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Identification of a Genetic Variant Associated with Abdominal Aortic

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Identification of a Genetic Variant Associated with Abdominal Aortic BASIC RESEARCH STUDIES From the Eastern Vascular Society Identification of a genetic variant associated with abdominal aortic aneurysms on chromosome 3p12.3 by genome wide association James R. Elmore, MD,a Melissa A. Obmann, DO,a Helena Kuivaniemi, MD, PhD,b,c Gerard Tromp, PhD,b,d Glenn S. Gerhard, MD,e David P. Franklin, MD,a Amy M. Boddy,b and David J. Carey, PhD,e Danville, Pa; and Detroit, Mich Objective: The goal of this project was to identify genetic variants associated with abdominal aortic aneurysms (AAAs). Methods: A genome wide association study was carried out using pooled DNA samples from 123 AAA cases and 112 controls matched for age, gender, and smoking history using Affymetrix 500K single nucleotide polymorphism (SNP) arrays (Affymetrix, Inc, Santa Clara, Calif). The difference in mean allele frequency between cases and controls was calculated for each SNP and used to identify candidate genomic regions. Association of candidate SNPs with AAA was confirmed by individual TaqMan genotype assays in a total of 2096 cases and controls that included an independent replication sample set. Results: A genome wide association study of AAA cases and controls identified a candidate AAA-associated haplotype on chromosome 3p12.3. By individual genotype analysis, four SNPs in this region were significantly associated with AAA in cases and controls from the original study population. One SNP in this region (rs7635818) was genotyped in a total of 502 cases and 448 cases and 410 controls from an independent (017. ؍ and 736 controls from the original study population (P An even stronger association .(1.33 ؍ [combined odds ratio [OR ;0028. ؍ combined P value ;013. ؍ replication sample (P which represent the highest ,(1.80 ؍ OR ,00041. ؍ with AAA was observed in a subset of smokers (391 cases, 241 controls, P risk group for AAA. The AAA-associated haplotype is located ϳ200 kbp upstream of the CNTN3 gene transcription start site. Conclusion: This study identifies a region on chromosome 3 that is significantly associated with AAA in 2 distinct study populations. (J Vasc Surg 2009;49:1525-31.) Clinical Relevance: Genotype data can be used to identify individuals at increased genetic risk for AAA. Ultimately this genetic information may lead to improved diagnosis and better understanding of the pathophysiology of AAAs. Abdominal aortic aneurysms (AAAs) are a leading lack of diagnosis increases their risk of death from AAA, cause of death in the elderly, usually from aneurysm rup- since surgical treatments to repair aneurysms before they ture.1,2 Many patients with AAAs are undiagnosed. The rupture are safe and effective. The most important risk From the Department of Vascular and Endovascular Surgery,a Geisinger factors for AAAs are old age, male gender, smoking, and Clinic, Center for Molecular Medicine and Genetics,b Departments of family history of AAA. The underlying causes of aneurysm Surgeryc and Neurology,d Wayne State University School of Medicine, formation are not known. Investigations into the patho- and Sigfried and Janet Weis Center for Research,e Geisinger Clinic. The research at Geisinger Clinic was funded by a grant from the Pennsylva- physiology of AAA have focused on remodeling of the nia Commonwealth Universal Research Enhancement program (to extracellular matrix and inflammation as important mecha- D.J.C.), a grant from the Geisinger Clinical Research Fund (to J.R.E.) and nisms in AAA formation.3-8 a Grant-In-Aid from the American Heart Association (to D.J.C.). The Family and epidemiologic studies demonstrate a sub- Geisinger MyCode Project was funded in part by a grant from the Ben 4,9 Franklin Technology Development Fund of PA. The work carried out in stantial genetic risk for AAA. AAA is a complex disease the Kuivaniemi laboratory was funded in part by the National Heart, with risk influenced by an unknown number of genes that Lung, and Blood Institute of the NIH (HL045996 and HL06410 to act in combination with environmental factors such as H.K.), as well as by the Office of the Vice President for Research and by smoking. Identifying specific genetic factors that are asso- the Department of Surgery of Wayne State University. Competition of interest: none. ciated with AAA would be extremely useful in developing Presented at the Twenty-second Annual Meeting of the Eastern Vascular improved methods to diagnose and treat the disease. While Society, Boston, Mass, Sep 20, 2008. a number of candidate gene association studies that exam- Additional material for this article may be found online at www.jvascsurg.org. Reprint requests: David J. Carey, PhD, Weis Center for Research, Geisinger ined genes selected on the basis of their predicted role in 4,9 Clinic, 100 N Academy Avenue, Danville, PA 17822-2601 (e-mail: AAA have been reported, none of these studies have [email protected]). conclusively identified any AAA-associated variants. Previ- 0741-5214/$36.00 ously, whole genome linkage analyses using family-based or Copyright © 2009 Published by Elsevier Inc. on behalf of the Society for Vascular Surgery. affected-relative-pair methods identified two AAA-associated doi:10.1016/j.jvs.2009.01.041 genetic loci designated as the AAA1 (on 19q13) and AAA2 1525 JOURNAL OF VASCULAR SURGERY 1526 Elmore et al June 2009 (4q31) susceptibility loci.4,10,11 The specific AAA-associated Replication sample set. These samples consisted of genetic variants in these regions have not yet been identified. 