Citations 2
Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study
Nounu, Aayah , Richmond, Rebecca C. , Stewart, Isobel D., Surendran, Praveen , Wareham, Nicholas J. , Butterworth, Adam S. , Weinstein, Stephanie J. , Figueiredo, Jane C. , Lindor, Noralane M. , Casey, Graham , Marchand, Loı̈c Le , Ulrich, Cornelia M. , Li, Christopher, Dujinhoven, Fränzel van, Gsur, Andrea , Moreno, Vı́ctor , Vodička, Pavel , Vodičková, Ludmila, Alwers, Elizabeth , Chang‐Claude, Jenny , Sakoda, Lori C. , Slattery, Martha L. , Schoen, Robert , Gunter, Marc J. , Castellvı́-Bel, Sergi , Kim, Hyeong Rok , Li, Li , Bishop, D. Timothy , Buchanan, Daniel D. , Gruber, Stephen B. , Rennert, Gad , Harrison, Tabitha A. , Woods, Michael O. , Schafmayer, Clemens , Guelpen, Bethany Van , Gallinger, Steven , Berndt, Sonja I. , Lindblom, Annika , Wu, Anna H. , Peters, Ulrike , Scherer, Dominique , Bermejo, Justo Lorenzo , Brenner, Hermann , Hoffmeister, Michael , Relton, Caroline L. , Drew, David A. , Figueiredo, Jane C , Marchand, Loïc Le , Ulrich, Cornelia M , Gsur, Andrea , Moreno, Victor , Sakoda, Lori C , Castellví-Bel, Sergi , Buchanan, Daniel D , Lorenzo-Bermejo, Justo , Hoffmeister, Michael , Rennert, Gad , Gunter, Marc J , Drew, David A , Harrison, Tabitha A , Van Guelpen, Bethany , Brenner, Hermann , Bishop, D Timothy , Vodicka, Pavel , Lindblom, Annika , Albanes, Demetrius , Baron, John A. , Hopper, John L. , Newcomb, Polly A. , Platz, Elizabeth A. , Campbell, Peter T. , Amitay, Efrat L. , Schoen, Robert, Kweon, Sun-Seog , Chan, Andrew T. , Zheng, Wei , Giles, Graham G. , Stadler, Zsofia , Lin, Yi , Keku, Temitope O , Hampel, Heather , Pharoah, Paul D.P. , Wolk, Alicja , White, Emily , Williams, Ann Caroline
Nutrients | November 21, 2021 | Volume: 13 | Issue: 11 | Pages: 4164
Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes’ coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84–1.27 and OR: 1.08, 95% CI: 0.86–1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.
Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates
Paige, Ellie , Lareyre, Fabien , Sweeting, Michael , Raffort, Juliette , Grenier, Céline , Finigan, Alison , Harrison, James , Peters, James E. , Sun, Benjamin B. , Butterworth, Adam S. , Harrison, Seamus C. , Bown, Matthew J. , Lindholt, Jes S. , Badger, Stephen A., Norman, Paul E., Bailey, Marc A. , Danesh, John , Freitag, Daniel F., Paul, Dirk S. , Mallat, Ziad , Clément, Marc , Kullo, Iftikhar J. , Powell, Janet T. , Scott, D. Julian A., Rose‐John, Stefan , Lindholt, Jes Sanddal
Circulation: Genomic and Precision Medicine | February 19, 2019 | Volume: 12 | Issue: 2 | Pages: No page available
Background: The Asp358Ala variant (rs2228145; A>C) in the IL (interleukin)-6 receptor ( IL6R ) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R -Asp358Ala variant and AAA growth and to assess the effect of blocking the IL-6 signaling pathway in mouse models of aortic aneurysm rupture or dissection. Methods: Using data from 2863 participants with AAA from 9 prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R -Asp358Ala variant and annual change in AAA diameter (mm/y). In a series of complementary randomized trials in mice, the effect of blocking the IL-6 signaling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter, and time to aortic rupture and death. Results: After adjusting for age and sex, baseline aneurysm size was 0.55 mm (95% CI, 0.13–0.98 mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. Change in AAA growth was −0.06 mm per year (−0.18 to 0.06) per copy of the minor allele; a result that was not statistically significant. Although all available worldwide data were used, the genetic analyses were not powered for an effect size as small as that observed. In 2 mouse models of AAA, selective blockage of the IL-6 trans-signaling pathway, but not combined blockage of both, the classical and trans-signaling pathways, was associated with improved survival ( P <0.05). Conclusions: Our proof-of-principle data are compatible with the concept that IL-6 trans-signaling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.