Nozomi Takahashi, Kyle R Campbell, Taka-Aki Nakada, Keith R Walley
{"title":"低密度脂蛋白胆固醇清除率降低与感染性休克死亡率增加有因果关系。","authors":"Nozomi Takahashi, Kyle R Campbell, Taka-Aki Nakada, Keith R Walley","doi":"10.1097/CCM.0000000000006809","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>To determine whether low-density lipoprotein cholesterol (LDL-C) levels, set by the balance of clearance and production, causally contribute to septic shock 28-day mortality.</p><p><strong>Design: </strong>We measured LDL-C levels and genotypes in patients with septic shock. Using Genotyping and Genome-Wide Association Study summary statistics from over 150,000 Japanese participants, we genetically predicted pre-infection LDL-C levels. Two-sample Mendelian randomization was used to assess the causal relationship between predicted pre-infection LDL-C levels and 28-day mortality. We analyzed PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) genotypes to determine if LDL-C clearance or production was the underlying mechanism.</p><p><strong>Setting: </strong>Multicenter ICUs in Japan.</p><p><strong>Patients: </strong>Genotyped septic shock patients (n = 614).</p><p><strong>Interventions: </strong>None.</p><p><strong>Measurements and main results: </strong>Predicted pre-infection LDL-C levels were much higher than directly measured LDL-C levels at the onset of septic shock (141 mg/dL vs. 40 mg/dL, p < 0.001). Two-sample Mendelian randomization revealed that high predicted pre-infection LDL-C levels were causally associated with increased septic shock 28-day mortality (hazard ratio, 2.78; p = 0.039). PCSK9 genetic variants that increase LDL-C clearance via the LDL receptor (genetically proxied PCSK9 inhibitor treatment) were associated with decreased mortality (p = 0.003) while HMGCR genetic variants that decrease LDL-C production (genetically proxied statin treatment) were not associated with decreased septic shock mortality (indeed the opposite effect was observed, p = 0.039). The two main genetic variants driving the association between high predicted pre-infection LDL-C levels and increased mortality were in apolipoprotein genes (ApoB100-rs13306206 and ApoE-rs7412), apolipoproteins involved in LDL-C binding to the LDL receptor.</p><p><strong>Conclusions: </strong>Low LDL-C clearance explains the causal association between high genetically predicted pre-infection LDL-C levels and increased septic shock mortality. PCSK9, ApoB, and ApoE variants were identified as causal, all related to the LDL receptor or its interaction with LDL-C. Enhancing LDL receptor-mediated clearance of pathogen lipid toxins may improve septic shock outcomes.</p>","PeriodicalId":10765,"journal":{"name":"Critical Care Medicine","volume":" ","pages":""},"PeriodicalIF":6.0000,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Decreased Clearance of Low-Density Lipoprotein Cholesterol is Causally Associate With Increased Mortality of Septic Shock.\",\"authors\":\"Nozomi Takahashi, Kyle R Campbell, Taka-Aki Nakada, Keith R Walley\",\"doi\":\"10.1097/CCM.0000000000006809\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>To determine whether low-density lipoprotein cholesterol (LDL-C) levels, set by the balance of clearance and production, causally contribute to septic shock 28-day mortality.</p><p><strong>Design: </strong>We measured LDL-C levels and genotypes in patients with septic shock. Using Genotyping and Genome-Wide Association Study summary statistics from over 150,000 Japanese participants, we genetically predicted pre-infection LDL-C levels. Two-sample Mendelian randomization was used to assess the causal relationship between predicted pre-infection LDL-C levels and 28-day mortality. We analyzed PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) genotypes to determine if LDL-C clearance or production was the underlying mechanism.</p><p><strong>Setting: </strong>Multicenter ICUs in Japan.</p><p><strong>Patients: </strong>Genotyped septic shock patients (n = 614).</p><p><strong>Interventions: </strong>None.