453 AAA cases and 418 controls that were recruited from Another approach to identifying genetic variants asso- Belgium, Canada, and the USA. These samples have been ciated with complex disease is a genome wide association used in other genetic studies of AAA, and have been study (GWAS) in unrelated groups of cases and matched described previously.12 controls, preferably using large numbers of genetic mark- Appropriate institutional approvals were obtained for ers. The genetic markers of choice for GWAS are single use of human subjects in this research. nucleotide polymorphisms (SNPs). Most SNPs are bi-allelic, DNA purification. DNA was purified from EDTA- stable in the genome, and easily assayed. Several million anti-coagulated blood using a Qiagen BioRobot M48 common SNPs have been identified. In a typical GWAS, Workstation and MagAttract DNA Blood Midi M48 kit the majority of SNP alleles that are assayed have no known (Qiagen, Valencia, Calif). The yield and purity of DNA was functional effects (eg, they do not alter protein coding determined by measuring the absorbance at 260 and 280 information). However, because genetic variants that are nm using a Nanodrop spectrophotometer (ThermoFisher physically close in the genome will generally be inherited Scientific, Waltham, Mass). together (are in linkage disequilibrium, linkage disequilib- Genome wide association study. We carried out an rium [LD]), SNPs that are nearby a functional genetic initial GWAS of AAA cases and controls using a DNA variant can serve as markers for the functional variant. A pooling strategy similar to that used in previous stud- previous GWAS identified a genetic variant on chromo- ies.13-16 A flow-chart that summarizes the GWAS strategy some 9 that is associated with a moderate increase in AAA is in Supplemental Fig 1, online only. Three identical DNA risk.12 pools were generated independently from DNA samples of We carried out a case-control GWAS using a DNA 123 cases or 112 controls (a total of 6 pools) from the GVC pooling strategy that identified a candidate AAA-associated samples. Cases and controls were matched for male/female genomic region on chromosome 3p12.3. An SNP within ratio and age; all had a smoking history of Ͼ20 years. The this region was significantly associated with AAA in two characteristics of the subjects used for the GWAS are shown independent study populations. in Supplementary Table II, online only. To create the DNA pools, 100 ng of DNA from each subject was combined and Ϫ o METHODS then precipitated at 20 C by adding 0.1 volume of 3 M sodium acetate, pH 5.2, and 2.5 volumes of ethanol. The Study populations DNA was collected by centrifugation, washed with 70% Geisinger vascular clinic (GVC) samples. The pri- ethanol, and air-dried. The dried pellets were dissolved in mary case and control groups consisted of patients enrolled water at a final concentration of 50 ng/mL. through the Geisinger Clinic Department of Vascular Sur- The six DNA pools were hybridized separately to Af- gery. Patients had a diagnosis of AAA (defined as an aortic fymetrix SNP arrays using the GeneChip Mapping 500K diameter of 3 cm or greater) as determined by abdominal Manual Protocol (Affymetrix, Inc, Santa Clara, Calif). imaging study and confirmed by an attending vascular Pooled DNA (250 ng/array) was digested with Nsp I or surgeon. Controls were patients of the same clinic that were Sty I and ligated to adapters that recognize overhangs AAA-free, based on evaluation by a vascular surgeon of an generated by the restriction enzymes. Oligonucleotides abdominal imaging study carried out within the preceding that recognize the adapter sequences were used as primers 5 years. At enrollment, all participants provided a blood to amplify the adapter-ligated DNA fragments. The ampli- sample for DNA extraction, completed a questionnaire that fied DNA was fragmented, labeled, and hybridized to collected information about smoking history, family history GeneChip Human Mapping 250K Nsp and 250K Sty of AAA, and other information potentially related to AAA arrays (Affymetrix, Inc) for 18 hours at 47oC. After hybrid- risk factors. Subjects also gave permission to extract clinical ization, the chips were washed and stained using an FS-450 and demographic information from their electronic medi- mapping 500Kv1-450 fluidics workstation (Affymetrix, cal record (EMR).
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