Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program.
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Klarin Derek, Verma Shefali Setia, Judy Renae, Dikilitas Ozan, Wolford Brooke N, Paranjpe Ishan, Levin Michael G, Pan Cuiping, Tcheandjieu Catherine, Spin Joshua M, Lynch Julie, Assimes Themistocles L, Åldstedt Nyrønning Linn, Mattsson Erney, Edwards Todd L, Denny Josh, Larson Eric, Lee Ming Ta Michael, Carrell David, Zhang Yanfei, Jarvik Gail P, Gharavi Ali G, Harley John, Mentch Frank, Pacheco Jennifer A, Hakonarson Hakon, Skogholt Anne Heidi, Thomas Laurent, Gabrielsen Maiken Elvestad, Hveem Kristian, Nielsen Jonas Bille, Zhou Wei, Fritsche Lars, Huang Jie, Natarajan Pradeep, Sun Yan V, DuVall Scott L, Rader Daniel J, Cho Kelly, Chang Kyong-Mi, Wilson Peter W F, O'Donnell Christopher J, Kathiresan Sekar, Scali Salvatore T, Berceli Scott A, Willer Cristen, Jones Gregory T, Bown Matthew J, Nadkarni Girish, Kullo Iftikhar J, Ritchie Marylyn, Damrauer Scott M, Tsao Philip S, Veterans Affairs Million Veteran Program†
Аннотация
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 ratioPRS, 1.26 [95% CI, 1.18-1.36]; PPRS=2.7×10-11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14-1.35]; PPRS=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.