Citations

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.

Abstract In vivo positron emission tomography (PET) imaging is a key modality to evaluate disease status of brain tumors. In recent years, tremendous efforts have been made in developing PET imaging methods for pediatric brain tumors. Carbon-11 labelled tryptophan derivatives are feasible as PET imaging probes in brain tumor patients with activation of the kynurenine pathway, but the short half-life of carbon-11 limits its application. Using a transgenic mouse model for the sonic hedgehog (Shh) subgroup of medulloblastoma, here we evaluated the potential of the newly developed 1-(2-[18F]fluoroethyl)-L-tryptophan (1-L-[18F]FETrp) as a PET imaging probe for this common malignant pediatric brain tumor. 1-L-[18F]FETrp was synthesized on a PETCHEM automatic synthesizer with good chemical and radiochemical purities and enantiomeric excess values. Imaging was performed in tumor-bearing Smo/Smo medulloblastoma mice using a Perkin-Elmer G4 PET-X-Ray scanner. Medulloblastoma tumors showed significant and specific accumulation of 1-L-[18F]FETrp. 1-L-[18F]FETrp also showed significantly higher tumor uptake than its D-enantiomer 1-D-[18F]FETrp. The uptake of 1-L-[18F]FETrp in normal brain tissue was low, suggesting that 1-L-[18F]FETrp may prove a valuable PET imaging probe for the Shh subgroup of medulloblastoma and possibly other pediatric and adult brain tumors. Citation Format: Xuyi Yue, Yangchun Xin, Hua Li, Zhiqin Li, Hancheng Cai, Sigrid A. Langhans. Tumor-specific PET imaging with an 18F-labeled tryptophan analogue in a transgenic medulloblastoma mouse model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1652.

Abstract We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

In this work related to familial aggregation of familial venous thromboembolism, the investigators report genomic and transcriptomic association of 16 novel susceptibility loci for venous thromboembolism.

The most recent late-onset Alzheimer's disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p = 1.6 × 10 −11 ) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p = 6.5 × 10 −9 ). We have genotyped these variants in a large (3,287 LOAD, 4,396 controls), independent dataset comprising eleven case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and also tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 status. Meta-analysis results showed no evidence of series heterogeneity and logistic regression analysis successfully replicated the association of BIN1 (rs744373) with LOAD with an odds ratio (OR = 1.17, p = 1.1 × 10 −4 ) comparable to that previously reported (OR = 1.15). The variant near EXOC3L2 (rs597668) showed only suggestive association with LOAD (p = 0.09) after correcting for the presence of the APOE ε4 allele. Addition of our follow-up data to the results previously reported increased the strength of evidence for association with BIN1 (11,825 LOAD, 32,570 controls, rs744373 Fisher combined p = 3.8 × 10 −20 ). We also tested for epistatic interaction between these variants and APOE ε4 as well as with the previously replicated LOAD GWAS genes (CLU: rs11136000, CR1: rs3818361, and PICALM: rs3851179). No significant interactions between these genes were detected. In summary, we provide additional evidence for the variant near BIN1 (rs744373) as a LOAD risk modifier, but our results indicate that the effect of EXOC3L2 independent of APOE ε4 should be studied further.