Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Mitchell KA

PROVIDER: S-EPMC6364964 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Mitchell Kellie A KA Moore Justin Xavier JX Rosenson Robert S RS Irvin Ryan R Guirgis Faheem W FW Shapiro Nathan N Safford Monika M Wang Henry E HE

PloS one 20190206 2

<h4>Background</h4>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 a ...[more]

PMID: 30726226

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Project description:BACKGROUND:Despite concerns about adverse neurocognitive events raised by prior trials, pharmacological PCSK9 (proprotein convertase subtilisin/kexin type-9) inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in lifelong exposure to lower levels of low-density lipoprotein cholesterol can provide information on the potential long-term effects of lower low-density lipoprotein cholesterol on neurocognitive impairment and decline. METHODS:We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among black REGARDS study (Reasons for Geographic and Racial Differences in Stroke) participants with (n=241) and without (n=10 454) C697X or Y142X LOF variants. Neurocognitive tests included the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery (Word List Learning, World List Delayed Recall, Semantic Animal Fluency) and Six-Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score ≥1.5 SD below age, sex, and education-based stratum-specific means on 2 or 3 CERAD assessments or, separately, a score <5 on any SIS assessment at baseline or during follow-up. Neurocognitive decline was assessed using standardized continuous scores on individual neurocognitive tests. RESULTS:The mean sample age was 64 years (SD, 9), 62% were women, and the prevalence of neurocognitive impairment at any assessment was 6.3% by CERAD and 15.4% by SIS definitions. Adjusted odds ratios for neurocognitive impairment for participants with versus without PCSK9 LOF variants were 1.11 (95% confidence interval [CI], 0.58-2.13) using the CERAD battery and 0.89 (95% CI, 0.61-1.30) using the SIS assessment. Standardized average differences in individual neurocognitive assessment scores over the 5.6-year (range, 0.1-9.1) study period ranged between 0.07 (95% CI, -0.06 to 0.20) and -0.07 (95% CI, -0.18 to 0.05) among participants with versus without PCSK9 LOF variants. Patterns of neurocognitive decline were similar between participants with and without PCSK9 LOF variants (all P>0.10). Odds ratios for neurocognitive impairment per 20 mg/dL low-density lipoprotein cholesterol decrements were 1.02 (95% CI, 0.96-1.08) and 0.99 (95% CI, 0.95-1.02) for the CERAD and SIS definitions of impairment, respectively. CONCLUSIONS:These results suggest that lifelong exposure to low PCSK9 levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks.

Project description:Albuminuria is an important risk factor for progressive chronic kidney disease (CKD) and is more prevalent in black than white adults. We sought to determine the association between low income and albuminuria and whether this association differs for blacks and whites.Cross-sectional study.9,144 black and 13,684 white US adults 45 years and older in the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.Self-reported annual household income category (?$75,000, $35,000-$74,999, $20,000-$34,999, and <$20,000); black and white race.Albuminuria defined as high (30-300 mg/g) or very high (>300 mg/g) urinary albumin-creatinine ratio (ACR). Multinomial logistic regression used to examine the race-stratified association between categories of income and albuminuria (normal, high, or very high ACR).Overall, geometric mean ACR was 10.2 mg/g and was higher for blacks (11.8 mg/g) than whites (9.3 mg/g), P<0.001. Lower income was associated with a higher prevalence of albuminuria for both whites and blacks in unadjusted analyses. After adjustment for demographics, lifestyle factors, comorbid illnesses, and estimated glomerular filtration rate, there was a trend toward a stronger association between lower income levels and high ACR in blacks (ORs of 1.38 [95% CI, 1.07-1.77], 1.36 [95% CI, 1.05-1.75], and 1.58 [95% CI, 1.21-2.05] for income levels of $35,000-$74,999, $20,000-$34,999, and <$20,000, respectively; reference group is those with income?$75,000) compared with whites (ORs of 0.95 [95% CI, 0.81-1.12], 0.95 [95% CI, 0.79-1.14], and 1.26 [95% CI, 1.02-1.55], respectively); P interaction=0.08 between race and income. Results were similar for very high ACR and subgroups of participants with diabetes or hypertension.Cross-sectional design; not all REGARDS participants provided their annual income.Lower income may be associated more strongly with albuminuria in blacks than whites and may be a determinant of racial disparities in albuminuria.

Dataset Information

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

Publications

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

Similar Datasets

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