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.

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

“…However, there is evidence supporting LRP1 as a biologically plausible candidate pathway for AAA55, 56. Variants at, or close to, LRP1 are also associated with other vascular/related phenotypes (aortic dissection57, migraine58 and lipid traits17). Since we observed a degree of heterogeneity at this locus in our analysis (Online Table VII) we consider that further investigation of this locus remains warranted despite our findings.…”

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

“…It is likely that these patients are carriers of a de novo mutation, making these “sporadic” patients founders of a new nonsyndromic aortopathy. For example, recent studies have identified gene deletions and uniparental disomy, and genetic variations in LRP1 and ULK4 in sporadic NS‐TAD 83. This suggests that the relatives of patients affected by both familial and sporadic NS‐TADs may benefit from screening.…”

News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1

“…By contrast, a clear genetic basis for the importance of LRP1 in the formation of abdominal aneurysms has emerged [42, 53**]. In recent years novel genes and proteins controlling LDLR function has been identified, resulting in the development of new therapies, such as PCSK9 inhibitors, to lower plasma cholesterol levels.…”