. 2021 Oct;14(5):e002862.

doi: 10.1161/CIRCGEN.119.002862. Epub 2021 Oct 4.

Genome-Wide Association Study of Peripheral Artery Disease

Natalie R van Zuydam^#^{1

2

3}, Alexander Stiby^#⁴, Moustafa Abdalla², Erin Austin⁵, Emma H Dahlström^{6

7

8}, Stela McLachlan⁹, Efthymia Vlachopoulou¹⁰, Emma Ahlqvist¹¹, Chen Di Liao^{12

13}, Niina Sandholm^{6

7

8}, Carol Forsblom^{6

7

8}, Anubha Mahajan^{2

3

14}, Neil R Robertson^{2

3}, N William Rayner^{2

3

15}, Eero Lindholm¹¹, Juha Sinisalo¹⁶, Markus Perola^{17

18}, Milla Kallio¹⁹, Emily Weiss⁹, Jackie Price⁹, Andrew Paterson^{12

13}, Barbara Klein²⁰, Veikko Salomaa¹⁸, Colin N A Palmer²¹, Per-Henrik Groop^{6

7

8

22}, Leif Groop^{17

11}, Mark I McCarthy^{2

3

23

14}, Mariza de Andrade⁵, Andrew P Morris^{2

24

25}, Jemma C Hopewell^#⁴, Helen M Colhoun^#²⁶, Iftikhar J Kullo^#⁵; GoLEAD Consortium, SUMMIT Consortium†

Collaborators, Affiliations

Collaborators

Affiliations

¹ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden (N.R.v.Z.).
² Wellcome Centre for Human Genetics, Nuffield Department of Medicine (N.R.v.Z., M.A., A.M., N.R.R., N.W.R., M.I.M., A.P.M.), University of Oxford, United Kingdom.
³ Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine (N.R.v.Z., A.M., N.R.R., N.W.R., M.I.M.), University of Oxford, United Kingdom.
⁴ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (A.S., J.C.H.), University of Oxford, United Kingdom.
⁵ Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic, Rochester, MN (E. Austin, M.d.A., I.J.K.).
⁶ Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland (E.H.D., N.S., C.F., P.-H.G.).
⁷ Abdominal Center, Nephrology (E.H.D., N.S., C.F., P.-H.G.), University of Helsinki, Finland.
⁸ Helsinki University Hospital, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine (E.H.D., N.S., C.F., P.-H.G.), University of Helsinki, Finland.
⁹ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, United Kingdom (S.M., E.W., J.P.).
¹⁰ Department of Medicine, Helsinki University Central Hospital (E.V.), University of Helsinki, Finland.
¹¹ Genomics, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden (E. Ahlqvist, E.L., L.G.).
¹² Dalla Lana School of Public Health, University of Toronto, ON, Canada (C.D.L., A.P.).
¹³ Genetics & Genome Biology, SickKids, Toronto, ON, Canada (C.D.L., A.P.).
¹⁴ Now with Genentech, South San Francisco, CA (A.M., M.I.M.).
¹⁵ Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom (N.W.R.).
¹⁶ Heart and Lung Center (J.S.), University of Helsinki, Finland.
¹⁷ Institute for Molecular Medicine Finland (FIMM) (M.P., L.G.), University of Helsinki, Finland.
¹⁸ Finnish Institute for Health and Welfare, Helsinki, Finland (M.P., V.S.).
¹⁹ Vascular Surgery, Abdominal Center (M.K.), University of Helsinki, Finland.
²⁰ Ocular Epidemiology Research Group, University of Wisconsin-Madison (B.K.).
²¹ Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, United Kingdom (C.N.A.P.).
²² Department of Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia (P.-H.G.).
²³ Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, United Kingdom (M.I.M.).
²⁴ Department of Biostatistics, University of Liverpool, United Kingdom (A.P.M.).
²⁵ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, United Kingdom (A.P.M.).
²⁶ Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Campus, United Kingdom (H.M.C.).

^# Contributed equally.

PMID: 34601942
PMCID: PMC8542067
DOI: 10.1161/CIRCGEN.119.002862

Genome-Wide Association Study of Peripheral Artery Disease

Natalie R van Zuydam et al. Circ Genom Precis Med. 2021 Oct.

