Plasma proteomic associations with genetics and health in the UK Biobank.

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.

Genetically proxied therapeutic prolyl-hydroxylase inhibition and cardiovascular risk.

Prolyl hydroxylase (PHD) inhibitors are in clinical development for anaemia in chronic kidney disease. Epidemiological studies have reported conflicting results regarding safety of long-term therapeutic haemoglobin (Hgb) rises through PHD inhibition on risk of cardiovascular disease. Genetic variation in genes encoding PHDs can be used as partial proxies to investigate the potential effects of long-term Hgb rises. We used Mendelian randomization to investigate the effect of long-term Hgb level rises through genetically proxied PHD inhibition on coronary artery disease (CAD: 60 801 cases; 123 504 controls), myocardial infarction (MI: 42 561 cases; 123 504 controls) or stroke (40 585 cases; 406 111 controls). To further characterize long-term effects of Hgb level rises, we performed a phenome-wide association study (PheWAS) in up to 451 099 UK Biobank individuals. Genetically proxied therapeutic PHD inhibition, equivalent to a 1.00 g/dl increase in Hgb levels, was not associated (at P < 0.05) with increased odds of CAD; odd ratio (OR) [95% confidence intervals (CI)] = 1.06 (0.84, 1.35), MI [OR (95% CI) = 1.02 (0.79, 1.33)] or stroke [OR (95% CI) = 0.91 (0.66, 1.24)]. PheWAS revealed associations with blood related phenotypes consistent with EGLN's role, relevant kidney- and liver-related biomarkers like estimated glomerular filtration rate and microalbuminuria, and non-alcoholic fatty liver disease (Bonferroni-adjusted P < 5.42E-05) but these were not clinically meaningful. These findings suggest that long-term alterations in Hgb through PHD inhibition are unlikely to substantially increase cardiovascular disease risk; using large disease genome-wide association study data, we could exclude ORs of 1.35 for cardiovascular risk with a 1.00 g/dl increase in Hgb.

Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.

The genetics of drug efficacy: opportunities and challenges.

Lack of sufficient efficacy is the most common cause of attrition in late-phase drug development. It has long been envisioned that genetics could drive stratified drug development by identifying those patient subgroups that are most likely to respond. However, this vision has not been realized as only a small proportion of drugs have been found to have germline genetic predictors of efficacy with clinically meaningful effects, and so far all but one were found after drug approval. With the exception of oncology, systematic application of efficacy pharmacogenetics has not been integrated into drug discovery and development across the industry. Here, we argue for routine, early and cumulative screening for genetic predictors of efficacy, as an integrated component of clinical trial analysis. Such a strategy would identify clinically relevant predictors that may exist at the earliest possible opportunity, allow these predictors to be integrated into subsequent clinical development and provide mechanistic insights into drug disposition and patient-specific factors that influence response, therefore paving the way towards more personalized medicine.

Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes.

Rosacea is a common, chronic skin disease of variable severity with limited treatment options. The cause of rosacea is unknown, but it is believed to be due to a combination of hereditary and environmental factors. Little is known about the genetics of the disease. We performed a genome-wide association study (GWAS) of rosacea symptom severity with data from 73 265 research participants of European ancestry from the 23andMe customer base. Seven loci had variants associated with rosacea at the genome-wide significance level (P < 5 × 10-8). Further analyses highlighted likely gene regions or effector genes including IRF4 (P = 1.5 × 10-17), a human leukocyte antigen (HLA) region flanked by PSMB9 and HLA-DMB (P = 2.2 × 10-15), HERC2-OCA2 (P = 4.2 × 10-12), SLC45A2 (P = 1.7 × 10-10), IL13 (P = 2.8 × 10-9), a region flanked by NRXN3 and DIO2 (P = 4.1 × 10-9), and a region flanked by OVOL1and SNX32 (P = 1.2 × 10-8). All associations with rosacea were novel except for the HLA locus. Two of these loci (HERC-OCA2 and SLC45A2) and another precedented variant (rs1805007 in melanocortin 1 receptor) with an association P value just below the significance threshold (P = 1.3 × 10-7) have been previously associated with skin phenotypes and pigmentation, two of these loci are linked to immuno-inflammation phenotypes (IL13 and PSMB9-HLA-DMA) and one has been associated with both categories (IRF4). Genes within three loci (PSMB9-HLA-DMA, HERC-OCA2 and NRX3-DIO2) were differentially expressed in a previously published clinical rosacea transcriptomics study that compared lesional to non-lesional samples. The identified loci provide specificity of inflammatory mechanisms in rosacea, and identify potential pathways for therapeutic intervention.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of âˆ¼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common condition that progresses in some patients to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Here we used healthcare records of 18 million adults to estimate risk of acquiring advanced liver disease diagnoses in patients with NAFLD or NASH compared to individually matched controls. METHODS: Data were extracted from four European primary care databases representing the UK, Netherlands, Italy and Spain. Patients with a recorded diagnosis of NAFLD or NASH (NAFLD/NASH) were followed up for incident cirrhosis and HCC diagnoses. Each coded NAFLD/NASH patient was matched to up to 100 "non-NAFLD" patients by practice site, gender, age ± 5 years and visit recorded within ± 6 months. Hazard ratios (HR) were estimated using Cox models adjusted for age and smoking status and pooled across databases by random effects meta-analyses. RESULTS: Out of 18,782,281 adults, we identified 136,703 patients with coded NAFLD/NASH. Coded NAFLD/NASH patients were more likely to have diabetes, hypertension and obesity than matched controls. HR for cirrhosis in patients compared to controls was 4.73 (95% CI 2.43-9.19) and for HCC, 3.51 (95% CI 1.72-7.16). HR for either outcome was higher in patients with NASH and those with high-risk Fib-4 scores. The strongest independent predictor of a diagnosis of HCC or cirrhosis was baseline diagnosis of diabetes. CONCLUSIONS: Real-world population data show that recorded diagnosis of NAFLD/NASH increases risk of life-threatening liver outcomes. Diabetes is an independent predictor of advanced liver disease diagnosis, emphasising the need to identify specific groups of patients at highest risk.

Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. It affects an estimated 20% of the general population, based on cohort studies of varying size and heterogeneous selection. However, the prevalence and incidence of recorded NAFLD diagnoses in unselected real-world health-care records is unknown. We harmonised health records from four major European territories and assessed age- and sex-specific point prevalence and incidence of NAFLD over the past decade. METHODS: Data were extracted from The Health Improvement Network (UK), Health Search Database (Italy), Information System for Research in Primary Care (Spain) and Integrated Primary Care Information (Netherlands). Each database uses a different coding system. Prevalence and incidence estimates were pooled across databases by random-effects meta-analysis after a log-transformation. RESULTS: Data were available for 17,669,973 adults, of which 176,114 had a recorded diagnosis of NAFLD. Pooled prevalence trebled from 0.60% in 2007 (95% confidence interval: 0.41-0.79) to 1.85% (0.91-2.79) in 2014. Incidence doubled from 1.32 (0.83-1.82) to 2.35 (1.29-3.40) per 1000 person-years. The FIB-4 non-invasive estimate of liver fibrosis could be calculated in 40.6% of patients, of whom 29.6-35.7% had indeterminate or high-risk scores. CONCLUSIONS: In the largest primary-care record study of its kind to date, rates of recorded NAFLD are much lower than expected suggesting under-diagnosis and under-recording. Despite this, we have identified rising incidence and prevalence of the diagnosis. Improved recognition of NAFLD may identify people who will benefit from risk factor modification or emerging therapies to prevent progression to cardiometabolic and hepatic complications.

Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.

Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on (1)H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10(-8)) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10(-44)) and lysine (rs8101881, P = 1.2×10(-33)), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers.

The benefits of using genetic information to design prevention trials.

Clinical trials for preventative therapies are complex and costly endeavors focused on individuals likely to develop disease in a short time frame, randomizing them to treatment groups, and following them over time. In such trials, statistical power is governed by the rate of disease events in each group and cost is determined by randomization, treatment, and follow-up. Strategies that increase the rate of disease events by enrolling individuals with high risk of disease can significantly reduce study size, duration, and cost. Comprehensive study of common, complex diseases has resulted in a growing list of robustly associated genetic markers. Here, we evaluate the utility--in terms of trial size, duration, and cost--of enriching prevention trial samples by combining clinical information with genetic risk scores to identify individuals at greater risk of disease. We also describe a framework for utilizing genetic risk scores in these trials and evaluating the associated cost and time savings. With type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), and advanced age-related macular degeneration (AMD) as examples, we illustrate the potential and limitations of using genetic data for prevention trial design. We illustrate settings where incorporating genetic information could reduce trial cost or duration considerably, as well as settings where potential savings are negligible. Results are strongly dependent on the genetic architecture of the disease, but we also show that these benefits should increase as the list of robustly associated markers for each disease grows and as large samples of genotyped individuals become available.

A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol.

Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.

The Population Reference Sample, POPRES: a resource for population, disease, and pharmacological genetics research.

Technological and scientific advances, stemming in large part from the Human Genome and HapMap projects, have made large-scale, genome-wide investigations feasible and cost effective. These advances have the potential to dramatically impact drug discovery and development by identifying genetic factors that contribute to variation in disease risk as well as drug pharmacokinetics, treatment efficacy, and adverse drug reactions. In spite of the technological advancements, successful application in biomedical research would be limited without access to suitable sample collections. To facilitate exploratory genetics research, we have assembled a DNA resource from a large number of subjects participating in multiple studies throughout the world. This growing resource was initially genotyped with a commercially available genome-wide 500,000 single-nucleotide polymorphism panel. This project includes nearly 6,000 subjects of African-American, East Asian, South Asian, Mexican, and European origin. Seven informative axes of variation identified via principal-component analysis (PCA) of these data confirm the overall integrity of the data and highlight important features of the genetic structure of diverse populations. The potential value of such extensively genotyped collections is illustrated by selection of genetically matched population controls in a genome-wide analysis of abacavir-associated hypersensitivity reaction. We find that matching based on country of origin, identity-by-state distance, and multidimensional PCA do similarly well to control the type I error rate. The genotype and demographic data from this reference sample are freely available through the NCBI database of Genotypes and Phenotypes (dbGaP).

Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

OBJECTIVE: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)). CONCLUSIONS: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

Meta-Analysis of 26 638 Individuals Identifies Two Genetic Loci Associated With Left Ventricular Ejection Fraction.

BACKGROUND: Left ventricular ejection fraction (EF) is an indicator of cardiac function, usually assessed in individuals with heart failure and other cardiac conditions. Although family studies indicate that EF has an important genetic component with heritability estimates up to 0.61, to date only 6 EF-associated loci have been reported. METHODS: Here, we conducted a genome-wide association study (GWAS) of EF in 26 638 adults from the Genetic Epidemiology Research on Adult Health and Aging and the UK Biobank cohorts. RESULTS: A meta-analysis combining results from Genetic Epidemiology Research on Adult Health and Aging and UK Biobank identified a novel locus: TMEM40 on chromosome 3p25 (rs11719526; ß=0.47 and P=3.10×10-8) that replicated in Biobank Japan and confirmed recent findings implicating the BAG3 locus on chromosome 10q26 in EF variation, with the strongest association observed for rs17617337 (ß=-0.83 and P=8.24×10-17). Although the minor allele frequencies of TMEM40 rs11719526 were generally common (between 0.13 and 0.44) in different ethnic groups, BAG3 rs17617337 was rare (minor allele frequencies<0.05) in Asian and African ancestry populations. These associations were slightly attenuated, after considering antecedent cardiac conditions (ie, heart failure/cardiomyopathy, hypertension, myocardial infarction, atrial fibrillation, valvular disease, and revascularization procedures). This suggests that the effects of the lead variants at TMEM40 or BAG3 on EF are largely independent of these conditions. CONCLUSIONS: In this large and multiethnic study, we identified 2 loci, TMEM40 and BAG3, associated with EF at a genome-wide significance level. Identifying and understanding the genetic determinants of EF is important to better understand the pathophysiology of this strong correlate of cardiac outcomes and to help target the development of future therapies.

