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Genetic Variants in LRP1 and ULK4 Are Associated with Acute Aortic Dissections.

TitleGenetic Variants in LRP1 and ULK4 Are Associated with Acute Aortic Dissections.
Publication TypeJournal Article
Year of Publication2016
AuthorsGuo D-C, Grove ML, Prakash SK, Eriksson P, Hostetler EM, LeMaire SA, Body SC, Shalhub S, Estrera AL, Safi HJ, Regalado ES, Zhou W, Mathis MR, Eagle KA, Yang B, Willer CJ, Boerwinkle E
Secondary AuthorsMilewicz DM
Corporate AuthorsGenTAC Investigators, BAVCon Investigators
JournalAm J Hum Genet
Volume99
Issue3
Pagination762-769
Date Published2016 09 01
ISSN1537-6605
KeywordsAged, Aneurysm, Dissecting, Aortic Aneurysm, Thoracic, Atherosclerosis, Case-Control Studies, Cohort Studies, DNA Copy Number Variations, Europe, Exome, Female, Fibrillin-1, Gene Deletion, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Hypertension, Linkage Disequilibrium, Low Density Lipoprotein Receptor-Related Protein-1, Male, Middle Aged, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases, Risk Factors
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.

DOI10.1016/j.ajhg.2016.06.034
Alternate JournalAm J Hum Genet
PubMed ID27569546
PubMed Central IDPMC5011062
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
R01 HL114823 / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
R01 HL062594 / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
/ RA / ARRA NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
UL1 RR024148 / RR / NCRR NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
P50 HL083794 / HL / NHLBI NIH HHS / United States