title: Genetic Variants in LRP1 and ULK4 Are Associated with Acute Aortic Dissections.
abstract: Acute aortic dissections are a preventable cause of sudden death if individuals at risk are identified and surgically repaired in a non-emergency setting. Although mutations in single genes can be used to identify at-risk individuals, the majority of dissection case subjects do not have evidence of a single gene disorder, but rather have the other major risk factor for dissections, hypertension. Initial genome-wide association studies (GWASs) identified SNPs at the FBN1 locus associated with both thoracic aortic aneurysms and dissections. Here, we used the Illumina HumanExome array to genotype 753 individuals of European descent presenting specifically with non-familial, sporadic thoracic aortic dissection (STAD) and compared them to the genotypes of 2,259 control subjects from the Atherosclerosis Risk in Communities (ARIC) study matched for age, gender, and, for the majority of cases, hypertension. SNPs in FBN1, LRP1, and ULK4 were identified to be significantly associated with STAD, and these results were replicated in two independent cohorts. Combining the data from all cohorts confirmed an inverse association between LRP1 rs11172113 and STAD (p = 2.74 × 10(-8); OR = 0.82, 95% CI = 0.76-0.89) and a direct association between ULK4 rs2272007 and STAD (p = 1.15 × 10(-9); OR = 1.35, 95% CI = 1.23-1.49). Genomic copy-number variation analysis independently confirmed that ULK4 deletions were significantly associated with development of thoracic aortic disease. These results indicate that genetic variations in LRP1 and ULK4 contribute to risk for presenting with an acute aortic dissection.
authors: Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors: Dong-Chuan
authors: DC
authors: Guo
authors: Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, TX 77030, USA.
authors: Megan L
authors: ML
authors: Grove
authors: Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors: Siddharth K
authors: SK
authors: Prakash
authors: Center for Molecular Medicine, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden.
authors: Per
authors: P
authors: Eriksson
authors: Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors: Ellen M
authors: EM
authors: Hostetler
authors: Cardiovascular Surgery, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX 77030, USA.
authors: Scott A
authors: SA
authors: LeMaire
authors: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Simon C
authors: SC
authors: Body
authors: Division of Vascular Surgery, University of Washington, Seattle, WA 98195, USA.
authors: Sherene
authors: S
authors: Shalhub
authors: Department of Cardiothoracic Vascular Surgery, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors: Anthony L
authors: AL
authors: Estrera
authors: Department of Cardiothoracic Vascular Surgery, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors: Hazim J
authors: HJ
authors: Safi
authors: Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors: Ellen S
authors: ES
authors: Regalado
authors: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Wei
authors: W
authors: Zhou
authors: Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Michael R
authors: MR
authors: Mathis
authors: Samuel and Jean Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Kim A
authors: KA
authors: Eagle
authors: Samuel and Jean Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Bo
authors: B
authors: Yang
authors: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Cristen J
authors: CJ
authors: Willer
authors: Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, TX 77030, USA; Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.
authors: Eric
authors: E
authors: Boerwinkle
authors: Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA. Electronic address: dianna.m.milewicz@uth.tmc.edu.
authors: Dianna M
authors: DM
authors: Milewicz
mesh_terms: D000368:Aged; D000784:Aortic Dissection / Q000150:complications / Q000235:genetics*; D017545:Aortic Aneurysm, Thoracic / Q000150:complications / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics; D005060:Europe / Q000208:ethnology; D059472:Exome / Q000235:genetics; D005260:Female; D000071838:Fibrillin-1 / Q000235:genetics; D017353:Gene Deletion; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000235:genetics; D015810:Linkage Disequilibrium; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D017346:Protein Serine-Threonine Kinases; C000605722:FBN1 protein, human; D054392:Adipokines; C475476:LRP1 protein, human; C570299:Ulk4 protein, human