Genetic determinants of the ankle-brachial index

A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium

Christina L. Wassel, Claudia Lamina, Vijay Nambi, Stefan Coassin, Kenneth J. Mukamal, Santhi K. Ganesh, David R. Jacobs, Nora Franceschini, George J. Papanicolaou, Quince Gibson, Lisa R. Yanek, Pim van der Harst, Jane F. Ferguson, Dana C. Crawford, Lindsay L. Waite, Matthew A. Allison, Michael H. Criqui, Mary M. McDermott, Reena Mehra, L. Adrienne Cupples & 41 others Shih Jen Hwang, Susan Redline, Robert C. Kaplan, Gerardo Heiss, Jerome I. Rotter, Eric Boerwinkle, Herman A. Taylor, Luis H. Eraso, Margot Haun, Mingyao Li, Christa Meisinger, Jeffrey R. O'Connell, Alan R. Shuldiner, Anne Tybjærg-Hansen, Ruth Frikke-Schmidt, Barbara Kollerits, Barbara Rantner, Benjamin Dieplinger, Marietta Stadler, Thomas Mueller, Meinhard Haltmayer, Peter Klein-Weigel, Monika Summerer, H. Erich Wichmann, Folkert W. Asselbergs, Gerjan Navis, Irene Mateo Leach, Kristin Brown-Gentry, Robert Goodloe, Themistocles L. Assimes, Diane M. Becker, John P. Cooke, Devin M. Absher, Jeffrey W. Olin, Braxton D. Mitchell, Muredach P. Reilly, Emile R. Mohler, Kari E. North, Alexander P. Reiner, Florian Kronenberg, Joanne M. Murabito

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI. Methods and results: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10 -6 to denote statistical significance. Results: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10 -7) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10 -7) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10 -5) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10 -3; rs290481, p=8.88×10 -5). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance. Conclusions: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.

Original languageEnglish (US)
Pages (from-to)138-147
Number of pages10
JournalAtherosclerosis
Volume222
Issue number1
DOIs
StatePublished - May 2012

Fingerprint

Ankle Brachial Index
Peripheral Arterial Disease
Single Nucleotide Polymorphism
Meta-Analysis
Genes
Genetic Association Studies
African Americans
Lipoprotein(a)
Genetic Models
Ethnic Groups
Type 2 Diabetes Mellitus
Population
Linear Models
Logistic Models
Smoking
Alleles

Keywords

  • Ankle brachial index
  • Candidate gene array
  • Ethnicity
  • Genetics
  • Meta-analysis
  • Peripheral artery disease

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Genetic determinants of the ankle-brachial index : A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium. / Wassel, Christina L.; Lamina, Claudia; Nambi, Vijay; Coassin, Stefan; Mukamal, Kenneth J.; Ganesh, Santhi K.; Jacobs, David R.; Franceschini, Nora; Papanicolaou, George J.; Gibson, Quince; Yanek, Lisa R.; van der Harst, Pim; Ferguson, Jane F.; Crawford, Dana C.; Waite, Lindsay L.; Allison, Matthew A.; Criqui, Michael H.; McDermott, Mary M.; Mehra, Reena; Cupples, L. Adrienne; Hwang, Shih Jen; Redline, Susan; Kaplan, Robert C.; Heiss, Gerardo; Rotter, Jerome I.; Boerwinkle, Eric; Taylor, Herman A.; Eraso, Luis H.; Haun, Margot; Li, Mingyao; Meisinger, Christa; O'Connell, Jeffrey R.; Shuldiner, Alan R.; Tybjærg-Hansen, Anne; Frikke-Schmidt, Ruth; Kollerits, Barbara; Rantner, Barbara; Dieplinger, Benjamin; Stadler, Marietta; Mueller, Thomas; Haltmayer, Meinhard; Klein-Weigel, Peter; Summerer, Monika; Wichmann, H. Erich; Asselbergs, Folkert W.; Navis, Gerjan; Leach, Irene Mateo; Brown-Gentry, Kristin; Goodloe, Robert; Assimes, Themistocles L.; Becker, Diane M.; Cooke, John P.; Absher, Devin M.; Olin, Jeffrey W.; Mitchell, Braxton D.; Reilly, Muredach P.; Mohler, Emile R.; North, Kari E.; Reiner, Alexander P.; Kronenberg, Florian; Murabito, Joanne M.

In: Atherosclerosis, Vol. 222, No. 1, 05.2012, p. 138-147.