</p><p><strong>Measurements and main results: </strong>Predicted pre-infection LDL-C levels were much higher than directly measured LDL-C levels at the onset of septic shock (141 mg/dL vs. 40 mg/dL, p < 0.001). Two-sample Mendelian randomization revealed that high predicted pre-infection LDL-C levels were causally associated with increased septic shock 28-day mortality (hazard ratio, 2.78; p = 0.039). PCSK9 genetic variants that increase LDL-C clearance via the LDL receptor (genetically proxied PCSK9 inhibitor treatment) were associated with decreased mortality (p = 0.003) while HMGCR genetic variants that decrease LDL-C production (genetically proxied statin treatment) were not associated with decreased septic shock mortality (indeed the opposite effect was observed, p = 0.039). The two main genetic variants driving the association between high predicted pre-infection LDL-C levels and increased mortality were in apolipoprotein genes (ApoB100-rs13306206 and ApoE-rs7412), apolipoproteins involved in LDL-C binding to the LDL receptor.</p><p><strong>Conclusions: </strong>Low LDL-C clearance explains the causal association between high genetically predicted pre-infection LDL-C levels and increased septic shock mortality. PCSK9, ApoB, and ApoE variants were identified as causal, all related to the LDL receptor or its interaction with LDL-C. Enhancing LDL receptor-mediated clearance of pathogen lipid toxins may improve septic shock outcomes.</p>\",\"PeriodicalId\":10765,\"journal\":{\"name\":\"Critical Care Medicine\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2025-08-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Critical Care Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/CCM.0000000000006809\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CRITICAL CARE MEDICINE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Critical Care Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/CCM.0000000000006809","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CRITICAL CARE MEDICINE","Score":null,"Total":0}
Decreased Clearance of Low-Density Lipoprotein Cholesterol is Causally Associate With Increased Mortality of Septic Shock.
Objective: To determine whether low-density lipoprotein cholesterol (LDL-C) levels, set by the balance of clearance and production, causally contribute to septic shock 28-day mortality.
Design: We measured LDL-C levels and genotypes in patients with septic shock. Using Genotyping and Genome-Wide Association Study summary statistics from over 150,000 Japanese participants, we genetically predicted pre-infection LDL-C levels. Two-sample Mendelian randomization was used to assess the causal relationship between predicted pre-infection LDL-C levels and 28-day mortality. We analyzed PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) genotypes to determine if LDL-C clearance or production was the underlying mechanism.
Measurements and main results: Predicted pre-infection LDL-C levels were much higher than directly measured LDL-C levels at the onset of septic shock (141 mg/dL vs. 40 mg/dL, p < 0.001). Two-sample Mendelian randomization revealed that high predicted pre-infection LDL-C levels were causally associated with increased septic shock 28-day mortality (hazard ratio, 2.78; p = 0.039). PCSK9 genetic variants that increase LDL-C clearance via the LDL receptor (genetically proxied PCSK9 inhibitor treatment) were associated with decreased mortality (p = 0.003) while HMGCR genetic variants that decrease LDL-C production (genetically proxied statin treatment) were not associated with decreased septic shock mortality (indeed the opposite effect was observed, p = 0.039). The two main genetic variants driving the association between high predicted pre-infection LDL-C levels and increased mortality were in apolipoprotein genes (ApoB100-rs13306206 and ApoE-rs7412), apolipoproteins involved in LDL-C binding to the LDL receptor.
Conclusions: Low LDL-C clearance explains the causal association between high genetically predicted pre-infection LDL-C levels and increased septic shock mortality. PCSK9, ApoB, and ApoE variants were identified as causal, all related to the LDL receptor or its interaction with LDL-C. Enhancing LDL receptor-mediated clearance of pathogen lipid toxins may improve septic shock outcomes.
期刊介绍:
Critical Care Medicine is the premier peer-reviewed, scientific publication in critical care medicine. Directed to those specialists who treat patients in the ICU and CCU, including chest physicians, surgeons, pediatricians, pharmacists/pharmacologists, anesthesiologists, critical care nurses, and other healthcare professionals, Critical Care Medicine covers all aspects of acute and emergency care for the critically ill or injured patient.
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