A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR.
Ontology highlight
ABSTRACT:
SUBMITTER: Safarova MS
PROVIDER: S-EPMC6370860 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
A phenome-wide association study to discover pleiotropic effects of <i>PCSK9</i>, <i>APOB</i>, and <i>LDLR</i>.
Safarova Maya S MS Satterfield Benjamin A BA Fan Xiao X Austin Erin E EE Ye Zhan Z Bastarache Lisa L Zheng Neil N Ritchie Marylyn D MD Borthwick Kenneth M KM Williams Marc S MS Larson Eric B EB Scrol Aaron A Jarvik Gail P GP Crosslin David R DR Leppig Kathleen K Rasmussen-Torvik Laura J LJ Pendergrass Sarah A SA Sturm Amy C AC Namjou Bahram B Shah Amy Sanghavi AS Carroll Robert J RJ Chung Wendy K WK Wei Wei-Qi WQ Feng QiPing Q Stein C Michael CM Roden Dan M DM Manolio Teri A TA Schaid Daniel J DJ Denny Joshua C JC Hebbring Scott J SJ de Andrade Mariza M Kullo Iftikhar J IJ
NPJ genomic medicine 20190211
We conducted an electronic health record (EHR)-based phenome-wide association study (PheWAS) to discover pleiotropic effects of variants in three lipoprotein metabolism genes <i>PCSK9</i>, <i>APOB</i>, and <i>LDLR</i>. Using high-density genotype data, we tested the associations of variants in the three genes with 1232 EHR-derived binary phecodes in 51,700 European-ancestry (EA) individuals and 585 phecodes in 10,276 African-ancestry (AA) individuals; 457 <i>PCSK9</i>, 730 <i>APOB</i>, and 720 < ...[more]
Similar Datasets
Project description:BackgroundFamilial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation.Methods and resultsExomes of 125 unrelated DFH patients were sequenced, as part of the UK10K project. First, analysis of known FH genes identified 23 LDLR and two APOB mutations, and patients with explained causes of FH were excluded from further analysis. Second, common and rare variants in genes associated with low-density lipoprotein cholesterol (LDL-C) levels in genome-wide association study (GWAS) meta-analysis were examined. There was no clear rare variant association in LDL-C GWAS hits; however, there were 29 patients with a high LDL-C SNP score suggestive of polygenic hypercholesterolaemia. Finally, a gene-based burden test for an excess of rare (frequency <0.005) or novel variants in cases versus 1926 controls was performed, with variants with an unlikely functional effect (intronic, synonymous) filtered out.ConclusionsNo major novel locus for FH was detected, with no gene having a functional variant in more than three patients; however, an excess of novel variants was found in 18 genes, of which the strongest candidates included CH25H and INSIG2 (p<4.3×10(-4) and p<3.7×10(-3), respectively). This suggests that the genetic cause of FH in these unexplained cases is likely to be very heterogeneous, which complicates the diagnostic and novel gene discovery process.
| S-EPMC4112429 | biostudies-literature
Project description:BackgroundWe characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.MethodsPublished 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.ResultsThe 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.ConclusionsGenetic 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.
| S-EPMC6820948 | biostudies-literature
Project description:Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized genetic variants associated with MPV and PLT using functional, pathway and disease enrichment analyses; we assessed pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic network had data for PLT and 6,291 participants had data for MPV. We identified five chromosomal regions associated with PLT and eight associated with MPV at genome-wide significance (P < 5E-8). In addition, we replicated 20 SNPs [out of 56 SNPs (?: 0.05/56 = 9E-4)] influencing PLT and 22 SNPs [out of 29 SNPs (?: 0.05/29 = 2E-3)] influencing MPV in a published meta-analysis of GWAS of PLT and MPV. While our GWAS did not find any new associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development, and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1,368 diagnoses (0.05/1368 = 3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune, and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.
| S-EPMC3880605 | biostudies-literature
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.
| S-EPMC6050027 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevations in total cholesterol (TC) and low density lipoprotein cholesterol (LDLc). Development of FH can result in the increase of risk for premature cardiovascular diseases (CVD). FH is primarily caused by genetic variations in Low Density Lipoprotein Receptor (LDLR), Apolipoprotein B (APOB) or Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) genes. Although FH has been extensively studied in the Caucasian population, there are limited reports of FH mutations in the Asian population. We investigated the association of previously reported genetic variants that are involved in lipid regulation in our study cohort. A total of 1536 polymorphisms previously implicated in FH were evaluated in 141 consecutive patients with clinical FH (defined by the Dutch Lipid Clinic Network criteria) and 111 unrelated control subjects without FH using high throughput microarray genotyping platform. Fourteen Single Nucleotide Polymorphisms (SNPs) were found to be significantly associated with FH, eleven with increased FH risk and three with decreased FH risk. Of the eleven SNPs associated with an increased risk of FH, only one SNP was found in the LDLR gene, seven in the APOB gene and three in the PCSK9 gene. SNP rs12720762 in APOB gene is associated with the highest risk of FH (odds ratio 14.78, p<0.001). Amongst the FH cases, 108 out of 141 (76.60%) have had at least one significant risk-associated SNP. Our study adds new information and knowledge on the genetic polymorphisms amongst Asians with FH, which may serve as potential markers in risk prediction and disease management.
| S-EPMC3620484 | biostudies-literature
Project description:Over the recent decades, genome-wide association studies (GWAS) have dramatically changed the understanding of human genetics. A recent genetic data release by UK Biobank (UKB) has allowed many researchers worldwide to have comprehensive look into the genetic architecture of thousands of human phenotypes. In this study, we used GWAS summary statistics derived from the UKB cohort to investigate functional mechanisms of pleiotropic effects across the human phenome. We find that highly pleiotropic variants often correspond to broadly expressed genes with ubiquitous functions, such as matrisome components and cell growth regulators; and tend to colocalize with tissue-shared eQTLs. At the same time, signaling pathway components are more prevalent among highly pleiotropic genes compared to regulatory proteins such as transcription factors. Our results suggest that protein-level pleiotropy mediated by ubiquitously expressed genes is the most prevalent mechanism of pleiotropic genetic effects across the human phenome.
| S-EPMC6978431 | biostudies-literature
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.
| S-EPMC7034850 | biostudies-literature
Project description:BackgroundABO blood group is associated with differences in lifespan, cardiovascular disease, and some cancers, for reasons which are incompletely understood. To gain sex-specific additional insight about potential mechanisms driving these common conditions for future interventions, we characterized associations of ABO blood group antigen across the phenotype sex-specifically.MethodsWe performed a phenome-wide association study (PheWAS) assessing the association of tag single nucleotide polymorphisms (SNPs) for ABO blood group antigens (O, B, A1, and A2) with 3873 phenotypes.ResultsThe tag SNP for the O antigen was inversely associated with diseases of the circulatory system (particularly deep vein thrombosis (DVT)), total cholesterol, low-density lipoprotein cholesterol (LDL-C), and ovarian cancer, and positively associated with erythrocyte traits, leukocyte counts, diastolic blood pressure (DBP), and healthy body composition; the tag SNP for the A1 antigen tended to have associations in reverse to O. Stronger associations were more apparent for men than women for DVT, DBP, leukocyte traits, and some body composition traits, whereas larger effect sizes were found for women than men for some erythrocyte and lipid traits.ConclusionBlood group has a complex association with cardiovascular diseases and its major risk factors, including blood pressure and lipids, as well as with blood cell traits and body composition, with some differences by sex. Lower LDL-C may underlie some of the benefits of blood group O, but the complexity of associations with blood group antigen suggests overlooked drivers of common chronic diseases.
| S-EPMC7669452 | biostudies-literature
Project description:BackgroundBeyond their success in cardiovascular disease prevention, statins are increasingly recognized to have sex-specific pleiotropic effects. To gain additional insight, we characterized associations of genetically mimicked statins across the phenotype sex-specifically. We also assessed whether any apparently non-lipid effects identified extended to genetically mimicking other widely used lipid modifiers (proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) or were a consequence of low-density lipoprotein cholesterol (LDL-c).MethodsWe performed a sex-specific phenome-wide association study assessing the association of genetic variants in HMGCR, mimicking statins, with 1701 phenotypes. We used Mendelian randomization (MR) to assess if any non-lipid effects found were evident for genetically mimicked PCSK9 inhibitors and ezetimibe or for LDL-c.ResultsAs expected, genetically mimicking statins was inversely associated with LDL-c, apolipoprotein B (ApoB), and total cholesterol (TC) and positively associated with glycated hemoglobin (HbA1c) and was related to body composition. Genetically mimicking statins was also inversely associated with serum calcium, sex hormone-binding globulin (SHBG), and platelet count and positively associated with basal metabolic rate (BMR) and mean platelet volume. Stronger associations with genetically mimicked statins were evident for women than men for lipid traits (LDL-c, ApoB, and TC), calcium, and SHBG, but not for platelet attributes, body composition, or BMR. Genetically mimicking PCSK9 inhibitors or ezetimibe was also associated with lower lipids, but was not related to calcium, SHBG, BMR, or body composition. Genetically higher LDL-c increased lipids and decreased BMR, but did not affect calcium, HbA1c, platelet attributes, or SHBG with minor effects on body composition.ConclusionsSimilar inverse associations were found for genetically mimicking statins on lipid traits in men and women as for other lipid modifiers. Besides the positive associations with HbA1c, BMI (which may explain the higher BMR), and aspects of body composition in men and women, genetically mimicking statins was additionally associated with platelet attributes in both sexes and was inversely associated with serum calcium and SHBG in women. This genetic evidence suggests potential pathways that contribute to the effects of statins particularly in women. Further investigation is needed to confirm these findings and their implications for clinical practice.
| S-EPMC8244164 | biostudies-literature
Project description:BackgroundPancreatic cancer is one of the most common causes of cancer-related deaths in the United States, it is difficult to detect early and typically has a very poor prognosis. We present a novel method of large-scale clinical hypothesis generation based on phenome wide association study performed using Electronic Health Records (EHR) in a pancreatic cancer cohort.MethodsThe study population consisted of 1,154 patients diagnosed with malignant neoplasm of pancreas seen at The Froedtert & The Medical College of Wisconsin academic medical center between the years 2004 and 2013. We evaluated death of a patient as the primary clinical outcome and tested its association with the phenome, which consisted of over 2.5 million structured clinical observations extracted out of the EHR including labs, medications, phenotypes, diseases and procedures. The individual observations were encoded in the EHR using 6,617 unique ICD-9, CPT-4, LOINC, and RxNorm codes. We remapped this initial code set into UMLS concepts and then hierarchically expanded to support generalization into the final set of 10,164 clinical concepts, which formed the final phenome. We then tested all possible pairwise associations between any of the original 10,164 concepts and death as the primary outcome.ResultsAfter correcting for multiple testing and folding back (generalizing) child concepts were appropriate, we found 231 concepts to be significantly associated with death in the study population.ConclusionsWith the abundance of structured EHR data, phenome wide association studies combined with knowledge engineering can be a viable method of rapid hypothesis generation.
| S-EPMC4333703 | biostudies-literature