Genetic analysis of over half a million people characterises C-reactive protein loci

Chronic low-grade inflammation is linked to a multitude of chronic diseases. We report the largest genome-wide association study (GWAS) on C-reactive protein (CRP), a marker of systemic inflammation, in UK Biobank participants (N = 427,367, European descent) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (total N = 575,531 European descent). We identify 266 independent loci, of which 211 are not previously reported. Gene-set analysis highlighted 42 gene sets associated with CRP levels (p ≤ 3.2 ×10−6) and tissue expression analysis indicated a strong association of CRP related genes with liver and whole blood gene expression. Phenome-wide association study identified 27 clinical outcomes associated with genetically determined CRP and subsequent Mendelian randomisation analyses supported a causal association with schizophrenia, chronic airway obstruction and prostate cancer. Our findings identified genetic loci and functional properties of chronic low-grade inflammation and provided evidence for causal associations with a range of diseases

Plasma proteomics to identify drug targets for ischemic heart disease

Background Integrated analyses of plasma proteomic and genetic markers in prospective studies can clarify the causal relevance of proteins and discover novel targets for ischemic heart disease (IHD) and other diseases. Objectives The purpose of this study was to examine associations of proteomics and genetics data with IHD in population studies to discover novel preventive treatments. Methods We conducted a nested case-cohort study in the China Kadoorie Biobank (CKB) involving 1,971 incident IHD cases and 2,001 subcohort participants who were genotyped and free of prior cardiovascular disease. We measured 1,463 proteins in the stored baseline samples using the OLINK EXPLORE panel. Cox regression yielded adjusted HRs for IHD associated with individual proteins after accounting for multiple testing. Moreover, cis-protein quantitative loci (pQTLs) identified for proteins in genome-wide association studies of CKB and of UK Biobank were used as instrumental variables in separate 2-sample Mendelian randomization (MR) studies involving global CARDIOGRAM+C4D consortium (210,842 IHD cases and 1,378,170 controls). Results Overall 361 proteins were significantly associated at false discovery rate <0.05 with risk of IHD (349 positively, 12 inversely) in CKB, including N-terminal prohormone of brain natriuretic peptide and proprotein convertase subtilisin/kexin type 9. Of these 361 proteins, 212 had cis-pQTLs in CKB, and MR analyses of 198 variants in CARDIOGRAM+C4D identified 13 proteins that showed potentially causal associations with IHD. Independent MR analyses of 307 cis-pQTLs identified in Europeans replicated associations for 4 proteins (FURIN, proteinase-activated receptor-1, Asialoglycoprotein receptor-1, and matrix metalloproteinase-3). Further downstream analyses showed that FURIN, which is highly expressed in endothelial cells, is a potential novel target and matrix metalloproteinase-3 a potential repurposing target for IHD. Conclusions Integrated analyses of proteomic and genetic data in Chinese and European adults provided causal support for FURIN and multiple other proteins as potential novel drug targets for treatment of IHD

Proteomic analyses in diverse populations improved risk prediction and identified new drug targets for type 2 diabetes

Objective: Integrated analyses of plasma proteomics and genetic data in prospective studies can help assess the causal relevance of proteins, improve risk prediction and discover novel protein drug targets for T2D. Research Design and Methods: We measured plasma levels of 2923 proteins using OLINK Explore among ~2000 randomly selected participants from CKB without prior diabetes at baseline. Cox regression assessed associations of individual protein with incident T2D (n=92 cases). Proteomic-based risk models were developed with discrimination, calibration, reclassification assessed using AUC, calibration plots and NRI, respectively. Two-sample MR analyses using cis-pQTLs identified in GWAS of CKB and UKB for specific proteins were conducted to assess their causal relevance for T2D, along with colocalization analyses to examine shared causal variants between proteins and T2D. Results: Overall 33 proteins were significantly associated (FDR0.6) of shared genetic variants of LPL and PON3 with T2D. Conclusion: Proteomic analyses in Chinese adults identified novel associations of multiple proteins with T2D with strong genetic evidence supporting their causal relevance and potential as novel drug targets for prevention and treatment of T2D

Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases. Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease

Multi-omics approach to explore the effects of chronic low-grade inflammation marked by c-reactive protein

Chronic low-grade inflammation is linked to a multitude of chronic diseases and conditions. However, chronic low-grade inflammation has not been fully characterised, as there remains conflicting and inconclusive evidence from epidemiological studies. My thesis aimed to explore chronic inflammation using a multi-omic approach. Data from the UK Biobank and Airwave cohort was used. Within this thesis I report genome-wide association on C-reactive protein (CRP), a marker of systemic inflammation, in UK Biobank participants (N = 427,367) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (total N= 575,531). I identify 266 independent loci, of which 211 were not previously reported. Gene-set analysis highlighted 42 gene sets associated with CRP levels (p ≤ 3.2 x 10-6) and tissue expression analysis indicated a strong association of CRP related genes to the liver and whole blood gene expression. Phenome-wide association identified 27 clinical outcomes associated with genetically determined CRP, including five phenotypes of the respiratory system, nine of the circulatory system, three musculoskeletal, three sense organs, one mental disorder, five endocrine/metabolic, and lastly one genitourinary. Mendelian randomisation analyses of chronic diseases supported a causal association with several outcomes, such as schizophrenia (beta (β) = -0.074, 95%, p = 7.83 x 10-6), chronic airway obstruction (β=0.330, p=7.94 x 10-4) and breast cancer (β = 0.044, p = 2.02 x 10-5). Metabolome-wide causal association MR analyses tested CRP associated genetic variants with 123 NMR platform measured metabolites and identified five with convincing evidence, including citrate (β=-0.13, p=1.6 x 10-5) and phenylalanine (β=0.13, p=1.3 x 10-5). In combination these results provides insight into the genomic, phenotypic, metabolomic profile, and functional properties of CRP proxied systemic chronic low-grade inflammation. Results provide novel findings, which can be investigated further to understand the underlying molecular pathways of disease afflicted by systemic chronic low-grade inflammation. As CRP proxied chronic inflammation is modifiable, this may be of interest for therapeutic intervention.Open Acces