@article {7144, title = {Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 May}, pages = {e1006034}, abstract = {

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36\% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006034}, author = {Smith, J Gustav and Felix, Janine F and Morrison, Alanna C and Kalogeropoulos, Andreas and Trompet, Stella and Wilk, Jemma B and Gidl{\"o}f, Olof and Wang, Xinchen and Morley, Michael and Mendelson, Michael and Joehanes, Roby and Ligthart, Symen and Shan, Xiaoyin and Bis, Joshua C and Wang, Ying A and Sj{\"o}gren, Marketa and Ngwa, Julius and Brandimarto, Jeffrey and Stott, David J and Aguilar, David and Rice, Kenneth M and Sesso, Howard D and Demissie, Serkalem and Buckley, Brendan M and Taylor, Kent D and Ford, Ian and Yao, Chen and Liu, Chunyu and Sotoodehnia, Nona and van der Harst, Pim and Stricker, Bruno H Ch and Kritchevsky, Stephen B and Liu, Yongmei and Gaziano, J Michael and Hofman, Albert and Moravec, Christine S and Uitterlinden, Andr{\'e} G and Kellis, Manolis and van Meurs, Joyce B and Margulies, Kenneth B and Dehghan, Abbas and Levy, Daniel and Olde, Bj{\"o}rn and Psaty, Bruce M and Cupples, L Adrienne and Jukema, J Wouter and Djouss{\'e}, Luc and Franco, Oscar H and Boerwinkle, Eric and Boyer, Laurie A and Newton-Cheh, Christopher and Butler, Javed and Vasan, Ramachandran S and Cappola, Thomas P and Smith, Nicholas L} } @article {7518, title = {Galectin-3 and Venous Thromboembolism Incidence: the Atherosclerosis Risk in Communities (ARIC) Study.}, journal = {Res Pract Thromb Haemost}, volume = {1}, year = {2017}, month = {2017 Oct}, pages = {223-230}, abstract = {

Background: The inflammatory biomarker galectin-3 contributes to pathologic conditions such as heart failure and stimulates murine thrombogenesis. Its association with venous thromboembolism (VTE) has been sparsely studied.

Objectives: To assess the prospective association of plasma galectin-3 and the LGALS3 rs4644 SNP with VTE incidence.

Methods: We measured plasma galectin-3 in 9,916 participants in the Atherosclerosis Risk in Communities (ARIC) study cohort in 1996 - 1998 and identified VTEs through 2013. Using Cox regression, we estimated the hazard ratio associating galectin-3 with incident VTE over a median of 13.9 years. Replication was sought in the Cardiovascular Health Study (CHS).

Results: ARIC included 21.8\% blacks and 56.2\% females with mean baseline age of 62.7 years. The incidence rate of VTE (n=389 events) increased across quintiles of galectin-3, with hazard ratios (95\% CI) of 1 (reference), 1.13 (0.80 - 1.61), 1.00 (0.70 - 1.43), 1.36 (0.96 - 1.91), and 1.55 (1.09 - 2.19) (p-trend = 0.005), adjusted for age, sex, race, body mass index, diabetes status, and renal function. Results did not replicate in the CHS (124 VTE), but meta-analysis of both studies yielded a pooled hazard ratio (95\% CI) for 1 SD increment in log galectin-3 of 1.10 (1.00 - 1.22). In ARIC, the C allele of rs4644 in the LGALS3 gene was associated with higher galectin-3 level, and in whites, with an increased rate of VTE.

Conclusion: Galectin-3 levels were associated positively with VTE incidence.

}, issn = {2475-0379}, doi = {10.1002/rth2.12038}, author = {Fashanu, Oluwaseun E and Heckbert, Susan R and Aguilar, David and Jensen, Paul N and Ballantyne, Christie M and Basu, Saonli and Hoogeveen, Ron C and DeFilippi, Christopher and Cushman, Mary and Folsom, Aaron R} }