No abstract

Abdominal aortic aneurysm (AAA) is a common disease with significant heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 144 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis was able to explain AAA beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in the pathogenesis of AAA. We further integrated functional data to elucidate expression of genes associated with AAA. These genes also indicate crossover between the development of AAA and other monogenic aortopathies, particularly via TGF-beta signaling pathways. Motivated by the strong evidence for the role of lipid levels in AAA by PheWAS, we identified therapeutic opportunities using Mendelian Randomization and, in pre-clinical studies, we demonstrated that PCSK9 inhibition in mice prevented the development of AAA.

BACKGROUND: Population-based epidemiologic studies of aortic dissections (ADs) are needed. This study aimed to report clinical characteristics, incidences, and mortality rates for adult patients admitted to Danish hospitals with type A AD (TAAD) or type B AD (TBAD) from 1996 through 2016. METHODS: We conducted a nationwide, population-based register study. All cases of AD registered with International Classification of Diseases, Tenth Revision codes in the Danish National Patient Registry at time of admission to a hospital with available medical records underwent validation. Data were merged between nationwide health registries including the cause of death registry. Patients with validated AD were matched 1:10 on sex and age with patients with hypertension from the general Danish population. RESULTS: Of 5018 registered cases of AD, 4183 cases underwent review and 3023 (60.2%) were confirmed as AD. After exclusions, the distribution of validated TAAD and TBAD was 1620 (60.5%) and 1059 (39.5%; P <0.001), 67.5% and 67.0% of patients were men, and mean ages at dissection were 63.5±12.9 and 67.5±12.2 years ( P <0.001), respectively. The most prevalent comorbidities for TAAD were hypertension (55.2%), thoracic aortic aneurysms (14.6%), and chronic obstructive pulmonary disease (13.1%); for TBAD, the most prevalent comorbidities were hypertension (64.1%), aortic aneurysms at any location (7.5% to 12.0%), and chronic obstructive pulmonary disease (15.7%). The overall mean annual incidence rate was 4.2/100 000 patient-years. Incidence was significantly higher for TAAD (2.2/100 000) compared with TBAD (1.5/100 000; P <0.001). The 30-day mortality rates for validated TAAD and TBAD were 22.0% and 13.9% ( P <0.001), respectively, with no significant changes over time or between sexes. Adjusted 5-year overall mortality rates for TAAD and TBAD were hazard ratio 3.2 (2.9 to 3.5; P <0.001; aortic-related cause of death, 57.0%) and hazard ratio 2.1 (1.9 to 2.4; P <0.001; aortic-related cause of death, 42.8%), respectively, compared with the general hypertensive population. Among patients who survived 30 days from dissection, the adjusted 5-year overall mortality rates were hazard ratio 1.1 (1.0 to 1.3; P =0.12; aortic-related cause of death, 23.2%) and hazard ratio 1.4 (1.2 to 1.6; P <0.001; aortic-related cause of death, 25.6%) for TAAD and TBAD, respectively. CONCLUSIONS: Hypertension, aortic aneurysms, and chronic obstructive pulmonary disease were the most prevalent comorbidities. The 30-day mortality frequencies were consistent over time with no significant differences between sexes. The 5-year mortality rate was higher for TAAD than TBAD. If the patient survived 30 days from dissection, the mortality rate for patients with TAAD was comparable with that of the general hypertensive population, but the mortality rate was significantly higher in patients with TBAD.