GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study

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; Genomic Investigation of Statin Therapy Consortium (GIST)

doi:10.1016/j.phrs.2024.107575

GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study

Pharmacol Res. 2025 Jan 9:212:107575. doi: 10.1016/j.phrs.2024.107575. Online ahead of print.

Authors

Emma F Magavern¹, Harshal Deshmukh², Geraldine Asselin³, Elizabeth Theusch⁴, Stella Trompet⁵, Xiaohui Li⁶, Raymond Noordam⁷, Y-D Ida Chen⁶, Teresa E Seeman⁸, Kent D Taylor⁶, Wendy S Post⁹, Jean-Claude Tardif³, Dirk S Paul¹⁰, Emelia J Benjamin¹¹, Nancy L Heard-Costa¹¹, Ramachandran S Vasan¹¹, Jerome I Rotter⁶, Ronald M Krauss⁴, J Wouter Jukema¹², Paul M Ridker¹³, Patricia B Munroe¹, Mark J Caulfield¹, Daniel I Chasman¹³, Marie-Pierre Dubé³, Graham A Hitman¹⁴, Helen R Warren¹⁵; Genomic Investigation of Statin Therapy Consortium (GIST)

Affiliations

¹ Centre 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.
² Mackay Base Hospital, Queensland Health, Queensland, Australia.
³ Faculty of Medicine, Université de Montréal, and the Montreal Heart Institute, Montreal, Canada.
⁴ Department of Pediatrics, University of California San Francisco, Oakland, CA, United States.
⁵ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
⁶ Institute for Translational Genomics and Population Sciences, Department of Pediatrics and The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁷ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
⁸ Division of Geriatrics, Dept of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁹ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁰ Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Cambridge, UK.
¹¹ Boston University Chobanian & Avedisian School of Medicine and School of Public Health, NHLBI and Boston University's Framingham Heart Study, Framingham, MA, United States.
¹² Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
¹³ Division of Preventive Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States.
¹⁴ Centre of Genomic Medicine and Child Health, Blizard Institute, Queen Mary University of London, London, UK.
¹⁵ Centre 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. Electronic address: h.r.warren@qmul.ac.uk.

PMID: 39798939
DOI: 10.1016/j.phrs.2024.107575

Abstract

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.

Keywords: C-Reactive Protein; GWAS; Pharmacogenetics; Pharmacology; Statins; Treatment Response.