Citations 2
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.
LPA Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins
Wei, Wei‐Qi, Li, Xiaohui , Feng, QiPing , Kubo, Michiaki , Peissig, Peggy , Karlson, Elizabeth W. , Jarvik, Gail P. , Shang, Ning , Larson, Eric , Shaffer, Christian M., Maeda, Shiro , Horikoshi, Momoko , Ritchie, Marylyn D. , Larson, Eric B. , Crosslin, David R. , Bland, Harris T. , Pacheco, Jennifer A. , Rasmussen‐Torvik, Laura J. , Cox, Nancy J. , Wilke, Russell A. , Rotter, Jerome I. , Momozawa, Yukihide , Roden, Dan M. , Krauss, Ronald M. , Denny, Joshua C. , Denny, Joshua C , Bland, Sarah T , Jarvik, Gail P , Wei, Wei-Qi , Rotter, Jerome I , Pacheco, Jennifer A , Kullo, Iftikhar J. , Lee, Ming Ta Michael , Edwards, Todd L. , Mosley, Jonathan D , Williams, Marc S , Cronkite, David , Hripcsak, George , Stein, Christoph , Roden, Dan M. , Feng, Qiping , Rasmussen-Torvik, Laura J
Circulation | April 27, 2018 | Volume: 138 | Issue: 17 | Pages: 1839-1849
10.1161/circulationaha.117.031356
Background: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. Methods: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. Results: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35–1.86; P =2.6×10 − 10 ). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14–2.57; P =0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17–2.24; P =0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18–4.75; P =0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. Conclusions: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.