechanisms may be responsible for links between LDL-C and sepsis risk.   Source: http://doi.org/10.1371/journal.pone.0210808

 

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