Genome-Wide Association Study of Peripheral Artery Disease
(2021) In Circulation. Genomic and precision medicine 14(5). p.002862-002862- Abstract
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... (More)
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.
(Less)
- author
- author collaboration
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- diabetes, genome-wide association study, peripheral vascular disease, smoking
- in
- Circulation. Genomic and precision medicine
- volume
- 14
- issue
- 5
- pages
- 002862 - 002862
- publisher
- Lippincott Williams & Wilkins
- external identifiers
-
- scopus:85119458238
- pmid:34601942
- ISSN
- 2574-8300
- DOI
- 10.1161/CIRCGEN.119.002862
- language
- English
- LU publication?
- yes
- id
- e1caed53-8988-4aec-bc62-cd3abd2a9d95
- date added to LUP
- 2021-12-03 11:15:10
- date last changed
- 2024-04-20 18:04:48
@article{e1caed53-8988-4aec-bc62-cd3abd2a9d95, abstract = {{<p>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.</p>}}, author = {{van Zuydam, Natalie R. and Stiby, Alexander and Abdalla, Moustafa and Austin, Erin and Dahlström, Emma H. and McLachlan, Stela and Vlachopoulou, Efthymia and Ahlqvist, Emma and Di Liao, Chen and Sandholm, Niina and Forsblom, Carol and Mahajan, Anubha and Robertson, Neil R. and Rayner, N. William and Lindholm, Eero and Sinisalo, Juha and Perola, Markus and Kallio, Milla and Weiss, Emily and Price, Jackie and Paterson, Andrew and Klein, Barbara and Salomaa, Veikko and Palmer, Colin N.A. and Groop, Per Henrik and Groop, Leif and McCarthy, Mark I. and de Andrade, Mariza and Morris, Andrew P. and Hopewell, Jemma C. and Colhoun, Helen M. and Kullo, Iftikhar J.}}, issn = {{2574-8300}}, keywords = {{diabetes; genome-wide association study; peripheral vascular disease; smoking}}, language = {{eng}}, number = {{5}}, pages = {{002862--002862}}, publisher = {{Lippincott Williams & Wilkins}}, series = {{Circulation. Genomic and precision medicine}}, title = {{Genome-Wide Association Study of Peripheral Artery Disease}}, url = {{http://dx.doi.org/10.1161/CIRCGEN.119.002862}}, doi = {{10.1161/CIRCGEN.119.002862}}, volume = {{14}}, year = {{2021}}, }