Citations 2
Abstract 154: Genetic Variants in CETP That Increase HDL Levels also Increase Risk of Intracerebral Hemorrhage
Falcone, Guido J. , Brown, Devin L. , Worrall, Bradford B. , Silliman, Scott, Tirschwell, David L, Jiménez-Conde, Jordi , Sudlow, Catherine L, Słowik, Agnieszka , Kidwell, Chelsea S., Kittner, Steven J. , Langefeld, Carl D. , Kathiresan, Sekar , Woo, Daniel , Phuah, Chia‐Ling , Radmanesh, Farid , Peloso, Gina M. , Meschia, James F. , Selim, Magdy H. , Tirschwell, David L, Klijn, Catharina J.M. , Sudlow, Catherine L, Rannikmäe, Kristiina , Pezzini, Alessandro , Norrving, Bo , Montaner, Joan , Lindgren, Arne G. , Abecasis, Gonçalo R. , Willer, Cristen J , Rosand, Jonathan M. , Anderson, Christopher D.
Stroke | June 21, 2021 | Volume: 48 | Issue: suppl_1 | Pages: No page available
Introduction: In observational studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of spontaneous intracerebral hemorrhage (ICH). Common DNA sequence variants within the cholesteryl ester transfer protein ( CETP ) gene decrease CETP protein activity and increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development to combat coronary artery disease. Hypothesis: Common CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed a two-stage case-control genetic association study in Caucasians. The discovery phase utilized data on 12 independent loci within CETP (+/- 50 kilobases) from 3 genome-wide association studies of ICH. Replication involved direct genotyping in 5 additional studies. We also constructed a genetic risk score with 7 independent CETP variants and tested it for association with HDL-C and ICH risk. We used principal component analysis to account for population structure and a Bonferroni-adjusted p<0.004 (12 tests) to declare statistical significance. Results: The discovery phase included 1149 ICH cases (43% lobar hemorrhages) and 1238 controls. Twelve variants were nominally associated (p<0.05) with ICH, with the strongest association at the rs173539 locus (Figure 1: OR 1.25, 95%CI 1.11-1.41; p=6.0x10 -4 ) and no heterogeneity across studies (I 2 =0%). This association was replicated in 1625 cases (43% lobar hemorrhages) and 1845 controls (OR 1.12, 95%CI 1.02-1.24; p=0.03). A genetic score of independent CETP variants known to increase HDL-C by ~2.85 mg/dL was strongly associated with ICH risk (OR 1.86, 95%CI 1.44-2.40; p=1.4x10 -6 ). Conclusion: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes is warranted.
Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program
Klarin, Derek , Judy, Renae , Dikilitas, Ozan , Wolford, Brooke N. , Paranjpe, Ishan , Levin, Michael G. , Pan, Cuiping , Tcheandjieu, Catherine , Spin, Joshua M. , Assimes, Themistocles L. , Nyrønning, Linn Åldstedt , Mattsson, Erney , Denny, Joshua C. , Zhang, Yanfei , Jarvik, Gail P. , Gharavi, Ali G. , Harley, John B. , Mentch, Frank , Håkonarson, Håkon , Skogholt, Anne Heidi , Thomas, Laurent F. , Gabrielsen, Maiken E. , Zhou, Wei , Fritsche, Lars G. , Huang, Jie , Natarajan, Pradeep , Sun, Yan V. , DuVall, Scott L. , Cho, Kelly , Chang, Kyong‐Mi , Wilson, Peter W.F. , O’Donnell, Christopher J., Kathiresan, Sekar , Scali, Salvatore T. , Jones, Gregory T. , Bown, Matthew J. , Nadkarni, Girish N. , Ritchie, Marylyn D. , Tsao, Philip S. , Gaziano, J. Michael , Ramoni, Rachel , Breeling, Jim, Huang, Grant D. , Muralidhar, Sumitra , O’Donnell, Christopher J. , Romero, Jonathan , Tsao, Philip S., Moser, Jennifer , Whitbourne, Stacey B. , Brewer, Jessica V., Warren, Stuart, Argyres, Dean P., Tsao, Philip S., Stephens, Brady, Brophy, Mary T. , Humphries, Donald E., Shayan, Shahpoor, O’Donnell, Christopher J., Pyarajan, Saiju , Tsao, Philip S., Dell’Italia, Louis J. , Zablocki, Clement J., Beckham, Jean, Wells, John A. , Gutierrez, Salvador, Kaminsky, Laurence S., Villareal, Gerardo, Xu, Junzhe, Hamner, Mark B. , Haddock, Kathlyn Sue, Bhushan, Sujata, Iruvanti, Pran, Godschalk, Michael, Buford, Malcolm, Mastorides, Stephen , Ratcliffe, Nora, Flórez, Hermes , Swann, Alan C. , Murdoch, Maureen, Yeh, Shing Shing, Washburn, Ronald G., Jhala, Darshana , Aguayo, Samuel M., Cohen, David , Sharma, Satish, Callaghan, John, Oursler, Kris Ann, Ahuja, Sunil K. , Gutierrez, Amparo, Schifman, Ronald, Greco, Jennifer , Oehlert, Mary E. , Wallbom, Agnes, Fernando, Ronald, Morgan, Timothy R. , Stapley, Todd, Anderson, Gwenevere, Sonel, Elif, Fayad, Joseph, Hung, Adriana M. , Lichy, Jack, Hurley, Robin A. , Hakonarson, Hakon , Denny, Joshua C , Jarvik, Gail P , Dikilitas, Ozan , Assimes, Themistocles L , Natarajan, Pradeep , Wolford, Brooke N , Scali, Salvatore , Chang, Kyong-Mi , Tsao, Philip S , Verma, Shefali S. , Lynch, Julie A. , Edwards, Todd L. , Larson, Eric B. , Lee, Ming Ta Michael , Carrell, David , Pacheco, Jennifer A. , Hveem, Kristian , Nielsen, Jonas Bille , Rader, Daniel J , O’Donnell, Christopher J., Berceli, Scott A. , Willer, Cristen J , Kullo, Iftikhar J. , Damrauer, Scott M , Beckham, Jean C , Tsao, Philip S., Concato, John , Tsao, Philip S., Do, Nhan , Nguyen, Xuan‐Mai T. , O’Donnell, Christopher J., Tsao, Philip S., Hauser, Elizabeth R. , Zhao, Hongyu , McArdle, Rachel , Whittle, Jeff , Beckham, Jean, Wells, John, Gibson, Gretchen , Kinlay, Scott , Ballas, Zuhair K. , Klein, Jon , Sriram, Peruvemba , Washburn, Ronald, Whooley, Mary A. , Rauchman, Michael I. , Servatius, Richard J. , Sherman, Scott E. , Boyko, Edward J. , Meyer, Laurence , Gupta, Samir , Robey, R. Brooks , Striker, Rob
Circulation | September 28, 2020 | Volume: 142 | Issue: 17 | Pages: 1633-1646
10.1161/circulationaha.120.047544
Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P =1.6×10 −6 ), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P =0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratio PRS , 1.26 [95% CI, 1.18–1.36]; P PRS =2.7×10 −11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratio PRS+family history+smoking , 1.24 [95% CI, 1.14–1.35]; P PRS =1.27×10 −6 ). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.