title: A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm.
abstract: 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 0.76-0.85, 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 case-control 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.
authors.affiliation: Department of Surgery, University of Otago, Dunedin 9054, New Zealand. greg.jones@otago.ac.nz
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Jones
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bown
authors.forename: Solveig
authors.initials: S
authors.lastname: Gretarsdottir
authors.forename: Simon P R
authors.initials: SP
authors.lastname: Romaine
authors.forename: Anna
authors.initials: A
authors.lastname: Helgadottir
authors.forename: Grace
authors.initials: G
authors.lastname: Yu
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.forename: Paul E
authors.initials: PE
authors.lastname: Norman
authors.forename: Cao
authors.initials: C
authors.lastname: Jin
authors.forename: Annette F
authors.initials: AF
authors.lastname: Baas
authors.forename: Jan D
authors.initials: JD
authors.lastname: Blankensteijn
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
authors.forename: L Victoria
authors.initials: LV
authors.lastname: Phillips
authors.forename: Michael J A
authors.initials: MJ
authors.lastname: Williams
authors.forename: Ruth
authors.initials: R
authors.lastname: Topless
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
authors.forename: Thodor M
authors.initials: TM
authors.lastname: Vasudevan
authors.forename: David R
authors.initials: DR
authors.lastname: Lewis
authors.forename: Ross D
authors.initials: RD
authors.lastname: Blair
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hill
authors.forename: Robert D
authors.initials: RD
authors.lastname: Sayers
authors.forename: Janet T
authors.initials: JT
authors.lastname: Powell
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Deloukas
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Matthiasson
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golledge
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ariëns
authors.forename: Anne
authors.initials: A
authors.lastname: Johnson
authors.forename: Soroush
authors.initials: S
authors.lastname: Sohrabi
authors.forename: D Julian
authors.initials: DJ
authors.lastname: Scott
authors.forename: David J
authors.initials: DJ
authors.lastname: Carey
authors.forename: Robert
authors.initials: R
authors.lastname: Erdman
authors.forename: James R
authors.initials: JR
authors.lastname: Elmore
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Andre M
authors.initials: AM
authors.lastname: van Rij
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000099183:Sortilin
references.citation: Lancet. 2005 Apr 30-May 6;365(9470):1577-89
references.pmid: 15866312
references.citation: Nat Genet. 2008 Feb;40(2):217-24
references.pmid: 18176561
references.citation: Circulation. 2008 Dec 2;118(23):2382-92
references.pmid: 19047592
references.citation: Atherosclerosis. 2010 Jan;208(1):183-9
references.pmid: 19660754
references.citation: Arterioscler Thromb Vasc Biol. 2010 Jun;30(6):1263-8
references.pmid: 20360536
references.citation: Am J Cardiol. 2010 May 15;105(10):1480-4
references.pmid: 20451699
references.citation: Nat Genet. 2010 Aug;42(8):692-7
references.pmid: 20622881
references.citation: J Vasc Surg. 2010 Sep;52(3):539-48
references.pmid: 20630687
references.citation: J Vasc Surg. 2009 Jun;49(6):1525-31
references.pmid: 19497516
references.citation: Nat Rev Genet. 2010 Dec;11(12):843-54
references.pmid: 21085203
references.citation: Am J Hum Genet. 2011 Nov 11;89(5):619-27
references.pmid: 22055160
references.citation: Arterioscler Thromb Vasc Biol. 2010 Jun;30(6):1075-7
references.pmid: 20484703
references.citation: Circ Cardiovasc Genet. 2010 Aug;3(4):365-73
references.pmid: 20562444
references.citation: Nature. 2010 Aug 5;466(7307):714-9
references.pmid: 20686566
references.citation: Atherosclerosis. 2000 Nov;153(1):99-106
references.pmid: 11058704
references.citation: Arch Intern Med. 2000 May 22;160(10):1425-30
references.pmid: 10826454
references.citation: Nature. 2010 Aug 5;466(7307):707-13
references.pmid: 20686565
references.citation: Nat Genet. 2011 Mar 06;43(4):333-8
references.pmid: 21378990
references.citation: Atherosclerosis. 2010 Apr;209(2):492-7
references.pmid: 19837406
references.citation: Trends Genet. 2012 Jul;28(7):323-32
references.pmid: 22480918