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

被引:66
作者
Guo, Dong-chuan [1 ]
Grove, Megan L. [2 ]
Prakash, Siddharth K. [1 ]
Eriksson, Per [3 ]
Hostetler, Ellen M. [1 ]
LeMaire, Scott A. [4 ]
Body, Simon C. [5 ]
Shalhub, Sherene [6 ]
Estrera, Anthony L. [7 ]
Safi, Hazim J. [7 ]
Regalado, Ellen S. [1 ]
Zhou, Wei [8 ]
Mathis, Michael R. [9 ]
Eagle, Kim A. [10 ]
Yang, Bo [10 ]
Willer, Cristen J. [8 ,11 ,12 ]
Boerwinkle, Eric [2 ,13 ]
Milewicz, Dianna M. [1 ]
机构
[1] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Internal Med, Houston, TX 77030 USA
[2] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA
[3] Karolinska Univ Hosp Solna, Ctr Mol Med, S-17176 Stockholm, Sweden
[4] St Lukes Episcopal Hosp, Cardiovasc Surg, Texas Heart Inst, Houston, TX 77030 USA
[5] Harvard Med Sch, Dept Anesthesiol Perioperat & Pain Med, Brigham & Womens Hosp, Boston, MA 02115 USA
[6] Univ Washington, Div Vasc Surg, Seattle, WA 98195 USA
[7] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Cardiothorac Vasc Surg, Houston, TX 77030 USA
[8] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA
[9] Univ Michigan, Dept Anesthesiol, Ann Arbor, MI 48109 USA
[10] Univ Michigan, Samuel & Jean Frankel Cardiovasc Ctr, Ann Arbor, MI 48109 USA
[11] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA
[12] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA
[13] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA
关键词
GENOME-WIDE ASSOCIATION; RECEPTOR-RELATED PROTEIN-1; BLOOD-PRESSURE; MARFAN-SYNDROME; ANEURYSMS; MUTATIONS; HYPERTENSION; DISEASE; INDIVIDUALS; POPULATION;
D O I
10.1016/j.ajhg.2016.06.034
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 x 10(-8); OR = 0.82, 95% CI = 0.76-0.89) and a direct association between ULK4 rs2272007 and STAD (p = 1.15 x 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.
引用
收藏
页码:762 / 769
页数:8
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