Research output: Contribution to journalArticle

Wassel, CL, Lamina, C, Nambi, V, Coassin, S, Mukamal, KJ, Ganesh, SK, Jacobs, DR, Franceschini, N, Papanicolaou, GJ, Gibson, Q, Yanek, LR, van der Harst, P, Ferguson, JF, Crawford, DC, Waite, LL, Allison, MA, Criqui, MH, McDermott, MM, Mehra, R, Cupples, LA, Hwang, SJ, Redline, S, Kaplan, RC, Heiss, G, Rotter, JI, Boerwinkle, E, Taylor, HA, Eraso, LH, Haun, M, Li, M, Meisinger, C, O'Connell, JR, Shuldiner, AR, Tybjærg-Hansen, A, Frikke-Schmidt, R, Kollerits, B, Rantner, B, Dieplinger, B, Stadler, M, Mueller, T, Haltmayer, M, Klein-Weigel, P, Summerer, M, Wichmann, HE, Asselbergs, FW, Navis, G, Leach, IM, Brown-Gentry, K, Goodloe, R, Assimes, TL, Becker, DM, Cooke, JP, Absher, DM, Olin, JW, Mitchell, BD, Reilly, MP, Mohler, ER, North, KE, Reiner, AP, Kronenberg, F & Murabito, JM 2012, 'Genetic determinants of the ankle-brachial index: A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium', Atherosclerosis, vol. 222, no. 1, pp. 138-147. https://doi.org/10.1016/j.atherosclerosis.2012.01.039
Wassel, Christina L. ; Lamina, Claudia ; Nambi, Vijay ; Coassin, Stefan ; Mukamal, Kenneth J. ; Ganesh, Santhi K. ; Jacobs, David R. ; Franceschini, Nora ; Papanicolaou, George J. ; Gibson, Quince ; Yanek, Lisa R. ; van der Harst, Pim ; Ferguson, Jane F. ; Crawford, Dana C. ; Waite, Lindsay L. ; Allison, Matthew A. ; Criqui, Michael H. ; McDermott, Mary M. ; Mehra, Reena ; Cupples, L. Adrienne ; Hwang, Shih Jen ; Redline, Susan ; Kaplan, Robert C. ; Heiss, Gerardo ; Rotter, Jerome I. ; Boerwinkle, Eric ; Taylor, Herman A. ; Eraso, Luis H. ; Haun, Margot ; Li, Mingyao ; Meisinger, Christa ; O'Connell, Jeffrey R. ; Shuldiner, Alan R. ; Tybjærg-Hansen, Anne ; Frikke-Schmidt, Ruth ; Kollerits, Barbara ; Rantner, Barbara ; Dieplinger, Benjamin ; Stadler, Marietta ; Mueller, Thomas ; Haltmayer, Meinhard ; Klein-Weigel, Peter ; Summerer, Monika ; Wichmann, H. Erich ; Asselbergs, Folkert W. ; Navis, Gerjan ; Leach, Irene Mateo ; Brown-Gentry, Kristin ; Goodloe, Robert ; Assimes, Themistocles L. ; Becker, Diane M. ; Cooke, John P. ; Absher, Devin M. ; Olin, Jeffrey W. ; Mitchell, Braxton D. ; Reilly, Muredach P. ; Mohler, Emile R. ; North, Kari E. ; Reiner, Alexander P. ; Kronenberg, Florian ; Murabito, Joanne M. / Genetic determinants of the ankle-brachial index : A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium. In: Atherosclerosis. 2012 ; Vol. 222, No. 1. pp. 138-147.
@article{d43c6a7006814de3b4f1d04d85e2d15d,
title = "Genetic determinants of the ankle-brachial index: A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium",
abstract = "Background: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI. Methods and results: We studied subjects of European ancestry from 8 studies (n=21,547, 55{\%} women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60{\%} women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10 -6 to denote statistical significance. Results: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10 -7) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10 -7) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10 -5) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10 -3; rs290481, p=8.88×10 -5). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance. Conclusions: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.",
keywords = "Ankle brachial index, Candidate gene array, Ethnicity, Genetics, Meta-analysis, Peripheral artery disease",
author = "Wassel, {Christina L.} and Claudia Lamina and Vijay Nambi and Stefan Coassin and Mukamal, {Kenneth J.} and Ganesh, {Santhi K.} and Jacobs, {David R.} and Nora Franceschini and Papanicolaou, {George J.} and Quince Gibson and Yanek, {Lisa R.} and {van der Harst}, Pim and Ferguson, {Jane F.} and Crawford, {Dana C.} and Waite, {Lindsay L.} and Allison, {Matthew A.} and Criqui, {Michael H.} and McDermott, {Mary M.} and Reena Mehra and Cupples, {L. Adrienne} and Hwang, {Shih Jen} and Susan Redline and Kaplan, {Robert C.} and Gerardo Heiss and Rotter, {Jerome I.} and Eric Boerwinkle and Taylor, {Herman A.} and Eraso, {Luis H.} and Margot Haun and Mingyao Li and Christa Meisinger and O'Connell, {Jeffrey R.} and Shuldiner, {Alan R.} and Anne Tybj{\ae}rg-Hansen and Ruth Frikke-Schmidt and Barbara Kollerits and Barbara Rantner and Benjamin Dieplinger and Marietta Stadler and Thomas Mueller and Meinhard Haltmayer and Peter Klein-Weigel and Monika Summerer and Wichmann, {H. Erich} and Asselbergs, {Folkert W.} and Gerjan Navis and Leach, {Irene Mateo} and Kristin Brown-Gentry and Robert Goodloe and Assimes, {Themistocles L.} and Becker, {Diane M.} and Cooke, {John P.} and Absher, {Devin M.} and Olin, {Jeffrey W.} and Mitchell, {Braxton D.} and Reilly, {Muredach P.} and Mohler, {Emile R.} and North, {Kari E.} and Reiner, {Alexander P.} and Florian Kronenberg and Murabito, {Joanne M.}",
year = "2012",
month = "5",
doi = "10.1016/j.atherosclerosis.2012.01.039",
language = "English (US)",
volume = "222",
pages = "138--147",
journal = "Atherosclerosis",
issn = "0021-9150",
publisher = "Elsevier Ireland Ltd",
number = "1",