. 2021 Oct;14(5):e002862.

doi: 10.1161/CIRCGEN.119.002862. Epub 2021 Oct 4.

Authors

Collaborators

Affiliations

¹ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden (N.R.v.Z.).
² Wellcome Centre for Human Genetics, Nuffield Department of Medicine (N.R.v.Z., M.A., A.M., N.R.R., N.W.R., M.I.M., A.P.M.), University of Oxford, United Kingdom.
³ Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine (N.R.v.Z., A.M., N.R.R., N.W.R., M.I.M.), University of Oxford, United Kingdom.
⁴ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (A.S., J.C.H.), University of Oxford, United Kingdom.
⁵ Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic, Rochester, MN (E. Austin, M.d.A., I.J.K.).
⁶ Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland (E.H.D., N.S., C.F., P.-H.G.).
⁷ Abdominal Center, Nephrology (E.H.D., N.S., C.F., P.-H.G.), University of Helsinki, Finland.
⁸ Helsinki University Hospital, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine (E.H.D., N.S., C.F., P.-H.G.), University of Helsinki, Finland.
⁹ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, United Kingdom (S.M., E.W., J.P.).
¹⁰ Department of Medicine, Helsinki University Central Hospital (E.V.), University of Helsinki, Finland.
¹¹ Genomics, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden (E. Ahlqvist, E.L., L.G.).
¹² Dalla Lana School of Public Health, University of Toronto, ON, Canada (C.D.L., A.P.).
¹³ Genetics & Genome Biology, SickKids, Toronto, ON, Canada (C.D.L., A.P.).
¹⁴ Now with Genentech, South San Francisco, CA (A.M., M.I.M.).
¹⁵ Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom (N.W.R.).
¹⁶ Heart and Lung Center (J.S.), University of Helsinki, Finland.
¹⁷ Institute for Molecular Medicine Finland (FIMM) (M.P., L.G.), University of Helsinki, Finland.
¹⁸ Finnish Institute for Health and Welfare, Helsinki, Finland (M.P., V.S.).
¹⁹ Vascular Surgery, Abdominal Center (M.K.), University of Helsinki, Finland.
²⁰ Ocular Epidemiology Research Group, University of Wisconsin-Madison (B.K.).
²¹ Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, United Kingdom (C.N.A.P.).
²² Department of Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia (P.-H.G.).
²³ Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, United Kingdom (M.I.M.).
²⁴ Department of Biostatistics, University of Liverpool, United Kingdom (A.P.M.).
²⁵ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, United Kingdom (A.P.M.).
²⁶ Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Campus, United Kingdom (H.M.C.).

^# Contributed equally.

PMID: 34601942
PMCID: PMC8542067
DOI: 10.1161/CIRCGEN.119.002862

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 identified 5 genome-wide significant (P_association ≤5×10^-8) associations with PAD in 449 548 (N_cases=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], P_diabetes=2.5×10^-9, P_{interactionwithdiabetes}=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], P_smokers=9.3×10^-10, P_{interactionwithsmoking}=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.

Keywords: diabetes; genome-wide association study; peripheral vascular disease; smoking.

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Figures

**Figure 1.**
**Study design.** A primary meta-analysis of allelic effect on peripheral artery disease (PAD) in all individuals was performed. Subsequently and where smoking or diabetes status were available, individual study centers stratified by diabetes or smoking status and four additional meta-analyses of allelic effects on PAD were performed in: individuals with diabetes; individuals without diabetes; ever smokers and never smokers.

**Figure 2.**
**Four loci were associated with peripheral artery disease overall.** A, A Manhattan plot shows genome-wide associations from the GoLEAD consortium at the *LPA (lipoprotein A), CDKN2BAS1 (CDKN2B antisense RNA 1), PTPN11 (protein tyrosine phosphatase, nonreceptor type 11), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit*) loci with peripheral artery disease and (B) a QQ-plot shows a deviation from the normal distribution showing an inflation in genetic signal for variants associated with peripheral arterial disease in the GoLEAD consortium.

See this image and copyright information in PMC

References

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Genome-Wide Association Study of Peripheral Artery Disease

Collaborators

Affiliations

Genome-Wide Association Study of Peripheral Artery Disease

Authors

Collaborators

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous