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PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations.
Holmes, Michael V; Kartsonaki, Christiana; Boxall, Ruth; Lin, Kuang; Reeve, Nicola; Yu, Canqing; Lv, Jun; Bennett, Derrick A; Hill, Michael R; Yang, Ling; Chen, Yiping; Du, Huaidong; Turnbull, Iain; Collins, Rory; Clarke, Robert J; Tobin, Martin D; Li, Liming; Millwood, Iona Y; Chen, Zhengming; Walters, Robin G.
Afiliación
  • Holmes MV; Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Kartsonaki C; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Boxall R; Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Lin K; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Reeve N; Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Yu C; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Lv J; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Bennett DA; Department of Population Health Sciences, University of Leicester, Leicester, UK.
  • Hill MR; Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
  • Yang L; Peking University Center for Public Health and Epidemic Preparedness and Response, Peking University, Beijing, China.
  • Chen Y; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China.
  • Du H; Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
  • Turnbull I; Peking University Center for Public Health and Epidemic Preparedness and Response, Peking University, Beijing, China.
  • Collins R; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China.
  • Clarke RJ; Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Tobin MD; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Li L; Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Millwood IY; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Chen Z; Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
  • Walters RG; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
Eur J Prev Cardiol ; 31(8): 1015-1025, 2024 Jun 03.
Article en En | MEDLINE | ID: mdl-38198221
ABSTRACT

AIMS:

Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition. METHODS AND

RESULTS:

In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)]. Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1 SD lower LDL-C. PCSK9-GS was associated with lower risks of carotid plaque [n = 8340 cases; OR = 0.61 (95% confidence interval 0.45-0.83); P = 0.0015], major occlusive vascular events [n = 15 752; 0.80 (0.67-0.95); P = 0.011], and ischaemic stroke [n = 11 467; 0.80 (0.66-0.98); P = 0.029]. However, PCSK9-GS was also associated with higher risk of hospitalization with chronic obstructive pulmonary disease [COPD n = 6836; 1.38 (1.08-1.76); P = 0.0089] and with even higher risk of fatal exacerbations amongst individuals with pre-existing COPD [n = 730; 3.61 (1.71-7.60); P = 7.3 × 10-4]. We also replicated associations for a PCSK9 variant, reported in UK Biobank, with increased risks of acute upper respiratory tract infection (URTI) [pooled OR after meta-analysis of 1.87 (1.38-2.54); P = 5.4 × 10-5] and self-reported asthma [pooled OR of 1.17 (1.04-1.30); P = 0.0071]. There was no association of a polygenic LDL-C score with COPD hospitalization, COPD exacerbation, or URTI.

CONCLUSION:

The LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease but higher risks of respiratory diseases. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections. LAY

SUMMARY:

Genetic analyses of over 100 000 participants of the China Kadoorie Biobank, mimicking the effect of new drugs intended to reduce cholesterol by targeting the PCSK9 protein, have identified potential severe effects of lower PCSK9 activity in patients with existing respiratory disease.PCSK9 genetic variants that are associated with lower cholesterol and reduced rates of cardiovascular disease are also associated with increased risk of a range of respiratory diseases, including asthma, upper respiratory tract infections, and hospitalization with chronic obstructive pulmonary disease (COPD).These genetic variants are not associated with whether or not individuals have COPD; instead, they are specifically associated with an increase in the chance of those who already have COPD being hospitalized and even dying, suggesting that careful monitoring of such patients should be considered during development of and treatment with anti-PCSK9 medication.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Predisposición Genética a la Enfermedad / Proproteína Convertasa 9 Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Aged / Female / Humans / Male / Middle aged País/Región como asunto: Asia / Europa Idioma: En Revista: Eur J Prev Cardiol Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Predisposición Genética a la Enfermedad / Proproteína Convertasa 9 Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Aged / Female / Humans / Male / Middle aged País/Región como asunto: Asia / Europa Idioma: En Revista: Eur J Prev Cardiol Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido