A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm

被引：76

作者：

Jones, Gregory T. ^{[1
]}

Bown, Matthew J. ^{[4
,5
]}

Gretarsdottir, Solveig ^{[6
,7
]}

Romaine, Simon P. R. ^{[8
]}

Helgadottir, Anna ^{[6
,7
]}

Yu, Grace ^{[1
]}

Tromp, Gerard ^{[9
]}

Norman, Paul E. ^{[10
]}

Jin, Cao ^{[1
]}

Baas, Annette F. ^{[11
]}

Blankensteijn, Jan D. ^{[12
]}

Kullo, Iftikhar J. ^{[13
]}

Phillips, L. Victoria ^{[1
]}

Williams, Michael J. A. ^{[2
]}

Topless, Ruth ^{[3
]}

Merriman, Tony R. ^{[3
]}

Vasudevan, Thodor M. ^{[14
]}

Lewis, David R. ^{[15
]}

Blair, Ross D. ^{[14
]}

Hill, Andrew A. ^{[16
]}

Sayers, Robert D. ^{[4
,5
]}

Powell, Janet T. ^{[17
]}

Deloukas, Panagiotis ^{[18
]}

Thorleifsson, Gudmar ^{[6
,7
]}

Matthiasson, Stefan E. ^{[6
,7
]}

Thorsteinsdottir, Unnur ^{[6
,7
]}

Golledge, Jonathan ^{[19
]}

Ariens, Robert A. ^{[8
]}

Johnson, Anne ^{[8
]}

Sohrabi, Soroush ^{[8
]}

Scott, D. Julian ^{[8
]}

Carey, David J. ^{[9
]}

Erdman, Robert ^{[9
]}

Elmore, James R. ^{[20
]}

Kuivaniemi, Helena ^{[9
]}

Samani, Nilesh J. ^{[4
,5
]}

Stefansson, Kari ^{[6
,7
]}

van Rij, Andre M. ^{[1
]}

机构：

[1] Univ Otago, Dept Surg, Dunedin 9054, New Zealand

[2] Univ Otago, Dept Med, Dunedin 9054, New Zealand

[3] Univ Otago, Dept Biochem, Dunedin 9054, New Zealand

[4] Univ Leicester, Dept Cardiovasc Sci, Leicester LE2 7LX, Leics, England

[5] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England

[6] DeCODE Genet, IS-101 Reykjavik, Iceland

[7] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

[8] Univ Leeds, Div Cardiovasc & Diabet Res, MCRC, Leeds LS2 9JT, W Yorkshire, England

[9] Geisinger Med Clin, Sigfried & Janet Weis Ctr Res, Danville, PA 17822 USA

[10] Univ Western Australia, Dept Surg, Crawley, WA 6009, Australia

[11] Univ Med Ctr Utrecht, Med Genet Res Sect, NL-3584 CG Utrecht, Netherlands

[12] Vrije Univ Amsterdam Med Ctr, Dept Vasc Surg, NL-1007 MB Amsterdam 115, Netherlands

[13] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA

[14] Waikato Hosp, Hamilton, New Zealand

[15] Christchurch Hosp, Christchurch, New Zealand

[16] Auckland City Hosp, Auckland, New Zealand

[17] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London SW7 2AZ, England

[18] Wellcome Trust Sanger Inst, Genet Complex Traits Humans Grp, Cambridge CB10 1SA, England

[19] James Cook Univ, Sch Med & Dent, Queensland Res Ctr Peripheral Vasc Dis, Vasc Biol Unit, Townsville, Qld, Australia

[20] Geisinger Med Clin, Dept Endovasc & Vasc Surg, Danville, PA 17822 USA

来源：

HUMAN MOLECULAR GENETICS | 2013年 / 22卷 / 14期

基金：

英国惠康基金; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

MYOCARDIAL-INFARCTION; RISK; SUSCEPTIBILITY; LOCI; GENE;

D O I：

10.1093/hmg/ddt141

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95 CI 0.760.85, P 7.2 10(14)). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized casecontrol cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.

引用

页码：2941 / 2947

页数：7

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