Advertisement

A multi-locus genetic risk score for abdominal aortic aneurysm

      Abstract

      Background

      We investigated whether a multi-locus genetic risk scores (GRS) was associated with presence and progression of abdominal aortic aneurysm (AAA) in a case - control study.

      Methods and Results

      The study comprised of 1124 patients with AAA (74 ± 8 years, 83% men, 52% of them with a maximal AAA size ≤ 5 cm) and 6524 non-cases (67 ± 11 years, 58% men) from the Mayo Vascular Disease Biorepository. AAA was defined as infrarenal abdominal aorta diameter ≥3.0 cm or history of AAA repair. Non-cases were participants without known AAA. A GRS was calculated using 4 SNPs associated with AAA at genome-wide significance (P ≤ 10−8). The GRS was associated with the presence of AAA after adjustment for age, sex, cardiovascular risk factors, atherosclerotic cardiovascular diseases and family history of aortic aneurysm: odds ratio (OR, 95% confidence interval, CI) 1.06 (1.04–1.09, p < 0.001). Adding GRS to conventional risk factors improved the association of presence of AAA (net reclassification index 14%, p < 0.001). In a subset of patients with AAA who had ≥2 imaging studies (n = 651, mean (SE) growth rate 2.47 (0.11) mm/year during a mean time interval of 5.41years), GRS, baseline size, diabetes and family history were each associated with aneurysm growth rate in univariate association (all p < 0.05). The estimated mean aneurysm growth rate was 0.50 mm/year higher in those with GRS > median (5.78) than those with GRS ≤ median (p = 0.01), after adjustment for baseline size (p < 0.001), diabetes (p = 0.046) and family history of aortic aneurysm (p = 0.02).

      Conclusions

      A multi-locus GRS was associated with presence of AAA and greater aneurysm expansion.

      Keywords

      Abbreviations:

      AAA (abdominal aortic aneurysm), ASCVD (atherosclerotic cardiovascular disease), CHD (coronary heart disease), CI (confidence interval), EHR (electronic health record), GWAS (Genome-wide association studies), OR (odds ratio), SNP (Single nucleotide polymorphism), T2D (Type 2 diabetes)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Go A.S.
        • et al.
        Heart disease and stroke statistics–2014 update: a report from the american heart association.
        Circulation. 2014; 129: e28-e292
        • Pande R.L.
        • Beckman J.A.
        Abdominal aortic aneurysm: populations at risk and how to screen.
        J. Vasc. Interv. Radiol. 2008; 19: S2-8
        • Nordon I.M.
        • Hinchliffe R.J.
        • Loftus I.M.
        • Thompson M.M.
        Pathophysiology and epidemiology of abdominal aortic aneurysms.
        Nat. Rev. Cardiol. 2011; 8: 92-102
        • Guirguis-Blake J.M.
        • Beil T.L.
        • Senger C.A.
        • Whitlock E.P.
        Ultrasonography screening for abdominal aortic aneurysms: a systematic evidence review for the u.S. Preventive services task force.
        Ann. Intern Med. 2014; 160: 321-329
        • Powell J.T.
        • Greenhalgh R.M.
        Multifactorial inheritance of abdominal aortic aneurysm.
        Eur. J. Vasc. Surg. 1987; 1: 29-31
        • Bown M.J.
        • et al.
        Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1.
        Am. J. Hum. Genet. 2011; 89: 619-627
        • Bradley D.T.
        • et al.
        A variant in LDLR is associated with abdominal aortic aneurysm.
        Circ. Cardiovasc Genet. 2013; 6: 498-504
        • Elmore J.R.
        • et al.
        Identification of a genetic variant associated with abdominal aortic aneurysms on chromosome 3p12.3 by genome wide association.
        J. Vasc. Surg. 2009; 49: 1525-1531
        • Gretarsdottir S.
        • et al.
        Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm.
        Nat. Genet. 2010; 42: 692-697
        • Helgadottir A.
        • et al.
        The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm.
        Nat. Genet. 2008; 40: 217-224
        • Jones G.T.
        • et al.
        A sequence variant associated with sortilin-1 (sort1) on 1p13.3 is independently associated with abdominal aortic aneurysm.
        Hum. Mol. Genet. 2013; 22: 2941-2947
        • Tragante V.
        • et al.
        The impact of susceptibility loci for coronary artery disease on other vascular domains and recurrence risk.
        Eur. Heart J. 2013; 34: 2896-2904
        • Ye Z.
        • Kalloo F.S.
        • Dalenberg A.K.
        • Kullo I.J.
        An electronic medical record-linked biorepository to identify novel biomarkers for atherosclerotic cardiovascular disease.
        Glob. Cardiol. Sci. Pract. 2013; 2013: 82-90
        • Devaraj S.
        • Dodds S.R.
        Ultrasound surveillance of ectatic abdominal aortas.
        Ann. R. Coll. Surg. Engl. 2008; 90: 477-482
        • Freiberg M.S.
        • et al.
        Abdominal aortic aneurysms, increasing infrarenal aortic diameter, and risk of total mortality and incident cardiovascular disease events: 10-year follow-up data from the cardiovascular health study.
        Circulation. 2008; 117: 1010-1017
        • Ding K.
        • Bailey K.R.
        • Kullo I.J.
        Genotype-informed estimation of risk of coronary heart disease based on genome-wide association data linked to the electronic medical record.
        BMC Cardiovasc Disord. 2011; 11: 66
        • Kullo I.J.
        • et al.
        Leveraging informatics for genetic studies: use of the electronic medical record to enable a genome-wide association study of peripheral arterial disease.
        J. Am. Med. Inf. Assoc. 2010; 17: 568-574
      1. State-specific Secondhand Smoke Exposure and Current Cigarette Smoking Among Adults – United States. 2008: 1232-1235 (MMWR Morb Mortal Wkly Rep. 2009;58)
        • LeFevre M.L.
        Screening for abdominal aortic aneurysm: U.S. Preventive services task force recommendation statement.
        Ann. Intern Med. 2014; 161: 281-290
        • Sidloff D.
        • et al.
        Aneurysm global epidemiology study: public health measures can further reduce abdominal aortic aneurysm mortality.
        Circulation. 2014; 129: 747-753
        • McPhee J.T.
        • Hill J.S.
        • Eslami M.H.
        The impact of gender on presentation, therapy, and mortality of abdominal aortic aneurysm in the united states, 2001-2004.
        J. Vasc. Surg. 2007; 45: 891-899
        • Mureebe L.
        • Egorova N.
        • McKinsey J.F.
        • Kent K.C.
        Gender trends in the repair of ruptured abdominal aortic aneurysms and outcomes.
        J. Vasc. Surg. 2010; 51: 9S-13S
        • Kent K.C.
        • et al.
        Analysis of risk factors for abdominal aortic aneurysm in a cohort of more than 3 million individuals.
        J. Vasc. Surg. 2010; 52: 539-548
        • Mega J.L.
        • et al.
        Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.
        Lancet. 2015 Jun 6; 385: 2264-2271
        • van 't Hof F.N.
        • et al.
        Impact of inherited genetic variants associated with lipid profile, hypertension, and coronary artery disease on the risk of intracranial and abdominal aortic aneurysms.
        Circ. Cardiovasc Genet. 2013; 6: 264-270
        • Schlosser F.J.
        • et al.
        Growth predictors and prognosis of small abdominal aortic aneurysms.
        J. Vasc. Surg. 2008; 47: 1127-1133
        • Sweeting M.J.
        • Thompson S.G.
        • Brown L.C.
        • Powell J.T.
        Meta-analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms.
        Br. J. Surg. 2012; 99: 655-665
        • Brady A.R.
        • Thompson S.G.
        • Fowkes F.G.
        • Greenhalgh R.M.
        • Powell J.T.
        Abdominal aortic aneurysm expansion: risk factors and time intervals for surveillance.
        Circulation. 2004; 110: 16-21
        • Kullo I.J.
        • et al.
        Return of results in the genomic medicine projects of the emerge network.
        Front. Genet. 2014; 5: 50
        • Kullo I.J.
        • Jarvik G.P.
        • Manolio T.A.
        • Williams M.S.
        • Roden D.M.
        Leveraging the electronic health record to implement genomic medicine.
        Genet. Med. 2013; 15: 270-271