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.

Figure 1

Linkage Disequilibrium Structure of the Regions Flanking LRP1 rs11172113 and ULK4 rs2272007 Based on the HapMap CEU Data (A) Linkage disequilibrium (LD) structure (D′) of chromosome 12 region flanking LRP1 rs11172113. Red arrow indicates LRP1 rs11172113, identified to be associated with thoracic aortic dissections in this study, and green arrow indicates LRP1 rs1466535 SNP, previously reported to be associated with abdominal aortic aneurysms. (B) LD structure of chromosome 3 region flanking ULK4 rs2272007. Red arrow indicates ULK4 SNPs that were significantly or marginally significantly associated with STAD in discovery study and blue arrow indicates ULK4 SNPs previously reported to be associated with hypertension.

Figure 2

Characterization of ULK4 Deletions in Individuals with Thoracic Aortic Disease and a Control Subject The black bars indicate the extent of genomic deletion in individuals with TAAD and the gray bar indicates the extent of genomic deletion identified in a control subject. The bar below the schematic of the ULK4 gene structure indicate the extent of the typical ULK4 deletion identified in individuals with schizophrenia. The scale is in kilobases.