GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study
Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin...
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2025-02-01
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| author | Emma F. Magavern Harshal Deshmukh Geraldine Asselin Elizabeth Theusch Stella Trompet Xiaohui Li Raymond Noordam Y.-D. Ida Chen Teresa E. Seeman Kent D. Taylor Wendy S. Post Jean-Claude Tardif Dirk S. Paul Emelia J. Benjamin Nancy L. Heard-Costa Ramachandran S. Vasan Jerome I. Rotter Ronald M. Krauss J.Wouter Jukema Paul M. Ridker Patricia B. Munroe Mark J. Caulfield Daniel I. Chasman Marie-Pierre Dubé Graham A. Hitman Helen R. Warren |
| author_facet | Emma F. Magavern Harshal Deshmukh Geraldine Asselin Elizabeth Theusch Stella Trompet Xiaohui Li Raymond Noordam Y.-D. Ida Chen Teresa E. Seeman Kent D. Taylor Wendy S. Post Jean-Claude Tardif Dirk S. Paul Emelia J. Benjamin Nancy L. Heard-Costa Ramachandran S. Vasan Jerome I. Rotter Ronald M. Krauss J.Wouter Jukema Paul M. Ridker Patricia B. Munroe Mark J. Caulfield Daniel I. Chasman Marie-Pierre Dubé Graham A. Hitman Helen R. Warren |
| author_sort | Emma F. Magavern |
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| description | Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response.CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts.Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer’s and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered.The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer’s, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment. |
| format | Article |
| id | doaj-art-2f1a2fa11fa44e9e8688f44ae10f03e9 |
| institution | Kabale University |
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| publishDate | 2025-02-01 |
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| spelling | doaj-art-2f1a2fa11fa44e9e8688f44ae10f03e92025-02-08T04:59:37ZengElsevierPharmacological Research1096-11862025-02-01212107575GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium studyEmma F. Magavern0Harshal Deshmukh1Geraldine Asselin2Elizabeth Theusch3Stella Trompet4Xiaohui Li5Raymond Noordam6Y.-D. Ida Chen7Teresa E. Seeman8Kent D. Taylor9Wendy S. Post10Jean-Claude Tardif11Dirk S. Paul12Emelia J. Benjamin13Nancy L. Heard-Costa14Ramachandran S. Vasan15Jerome I. Rotter16Ronald M. Krauss17J.Wouter Jukema18Paul M. Ridker19Patricia B. Munroe20Mark J. Caulfield21Daniel I. Chasman22Marie-Pierre Dubé23Graham A. Hitman24Helen R. Warren25Centre of Clinical Pharmacology & Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UKMackay Base Hospital, Queensland Health, Queensland, AustraliaFaculty of Medicine, Université de Montréal, and the Montreal Heart Institute, Montreal, CanadaDepartment of Pediatrics, University of California San Francisco, Oakland, CA, United StatesDepartment of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the NetherlandsInstitute for Translational Genomics and Population Sciences, Department of Pediatrics and The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USADepartment of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the NetherlandsInstitute for Translational Genomics and Population Sciences, Department of Pediatrics and The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USADivision of Geriatrics, Dept of Medicine, University of California Los Angeles, Los Angeles, CA, USAInstitute for Translational Genomics and Population Sciences, Department of Pediatrics and The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USADivision of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USAFaculty of Medicine, Université de Montréal, and the Montreal Heart Institute, Montreal, CanadaCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Cambridge, UKBoston University Chobanian & Avedisian School of Medicine and School of Public Health, NHLBI and Boston University’s Framingham Heart Study, Framingham, MA, United StatesBoston University Chobanian & Avedisian School of Medicine and School of Public Health, NHLBI and Boston University’s Framingham Heart Study, Framingham, MA, United StatesBoston University Chobanian & Avedisian School of Medicine and School of Public Health, NHLBI and Boston University’s Framingham Heart Study, Framingham, MA, United StatesInstitute for Translational Genomics and Population Sciences, Department of Pediatrics and The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USADepartment of Pediatrics, University of California San Francisco, Oakland, CA, United StatesDepartment of Cardiology, Leiden University Medical Center, Leiden, the NetherlandsDivision of Preventive Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United StatesCentre of Clinical Pharmacology & Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UKCentre of Clinical Pharmacology & Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UKDivision of Preventive Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United StatesFaculty of Medicine, Université de Montréal, and the Montreal Heart Institute, Montreal, CanadaCentre of Genomic Medicine and Child Health, Blizard Institute, Queen Mary University of London, London, UKCentre of Clinical Pharmacology & Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UK; Correspondence to: Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, USA.Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response.CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts.Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer’s and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered.The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer’s, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.http://www.sciencedirect.com/science/article/pii/S1043661824005206StatinsC-Reactive ProteinPharmacogeneticsGWASTreatment ResponsePharmacology |
| spellingShingle | Emma F. Magavern Harshal Deshmukh Geraldine Asselin Elizabeth Theusch Stella Trompet Xiaohui Li Raymond Noordam Y.-D. Ida Chen Teresa E. Seeman Kent D. Taylor Wendy S. Post Jean-Claude Tardif Dirk S. Paul Emelia J. Benjamin Nancy L. Heard-Costa Ramachandran S. Vasan Jerome I. Rotter Ronald M. Krauss J.Wouter Jukema Paul M. Ridker Patricia B. Munroe Mark J. Caulfield Daniel I. Chasman Marie-Pierre Dubé Graham A. Hitman Helen R. Warren GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study Pharmacological Research Statins C-Reactive Protein Pharmacogenetics GWAS Treatment Response Pharmacology |
| title | GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study |
| title_full | GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study |
| title_fullStr | GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study |
| title_full_unstemmed | GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study |
| title_short | GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study |
| title_sort | gwas of crp response to statins further supports the role of apoe in statin response a gist consortium study |
| topic | Statins C-Reactive Protein Pharmacogenetics GWAS Treatment Response Pharmacology |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824005206 |
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