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TY - JOUR

T1 - Genetic determinants of the ankle-brachial index

T2 - A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium

AU - Wassel, Christina L.

AU - Lamina, Claudia

AU - Nambi, Vijay

AU - Coassin, Stefan

AU - Mukamal, Kenneth J.

AU - Ganesh, Santhi K.

AU - Jacobs, David R.

AU - Franceschini, Nora

AU - Papanicolaou, George J.

AU - Gibson, Quince

AU - Yanek, Lisa R.

AU - van der Harst, Pim

AU - Ferguson, Jane F.

AU - Crawford, Dana C.

AU - Waite, Lindsay L.

AU - Allison, Matthew A.

AU - Criqui, Michael H.

AU - McDermott, Mary M.

AU - Mehra, Reena

AU - Cupples, L. Adrienne

AU - Hwang, Shih Jen

AU - Redline, Susan

AU - Kaplan, Robert C.

AU - Heiss, Gerardo

AU - Rotter, Jerome I.

AU - Boerwinkle, Eric

AU - Taylor, Herman A.

AU - Eraso, Luis H.

AU - Haun, Margot

AU - Li, Mingyao

AU - Meisinger, Christa

AU - O'Connell, Jeffrey R.

AU - Shuldiner, Alan R.

AU - Tybjærg-Hansen, Anne

AU - Frikke-Schmidt, Ruth

AU - Kollerits, Barbara

AU - Rantner, Barbara

AU - Dieplinger, Benjamin

AU - Stadler, Marietta

AU - Mueller, Thomas

AU - Haltmayer, Meinhard

AU - Klein-Weigel, Peter

AU - Summerer, Monika

AU - Wichmann, H. Erich

AU - Asselbergs, Folkert W.

AU - Navis, Gerjan

AU - Leach, Irene Mateo

AU - Brown-Gentry, Kristin

AU - Goodloe, Robert

AU - Assimes, Themistocles L.

AU - Becker, Diane M.

AU - Cooke, John P.

AU - Absher, Devin M.

AU - Olin, Jeffrey W.

AU - Mitchell, Braxton D.

AU - Reilly, Muredach P.

AU - Mohler, Emile R.

AU - North, Kari E.

AU - Reiner, Alexander P.

AU - Kronenberg, Florian

AU - Murabito, Joanne M.

PY - 2012/5

Y1 - 2012/5

N2 - Background: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI. Methods and results: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10 -6 to denote statistical significance. Results: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10 -7) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10 -7) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10 -5) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10 -3; rs290481, p=8.88×10 -5). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance. Conclusions: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.

AB - Background: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI. Methods and results: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10 -6 to denote statistical significance. Results: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10 -7) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10 -7) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10 -5) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10 -3; rs290481, p=8.88×10 -5). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance. Conclusions: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.

KW - Ankle brachial index

KW - Candidate gene array

KW - Ethnicity

KW - Genetics

KW - Meta-analysis

KW - Peripheral artery disease

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UR - http://www.scopus.com/inward/citedby.url?scp=84862819551&partnerID=8YFLogxK

U2 - 10.1016/j.atherosclerosis.2012.01.039

DO - 10.1016/j.atherosclerosis.2012.01.039

M3 - Article

VL - 222

SP - 138

EP - 147

JO - Atherosclerosis

JF - Atherosclerosis

SN - 0021-9150

IS - 1

ER -