LDL-cholesterol concentrations: a genome-wide association study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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.

Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease.

CONTEXT: Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain. OBJECTIVE: To investigate association of genetic loci with CRP levels and risk of coronary heart disease. DESIGN, SETTING, AND PARTICIPANTS: We first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls. MAIN OUTCOME MEASURE: Risk of coronary heart disease. RESULTS: Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease. CONCLUSION: The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million European adults.

OBJECTIVE: To estimate the risk of acute myocardial infarction (AMI) or stroke in adults with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). DESIGN: Matched cohort study. SETTING: Population based, electronic primary healthcare databases before 31 December 2015 from four European countries: Italy (n=1 542 672), Netherlands (n=2 225 925), Spain (n=5 488 397), and UK (n=12 695 046). PARTICIPANTS: 120 795 adults with a recorded diagnosis of NAFLD or NASH and no other liver diseases, matched at time of NAFLD diagnosis (index date) by age, sex, practice site, and visit, recorded at six months before or after the date of diagnosis, with up to 100 patients without NAFLD or NASH in the same database. MAIN OUTCOME MEASURES: Primary outcome was incident fatal or non-fatal AMI and ischaemic or unspecified stroke. Hazard ratios were estimated using Cox models and pooled across databases by random effect meta-analyses. RESULTS: 120 795 patients with recorded NAFLD or NASH diagnoses were identified with mean follow-up 2.1-5.5 years. After adjustment for age and smoking the pooled hazard ratio for AMI was 1.17 (95% confidence interval 1.05 to 1.30; 1035 events in participants with NAFLD or NASH, 67 823 in matched controls). In a group with more complete data on risk factors (86 098 NAFLD and 4 664 988 matched controls), the hazard ratio for AMI after adjustment for systolic blood pressure, type 2 diabetes, total cholesterol level, statin use, and hypertension was 1.01 (0.91 to 1.12; 747 events in participants with NAFLD or NASH, 37 462 in matched controls). After adjustment for age and smoking status the pooled hazard ratio for stroke was 1.18 (1.11 to 1.24; 2187 events in participants with NAFLD or NASH, 134 001 in matched controls). In the group with more complete data on risk factors, the hazard ratio for stroke was 1.04 (0.99 to 1.09; 1666 events in participants with NAFLD, 83 882 in matched controls) after further adjustment for type 2 diabetes, systolic blood pressure, total cholesterol level, statin use, and hypertension. CONCLUSIONS: The diagnosis of NAFLD in current routine care of 17.7 million patient appears not to be associated with AMI or stroke risk after adjustment for established cardiovascular risk factors. Cardiovascular risk assessment in adults with a diagnosis of NAFLD is important but should be done in the same way as for the general population.

Phenome-wide association study using research participants' self-reported data provides insight into the Th17 and IL-17 pathway.

