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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

ABSTRACT: BACKGROUND:We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS:Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS:The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS:Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

SUBMITTER: Schmidt AF

PROVIDER: S-EPMC6820948 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

Schmidt Amand F AF Holmes Michael V MV Preiss David D Swerdlow Daniel I DI Denaxas Spiros S Fatemifar Ghazaleh G Faraway Rupert R Finan Chris C Valentine Dennis D Fairhurst-Hunter Zammy Z Hartwig Fernando Pires FP Horta Bernardo Lessa BL Hypponen Elina E Power Christine C Moldovan Max M van Iperen Erik E Hovingh Kees K Demuth Ilja I Norman Kristina K Steinhagen-Thiessen Elisabeth E Demuth Juri J Bertram Lars L Lill Christina M CM Coassin Stefan S Willeit Johann J Kiechl Stefan S Willeit Karin K Mason Dan D Wright John J Morris Richard R Wanamethee Goya G Whincup Peter P Ben-Shlomo Yoav Y McLachlan Stela S Price Jackie F JF Kivimaki Mika M Welch Catherine C Sanchez-Galvez Adelaida A Marques-Vidal Pedro P Nicolaides Andrew A Panayiotou Andrie G AG Onland-Moret N Charlotte NC van der Schouw Yvonne T YT Matullo Giuseppe G Fiorito Giovanni G Guarrera Simonetta S Sacerdote Carlotta C Wareham Nicholas J NJ Langenberg Claudia C Scott Robert A RA Luan Jian'an J Bobak Martin M Malyutina Sofia S Pająk Andrzej A Kubinova Ruzena R Tamosiunas Abdonas A Pikhart Hynek H Grarup Niels N Pedersen Oluf O Hansen Torben T Linneberg Allan A Jess Tine T Cooper Jackie J Humphries Steve E SE Brilliant Murray M Kitchner Terrie T Hakonarson Hakon H Carrell David S DS McCarty Catherine A CA Lester Kirchner H KH Larson Eric B EB Crosslin David R DR de Andrade Mariza M Roden Dan M DM Denny Joshua C JC Carty Cara C Hancock Stephen S Attia John J Holliday Elizabeth E Scott Rodney R Schofield Peter P O'Donnell Martin M Yusuf Salim S Chong Michael M Pare Guillaume G van der Harst Pim P Said M Abdullah MA Eppinga Ruben N RN Verweij Niek N Snieder Harold H Christen Tim T Mook-Kanamori D O DO Gustafsson Stefan S Lind Lars L Ingelsson Erik E Pazoki Raha R Franco Oscar O Hofman Albert A Uitterlinden Andre A Dehghan Abbas A Teumer Alexander A Baumeister Sebastian S Dörr Marcus M Lerch Markus M MM Völker Uwe U Völzke Henry H Ward Joey J Pell Jill P JP Meade Tom T Christophersen Ingrid E IE Maitland-van der Zee Anke H AH Baranova Ekaterina V EV Young Robin R Ford Ian I Campbell Archie A Padmanabhan Sandosh S Bots Michiel L ML Grobbee Diederick E DE Froguel Philippe P Thuillier Dorothée D Roussel Ronan R Bonnefond Amélie A Cariou Bertrand B Smart Melissa M Bao Yanchun Y Kumari Meena M Mahajan Anubha A Hopewell Jemma C JC Seshadri Sudha S Dale Caroline C Costa Rui Providencia E RPE Ridker Paul M PM Chasman Daniel I DI Reiner Alex P AP Ritchie Marylyn D MD Lange Leslie A LA Cornish Alex J AJ Dobbins Sara E SE Hemminki Kari K Kinnersley Ben B Sanson Marc M Labreche Karim K Simon Matthias M Bondy Melissa M Law Philip P Speedy Helen H Allan James J Li Ni N Went Molly M Weinhold Niels N Morgan Gareth G Sonneveld Pieter P Nilsson Björn B Goldschmidt Hartmut H Sud Amit A Engert Andreas A Hansson Markus M Hemingway Harry H Asselbergs Folkert W FW Patel Riyaz S RS Keating Brendan J BJ Sattar Naveed N Houlston Richard R Casas Juan P JP Hingorani Aroon D AD

