Cardiovascular events are not associated with MTHFR polymorphisms, but are associated with methotrexate use and traditional risk factors in US veterans with rheumatoid arthritis

Lisa A. