Behrooz Alizadeh

We analyzed 17 traits in 85,523 participants from 14 large epidemiologic studies within the XCPleiotropy Consortium. Individuals classified with metabolic syndrome (MetS, NCEP definition), versus those without, showed on average statistically significant different levels for most inflammatory markers studied. Average correlations estimated with two methods, and factor analyses on large simulated data assisted in identifying 8 choice trait combinations for follow-up meta-analyses. Nine correlated meta-analyses using full published genetic results (predominantly of large consortia) for 8 metabolic traits and 6 inflammatory markers, yielded 130 unique SNPs / genes with pleiotropic effects (a gene affecting at least a metabolic trait and an inflammatory marker). Twenty-five genes (two-third new) are proposed as MetS candidates. Pleiotropic effects identified add to the understanding of MetS and the correlated architecture of its risk factors.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and infla...

The 7th Santorini Conference was held in Santorini, Greece, and brought together 200 participants from 40 countries in several continents, including Europe, USA but also Japan, Korea, Brazil and South Africa. The attendees had the opportunity to: listen to 60 oral presentations; participate in two lunch symposia; look at 103 posters, which were divided in two groups ('systems medicine and environment' and 'pharmacogenomics and cancer') and attend a dedicated exhibition with six companies. The meeting was organized by the Institut National de la Santé et de la Recherche Médicale (INSERM) U1122; IGE-PCV and by…

From the Department of Medical Genetics, University Medical Center Utrecht, Utrecht; Department of Rheumatology and the Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen; Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The ...

C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal ...

-Genome-wide association studies (GWASs) have successfully identified a number of Single Nucleotide Polymorphisms (SNPs) associated with serum levels of C-reactive protein (CRP). An important limitation of GWASs is that the identified variants merely flag the nearby genomic region and do not necessarily provide a direct link to the biological mechanisms underlying their corresponding phenotype. Here we apply a bioinformatics-based approach to uncover the functional characteristics of the 18 SNPs that had previously been associated with CRP at a genome-wide significant level. -In the first phase of 'in silico' sequencing we explore the vicinity of GWAS SNPs to identify all linked variants. In the second phase of eQTL analysis, we attempt to identify all nearby genes whose expression levels are associated with the corresponding GWAS SNPs. These two phases generate a number of relevant genes that serve as input to the next phase of functional network analysis. Our in silico sequencing analysis using 1000 Genomes Project data identified seven non-synonymous SNPs which are in moderate to high LD (r(2)>0.5) with the GWAS SNPs. Our eQTL analysis, which was based on one of the largest single datasets of genome-wide expression probes (n>5,000) identified 23 significantly associated expression probes belonging to 15 genes (FDR<0.01). The final phase of functional network analysis revealed 93 significantly enriched biological processes (FDR<0.01). -Our post-GWAS analysis of CRP GWAS SNPs confirmed the previously known overlap between CRP and lipids biology. Additionally, it suggested an important role for interferons in the metabolism of CRP.

ABSTRACT Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N r 71,225 European ancestry, N r 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N ¼ 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P ¼ 7 10 24), CYP1A2 (P ¼ 1 10 23), FGF5 (P ¼ 1 10 21), SH2B3 (P ¼ 3 10 18), MTHFR (P ¼ 2 10 13), c10orf107 (P ¼ 1 10 9), ZNF652 (P ¼ 5 10 9) and PLCD3 (P ¼ 1 10 8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans 1, 2, 3. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N= 74,064) and follow-up studies (N= 48,607), we identified at genome-wide significance (P= 2.7× 10− 8 to P= 2.3× 10− 13) four new PP loci (at 4q12 near CHIC2, 7q22. 3 near PIK3CG, 8q24. 12 in NOV and 11q24. 3 near ADAMTS8), two new MAP loci (3p21. 31 in ...