@article {6612, title = {Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration.}, journal = {Eur J Prev Cardiol}, volume = {23}, year = {2016}, month = {2016 Jan}, pages = {194-205}, abstract = {

BACKGROUND: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.

METHODS: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.

RESULTS: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). {\textquoteright}Inflammatory load{\textquoteright}, defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest {\textquoteright}inflammatory load{\textquoteright} had a greater CCA-IMT progression (p = 0.015).

CONCLUSION: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for {\textquoteright}inflammatory load{\textquoteright} suggest important combined effects of the three inflammatory markers on early atherosclerosis.

}, issn = {2047-4881}, doi = {10.1177/2047487314560664}, author = {Willeit, Peter and Thompson, Simon G and Agewall, Stefan and Bergstr{\"o}m, G{\"o}ran and Bickel, Horst and Catapano, Alberico L and Chien, Kuo-Liong and de Groot, Eric and Empana, Jean-Philippe and Etgen, Thorleif and Franco, Oscar H and Iglseder, Bernhard and Johnsen, Stein H and Kavousi, Maryam and Lind, Lars and Liu, Jing and Mathiesen, Ellisiv B and Norata, Giuseppe D and Olsen, Michael H and Papagianni, Aikaterini and Poppert, Holger and Price, Jackie F and Sacco, Ralph L and Yanez, David N and Zhao, Dong and Schminke, Ulf and B{\"u}lb{\"u}l, Alpaslan and Polak, Joseph F and Sitzer, Matthias and Hofman, Albert and Grigore, Liliana and D{\"o}rr, Marcus and Su, Ta-Chen and Ducimetiere, Pierre and Xie, Wuxiang and Ronkainen, Kimmo and Kiechl, Stefan and Rundek, Tatjana and Robertson, Christine and Fagerberg, Bj{\"o}rn and Bokemark, Lena and Steinmetz, Helmuth and Ikram, M Arfan and V{\"o}lzke, Henry and Lin, Hung-Ju and Plichart, Matthieu and Tuomainen, Tomi-Pekka and Desvarieux, Mo{\"\i}se and McLachlan, Stela and Schmidt, Caroline and Kauhanen, Jussi and Willeit, Johann and Lorenz, Matthias W and Sander, Dirk} } @article {7979, title = {A large-scale exome array analysis of venous thromboembolism.}, journal = {Genet Epidemiol}, year = {2019}, month = {2019 Jan 19}, abstract = {

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08\%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80\% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.

}, issn = {1098-2272}, doi = {10.1002/gepi.22187}, author = {Lindstr{\"o}m, Sara and Brody, Jennifer A and Turman, Constance and Germain, Marine and Bartz, Traci M and Smith, Erin N and Chen, Ming-Huei and Puurunen, Marja and Chasman, Daniel and Hassler, Jeffrey and Pankratz, Nathan and Basu, Saonli and Guan, Weihua and Gyorgy, Beata and Ibrahim, Manal and Empana, Jean-Philippe and Olaso, Robert and Jackson, Rebecca and Braekkan, Sigrid K and McKnight, Barbara and Deleuze, Jean-Francois and O{\textquoteright}Donnell, Cristopher J and Jouven, Xavier and Frazer, Kelly A and Psaty, Bruce M and Wiggins, Kerri L and Taylor, Kent and Reiner, Alexander P and Heckbert, Susan R and Kooperberg, Charles and Ridker, Paul and Hansen, John-Bjarne and Tang, Weihong and Johnson, Andrew D and Morange, Pierre-Emmanuel and Tr{\'e}gou{\"e}t, David A and Kraft, Peter and Smith, Nicholas L and Kabrhel, Christopher} } @article {9194, title = {Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors.}, journal = {Circulation}, volume = {146}, year = {2022}, month = {2022 Oct 18}, pages = {1225-1242}, abstract = {

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.

METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.

RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1\% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.

CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

}, keywords = {Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Thrombosis, Venous Thromboembolism}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.122.059675}, author = {Thibord, Florian and Klarin, Derek and Brody, Jennifer A and Chen, Ming-Huei and Levin, Michael G and Chasman, Daniel I and Goode, Ellen L and Hveem, Kristian and Teder-Laving, Maris and Martinez-Perez, Angel and A{\"\i}ssi, Dylan and Daian-Bacq, Delphine and Ito, Kaoru and Natarajan, Pradeep and Lutsey, Pamela L and Nadkarni, Girish N and de Vries, Paul S and Cuellar-Partida, Gabriel and Wolford, Brooke N and Pattee, Jack W and Kooperberg, Charles and Braekkan, Sigrid K and Li-Gao, Ruifang and Saut, No{\'e}mie and Sept, Corriene and Germain, Marine and Judy, Renae L and Wiggins, Kerri L and Ko, Darae and O{\textquoteright}Donnell, Christopher J and Taylor, Kent D and Giulianini, Franco and de Andrade, Mariza and N{\o}st, Therese H and Boland, Anne and Empana, Jean-Philippe and Koyama, Satoshi and Gilliland, Thomas and Do, Ron and Huffman, Jennifer E and Wang, Xin and Zhou, Wei and Manuel Soria, Jose and Carlos Souto, Juan and Pankratz, Nathan and Haessler, Jeffery and Hindberg, Kristian and Rosendaal, Frits R and Turman, Constance and Olaso, Robert and Kember, Rachel L and Bartz, Traci M and Lynch, Julie A and Heckbert, Susan R and Armasu, Sebastian M and Brumpton, Ben and Smadja, David M and Jouven, Xavier and Komuro, Issei and Clapham, Katharine R and Loos, Ruth J F and Willer, Cristen J and Sabater-Lleal, Maria and Pankow, James S and Reiner, Alexander P and Morelli, Vania M and Ridker, Paul M and Vlieg, Astrid van Hylckama and Deleuze, Jean-Francois and Kraft, Peter and Rader, Daniel J and Min Lee, Kyung and Psaty, Bruce M and Heidi Skogholt, Anne and Emmerich, Joseph and Suchon, Pierre and Rich, Stephen S and Vy, Ha My T and Tang, Weihong and Jackson, Rebecca D and Hansen, John-Bjarne and Morange, Pierre-Emmanuel and Kabrhel, Christopher and Tr{\'e}gou{\"e}t, David-Alexandre and Damrauer, Scott M and Johnson, Andrew D and Smith, Nicholas L} }