BMC cardiovascular disorders 20191029 1

<h4>Background</h4>We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.<h4>Methods</h4>Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower L ...[more]

PMID: 31664920

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Project description:BackgroundPCSK9 inhibition is a potent new therapy for hypercholesterolemia and cardiovascular disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes.MethodsWe tested the association of the PCSK9 missense variant rs11591147 with predefined phenotypes and phenome-wide, in 337 536 individuals of British ancestry in the UK Biobank, with independent discovery and replication. Using a Bayesian statistical method, we leveraged phenotype correlations to evaluate the phenome-wide impact of PCSK9 inhibition with higher power at a finer resolution.ResultsThe T allele of rs11591147 showed a protective effect on hyperlipidemia (odds ratio, 0.63±0.04; P=2.32×10-38), coronary heart disease (odds ratio, 0.73±0.09; P=1.05×10-6), and ischemic stroke (odds ratio, 0.61±0.18; P=2.40×10-3) and was associated with increased type 2 diabetes mellitus risk adjusted for lipid-lowering medication status (odds ratio, 1.24±0.10; P=1.98×10-7). We did not observe associations with cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. Leveraging phenotype correlations, we observed evidence of a protective association with cerebral infarction and vascular occlusion. These results explore the effects of direct PCSK9 inhibition; off-target effects cannot be predicted using this approach.ConclusionsThis result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to LDL (low-density lipoprotein) cholesterol, atherosclerosis, and type 2 diabetes mellitus, suggesting that other effects are either small or absent.

Project description:Non-communicable diseases, including cardiovascular diseases (CVDs), are increasing in African populations. High serum low density lipoprotein cholesterol (LDL-cholesterol) levels are a known risk factor for CVDs in European populations, but the link remains poorly understood among Africans. This study investigated the associations between serum LDL-cholesterol levels and selected variants in the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and low density lipoprotein receptor adaptor protein 1 (LDLRAP1) genes in some selected African populations. Nineteen SNPs were selected from publicly available African whole genome sequence data based on functional prediction and allele frequency. SNPs were genotyped in 1000 participants from the AWI-Gen, study selected from the extremes of LDL-cholesterol level distribution (500 with LDL-cholesterol>3.5 mmol/L and 500 with LDL-cholesterol<1.1 mmol/L). The minor alleles at five of the six associated SNPs were significantly associated (P<0.05) with lower LDL-cholesterol levels: LDLRAP1 rs12071264 (OR 0.56, 95% CI: 0.39-0.75, P = 2.73x10-4) and rs35910270 (OR 0.78, 95% CI: 0.64-0.94, P = 0.008); APOB rs6752026 (OR 0. 55, 95% CI: 0.41-0.72, P = 2.82x10-5); LDLR: rs72568855 (OR 0.47, 95% CI: 0.27-0.82, P = 0.008); and PCSK9 rs45613943 (OR = 0.72, 95% CI: 0.58-0.88, P = 0.001). The minor allele of the sixth variant was associated with higher LDL-cholesterol levels: APOB rs679899 (OR 1.41, 95% CI: 1.06-1.86, P = 0.016). A replication analysis in the Africa America Diabetes Mellitus (AADM) study found the PCSK9 variant to be significantly associated with low LDL-cholesterol levels (Beta = -0.10). Since Africans generally have lower LDL-cholesterol levels, these LDL-cholesterol associated variants may be involved in adaptation due to unique gene-environment interactions. In conclusion, using a limited number of potentially functional variants in four genes, we identified significant associations with lower LDL-cholesterol levels in sub-Saharan Africans.

Project description:LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations.We used genome-wide association data from up to 11,685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290,140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations.In our initial scan, we found two SNPs (rs599839 [p=1.7x10(-15)] and rs4970834 [p=3.0x10(-11)]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4.3x10(-9)]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1.2x10(-33)) and rs646776 (p=4.8x10(-20)) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L.We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.

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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

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