@article {958, title = {The association of alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism in the LITE study.}, journal = {Thromb Res}, volume = {121}, year = {2007}, month = {2007}, pages = {1-7}, abstract = {

INTRODUCTION: The alpha-fibrinogen Thr312Ala variant has been shown to influence clot structure through increased factor XIII cross-linking and formation of thicker fibrin fibers. However, the effect of this common variant on risk of venous thromboembolism (VTE) is unclear. This paper reports the association between the Thr312Ala variant and VTE in the LITE study.

MATERIALS AND METHODS: 506 cases and 1014 controls frequency matched on age, sex, race, and study were drawn from two prospective studies and included in the analysis. Logistic regression was used to examine the association between Thr312Ala and VTE.

RESULTS: In a logistic regression model minimally adjusted for the matching variables, the Thr312Ala TA and AA genotypes were associated with a significantly higher risk of VTE than the TT genotype (TA OR and 95\% confidence interval 1.27 [1.01-1.60], AA OR 1.49 [1.00-2.22]). Associations were similar in analyses of PE and DVT considered separately and across racial and study subgroups. The association between alpha-fibrinogen Thr312Ala and VTE was modified by both BMI and the FXIII Val34Leu variant; the combination of elevated BMI or FXIII Val34Leu with alpha-fibrinogen Thr312Ala conveyed lower odds of VTE than would be expected by an additive or multiplicative model of individual risk factors.

CONCLUSIONS: These results suggest that alpha-fibrinogen Thr312Ala is involved in the pathogenesis of VTE and that its action may be modified by other VTE risk factors.

}, keywords = {African Continental Ancestry Group, Aged, Case-Control Studies, European Continental Ancestry Group, Female, Fibrinogen, Genotype, Humans, Logistic Models, Male, Middle Aged, Mutation, Missense, Polymorphism, Genetic, Venous Thromboembolism}, issn = {0049-3848}, doi = {10.1016/j.thromres.2007.02.008}, author = {Rasmussen-Torvik, Laura J and Cushman, Mary and Tsai, Michael Y and Zhang, Yan and Heckbert, Susan R and Rosamond, Wayne D and Folsom, Aaron R} } @article {9094, title = {Integrative analysis of clinical and epigenetic biomarkers of mortality.}, journal = {Aging Cell}, volume = {21}, year = {2022}, month = {2022 Jun}, pages = {e13608}, abstract = {

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n~=~15,013). During a mean follow-up of 10~years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p~<~1~{\texttimes}~10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5\% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta~=~1.2, P ~=~4.1~{\texttimes}~10 ) and negatively associated with longevity (Beta~=~-1.9, P ~=~0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

}, keywords = {Biomarkers, Cardiovascular Diseases, DNA Methylation, Epigenesis, Genetic, Epigenomics, Humans, Male, Neoplasms}, issn = {1474-9726}, doi = {10.1111/acel.13608}, author = {Huan, Tianxiao and Nguyen, Steve and Colicino, Elena and Ochoa-Rosales, Carolina and Hill, W David and Brody, Jennifer A and Soerensen, Mette and Zhang, Yan and Baldassari, Antoine and Elhadad, Mohamed Ahmed and Toshiko, Tanaka and Zheng, Yinan and Domingo-Relloso, Arce and Lee, Dong Heon and Ma, Jiantao and Yao, Chen and Liu, Chunyu and Hwang, Shih-Jen and Joehanes, Roby and Fornage, Myriam and Bressler, Jan and van Meurs, Joyce B J and Debrabant, Birgit and Mengel-From, Jonas and Hjelmborg, Jacob and Christensen, Kaare and Vokonas, Pantel and Schwartz, Joel and Gahrib, Sina A and Sotoodehnia, Nona and Sitlani, Colleen M and Kunze, Sonja and Gieger, Christian and Peters, Annette and Waldenberger, Melanie and Deary, Ian J and Ferrucci, Luigi and Qu, Yishu and Greenland, Philip and Lloyd-Jones, Donald M and Hou, Lifang and Bandinelli, Stefania and Voortman, Trudy and Hermann, Brenner and Baccarelli, Andrea and Whitsel, Eric and Pankow, James S and Levy, Daniel} }