A phenome-wide association study of variants in genes in the Th17 and IL-17 pathway was performed using self-reported phenotypes and genetic data from 521,000 research participants of 23andMe. Results replicated known associations with similar effect sizes for autoimmune traits illustrating self-reported traits can be a surrogate for clinically assessed conditions. Novel associations controlling for a false discovery rate of 5% included the association of the variant encoding p.Ile684Ser in TYK2 with increased risk of tonsillectomy, strep throat occurrences and teen acne, the variant encoding p.Arg381Gln in IL23R with a decrease in dandruff frequency, the variant encoding p.Asp10Asn in TRAF3IP2 with risk of male-pattern balding, and the RORC regulatory variant (rs4845604) with protection from allergies. This approach enabled rapid assessment of association with a wide variety of traits and investigation of traits with limited reported associations to overlay meaningful phenotypic context on the range of conditions being considered for drugs targeting this pathway.

Interaction between insulin (VNTR) and hepatic lipase (LIPC-514C>T) variants on the response to an oral glucose tolerance test in the EARSII group of young healthy men.

Insulin resistance is polygenic in origin, and can be observed at an early age. We have shown that variations in APOC3-482T>C and hepatic lipase (LIPC)-514C>T), individually (APOC3 alone) and interactively, modulate insulin and glucose levels after an OGTT in young healthy men participating in the European Atherosclerosis Research Study II (EARSII). Variation in the insulin gene (INS) variable number tandem repeat (VNTR) has been found to predispose to type 1 and type 2 diabetes. We have evaluated the HphI site 23 bp upstream of the INS gene (a surrogate marker for the VNTR) in EARSII (n=822), to determine if variation in INS contributes to insulin resistance. Carriers of the INS VNTR class III (HphI-) allele (frequency=0.29 (95%CI 0.27, 0.31)) had significantly higher 60-min insulin concentrations after the OGTT (P=0.014) and a marginally higher AUC insulin (P=0.07), compared to class I (HphI+) homozygotes. However, this effect on AUC insulin was modified by the level of physical activity, displaying significant gene:environment interaction (P=0.03). We tested for gene:gene interaction between the INS VNTR and both the LIPC-514C>T and APOC3-482T>C. While there was a significant interaction between INS VNTR and LIPC-514C>T on AUC glucose (P=0.013) and on AUC insulin (P=0.015), there was no interaction with APOC3-482T>C. Thus, despite a modest effect of the INS VNTR alone, the influence of this variant on insulin sensitivity was modified by gene:environment and gene:gene interactions, illustrating the biological complexity of insulin resistance.

Relation between atherogenic dyslipidemia and the Adult Treatment Program-III definition of metabolic syndrome (Genetic Epidemiology of Metabolic Syndrome Project).

Genetic Epidemiology of Metabolic Syndrome is a multinational, family-based study to explore the genetic basis of the metabolic syndrome. Atherogenic dyslipidemia (defined as low plasma high-density lipoprotein cholesterol with elevated triglycerides (<25th and >75th percentile for age, gender, and country, respectively) identified affected subjects for the metabolic syndrome. This report examines the frequency at which atherogenic dyslipidemia predicts the metabolic syndrome of the National Cholesterol Education Program Adult Treatment Panel III (ATP-III). One thousand four hundred thirty-six (854 men/582 women) affected patients by our criteria were compared with 1,672 (737 men/935 women) unaffected persons. Affected patients had more hypertension, obesity, and hyperglycemia, and they met a higher number of ATP-III criteria (3.2 +/- 1.1 SD vs 1.3 +/- 1.1 SD, p <0.001). Overall, 76% of affected persons also qualified for the ATP-III definition (Cohen's kappa 0.61, 95% confidence interval 0.59 to 0.64), similar to a separate group of 464 sporadic, unrelated cases (75%). Concordance increased from 41% to 82% and 88% for ages < or =35, 36 to 55, and > or =55 years, respectively. Affected status was also independently associated with waist circumference (p <0.001) and fasting glucose (p <0.001) but not systolic blood pressure (p = 0.43). Thus, the lipid-based criteria used to define affection status in this study substantially parallels the ATP-III definition of metabolic syndrome in subjects aged >35 years. In subjects aged <35 years, atherogenic dyslipidemia frequently occurs in the absence of other metabolic syndrome risk factors.