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 - Publisher Copyright:
© 2021 The Authors.
PY - 2021/10/1
Y1 - 2021/10/1
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 - diabetes
KW - genome-wide association study
KW - peripheral vascular disease
KW - smoking
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U2 - 10.1161/CIRCGEN.119.002862
DO - 10.1161/CIRCGEN.119.002862
M3 - Article
C2 - 34601942
AN - SCOPUS:85119458238
SN - 1942-325X
VL - 14
SP - E002862
JO - Circulation: Genomic and Precision Medicine
JF - Circulation: Genomic and Precision Medicine
IS - 5
ER -