A Multi-locus Genetic Risk Score for Abdominal Aortic Aneurysm Zi Ye, 1 MD, Erin Austin, 1,2 PhD, Daniel J Schaid, 2 PhD, Iftikhar J. Kullo, 1 MD Affiliations: 1 Division of Cardiovascular Diseases and the Gonda Vascular Center, Mayo Clinic, Rochester, MN; 2 Division of Health Science Research AHA ATVB 2015 2014 MFMER slide-1
Disclosure None 2014 MFMER slide-2
Background Abdominal aortic aneurysm (AAA): transverse diameter 3.0cm Prevalence: 12.8% in men; 4.1% in women above 65 years old respectively. Prognosis: mortality of 80% associated with aneurysm rupture; rupture determined by size and aneurysm growth rate Treatment: no pharmacological treatment is available to limit disease progression. 2014 MFMER slide-3
Background AAA is a multifactorial disease with a heritable component GWAS reported several common single nucleotide polymorphisms to be associated with AAA 2014 MFMER slide-4
Questions remain Identify biomarkers of AAA to improve disease prediction and enable individualized screening? Genetic risk improve prediction of presence of AAA beyond conventional risk factors? Genetic risk predict aneurysm growth? 2014 MFMER slide-5
Hypothesis A multi-locus genetic risk score (GRS) based on SNPs of GWAS may improve disease prediction beyond conventional risk factors and associated with aneurysm growth 2014 MFMER slide-6
Study design Case control study Study population: participants from Vascular Disease Biorepository. patients referred for noninvasive vascular evaluation in the Mayo Gonda Vascular Center and stress EKG lab, from 2008 to 2013, consent to give blood sample Ascertainment of conventional risk factors and comorbidities: electronic phenotype algorithms Information from institutional EHR Study questionnaire for smoking status 2014 MFMER slide-7
Study design Ascertainment of cases and non-cases: AAA: infrarenal abdominal aortic diameter 3 cm or history of aneurysm repair; Non-AAA: without ICD-9 codes of aortic aneurysm Aneurysm growth rate: latest/pre-operation first diameter / time interval (mm/ year) 2014 MFMER slide-8
Study design-genotyping Genomic DNA extracted from whole blood samples drawn at the recruitment Performed in Mayo clinic core lab using Illumina infinium Human core Exome Array, Ilumina Human 610 and 660w Quad-v1 (call rates>95%) Candidate SNPs from GWAS catalog and Pubmed. 2014 MFMER slide-9
Study design-grs Z-test to assess whether the risk estimates of SNPs were substantially different from that in the published literature Candidate SNPs from independent loci (linkage disequilibrium=0) GRS calculation Genotype-informed estimation of risk of coronary heart disease based on genome-wide association data linked to the electronic medical record Keyue Ding, Kent R Bailey and Iftikhar J Kullo BMC Cardiovascular disease 2011, 11:66 2014 MFMER slide-10
Statistical methods Logistic regression analysis: presence of AAA as dependent variable Adjustment: 1) age and sex; and 2) additionally for BMI, hypertension, diabetes, dyslipidemia, ASCVD and family history of aortic aneurysm AUC and net reclassification index were estimated to assess whether GRS can improve disease prediction beyond conventional risk factors. Aneurysm growth rate 2014 MFMER slide-11
Results 2014 MFMER slide-12
Table. Associations of SNPs with presence of AAA Locus Gene SNPs (risk allele) MAF OR (95% CI) 19p13.2 LDLR rs6511720 (G) 0.90 1.32 (1.20-1.43) 12q13.3 LRP1 rs1466535(c) 0.58 1.15 (1.10-1.21) 9p33.2 DAB2IP rs7025846 (A) 0.23 1.21 (1.14-1.28) 9p21 CDKN2 A-2B In literature In VDB Z test P- MAF value 2x10^ -10 0.90 5x10^ -10 0.65 5x10^ -10 0.27 rs2383207 (T) 0.49 1.27 2x10^ -8 0.52 1p13.3 SORT1 rs599839 (G) 0.22 0.81 (0.76-0.85) 7.2x1 0^-14 0.23 OR (95% CI) 1.04 (0.89-1.21) 1.04 (0.94-1.15) 1.17 (1.05-1.29) 1.22 (1.11-1.34) 0.90 (0.80-1.00) P-value P- value 0.009 0.66 0.4 0.004 0.0001 0.06 0.08 0.54 0.51 0.14 2014 MFMER slide-13
Table. Patient characteristics AAA (n=1098) Non-AAA (n=6538) Age, years 74 (8) 67 (11) Men 915 (83) 4039 (62) Body mass index, kg/m 2 29.3 (4.9) 29.1 (5.6) *Smoking (ever) 952 (87) 3800 (58) *Hypertension 908 (82) 4203 (64) Type 2 diabetes 342 (25) 1819 (22) *Dyslipidemia 959 (87) 4931 (75) *ASCVD 966 (88) 4552 (70) *Family history of aortic aneurysm 178 (16) 471 (7) *GRS 5.34 (2.74) 4.89 (2.86) Values expressed as mean (SD) or number (%).*P-value < 0.05 for comparisons in cases vs. non-cases adjusted for age and sex. Abbreviations: AAA=abdominal aortic aneurysm; ASCVD=atherosclerotic cardiovascular disease; GRS=genetic risk score. 2014 MFMER slide-14
Age & sex adjusted odds ratio for AAA Covariates OR ( 95% CI) GRS above median 1.37 (1.20-1.56) FHx of AA 2.49 (2.04-3.02) ASCVD 2.74 (2.26-3.34) Type 2 diabetes 1.00 (0.86-1.17) Dyslipidemia 2.02 (1.67-2.45) Hypertension 2.43 (2.06-2.89) Smoker 3.55 (2.96-4.28) BMI 30kg/m2 1.02 (0.89-1.17) 0 1 2 3 4 5 2014 MFMER slide-15
Multivariable regression analysis: odds ratio for presence of AAA Covariates OR ( 95% CI) Age >65 years 1.55 (1.35-1.77) Male sex 2.98 (2.52-3.56) GRS above median 1.31 (1.14-1.50) FHx of AA 2.43 (1.96-2.98) ASCVD 2.09 (1.70-2.59) Type 2 diabetes 0.78 (0.66-0.92) Dyslipidemia 1.32 (1.07-1.65) Hypertension 1.86 (1.54-2.26) Smoker 3.35 (2.77-4.06) BMI 30kg/m2 0.93 (0.80-1.07) 0 1 2 3 4 5 2014 MFMER slide-16
Association with AAA size change (N=628) 45% 55% Growth rate median 55% 45% Growth rate < median GRS < median GRS median GRS < median GRS median Linear regression Beta (SE) P-value AAA size baseline 1.29 (0.13) <0.001 GRS median 0.44 (0.20) 0.03 Logistic regression OR (95% CI) P- value AAA size baseline 2.78 (2.18-3.57) <0.001 GRS median 1.5 (1.07-2.11) 0.02 2014 MFMER slide-17
Conclusions A multi-locus GRS was associated with presence of AAA and greater aneurysm growth, suggesting genetic predisposition to disease initiation and progression 2014 MFMER slide-18
Limitations May not generalized to other population Not non-diseased participants with ultrasound screening GRS built based on additive model that may be an over simplification of the true biological mechanism 2014 MFMER slide-19
Questions & Discussion 2014 MFMER slide-20