TY - JOUR
T1 - Genome-Wide Association Study of Peripheral Artery Disease
AU - van Zuydam, Natalie R.
AU - Stiby, Alexander
AU - Abdalla, Moustafa
AU - Austin, Erin
AU - Dahlström, Emma H.
AU - McLachlan, Stela
AU - Vlachopoulou, Efthymia
AU - Ahlqvist, Emma
AU - Di Liao, Chen
AU - Sandholm, Niina
AU - Forsblom, Carol
AU - Mahajan, Anubha
AU - Robertson, Neil R.
AU - Rayner, N. William
AU - Lindholm, Eero
AU - Sinisalo, Juha
AU - Perola, Markus
AU - Kallio, Milla
AU - Weiss, Emily
AU - Price, Jackie
AU - Paterson, Andrew
AU - Klein, Barbara
AU - Salomaa, Veikko
AU - Palmer, Colin N. A.
AU - Groop, Per-Henrik
AU - Groop, Leif
AU - McCarthy, Mark I.
AU - de Andrade, Mariza
AU - Morris, Andrew P.
AU - Hopewell, Jemma C.
AU - Colhoun, Helen M.
AU - Kullo, Iftikhar J.
N1 - This study was supported by: European Union’s Seventh Framework Program (FP7/2007–2013) for the Innovative Medicine Initiative under grant agreement IMI/115006 (the SUMMIT consortium); the Aarno Koskelo Foundation; the Academy of Finland (299200, 316664); Professor Kullo is additionally supported by the National Heart, Lung, and Blood Institute (NHLBI) grant K24-HL707710; Dr Hopewell acknowledges personal support from the British Heart Foundation (FS/14/55/30806); the Chief Scientist Office of Scotland (Project Grant CZB/4/672); DOLOrisk (European Union’s Horizon 2020 research and innovation programme grant No 633491); the European Foundation for the Study of Diabetes (EFSD); EFSD/Sanofi European Diabetes Research Programme in Macrovascular Complications; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research; the Folkhälsan Research Foundation; the Helsinki University Central Hospital special government funds (nos. TYH2012209, TYH2014312, and TYH2017250); the Juvenile Diabetes Research Foundation (2-SRA-2014-276-Q-R); the Liv och Hälsa Foundation; the Mayo Foundation; the National Human Genome Research Institute (NHGRI, HG04599, and HG06379); the National Institute of General Medical Sciences (NIGMS), Bethesda, MA; NIH: U01-DK105535; Nylands Nation; Oxford University; TRIiC (the Novo Nordisk Foundation); the UK Medical Research Council (MRC); the Waldemar von Frenckell Foundation; the Wellcome Trust (076113, 090532, 098381, 203141, and 212259); and the Wilhelm and Else Stockmann Foundation.
PY - 2021/10
Y1 - 2021/10
N2 - Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status.Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status.Results: We identified 5 genome-wide significant (Passociation ≤5×10-8) associations with PAD in 449 548 (Ncases=12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], Pdiabetes=2.5×10-9, Pinteractionwithdiabetes=5.3×10-7). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], Psmokers=9.3×10-10, Pinteractionwithsmoking=3.9×10-5).Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
AB - Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status.Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status.Results: We identified 5 genome-wide significant (Passociation ≤5×10-8) associations with PAD in 449 548 (Ncases=12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], Pdiabetes=2.5×10-9, Pinteractionwithdiabetes=5.3×10-7). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], Psmokers=9.3×10-10, Pinteractionwithsmoking=3.9×10-5).Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
KW - peripheral vascular diseases
KW - genome-wide association study
KW - smoking
KW - diabetes
KW - peripheral vascular disease
UR - http://www.scopus.com/inward/record.url?scp=85119458238&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.119.002862
DO - 10.1161/CIRCGEN.119.002862
M3 - Article
C2 - 34601942
SN - 2574-8300
VL - 14
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
IS - 5
M1 - e002862
ER -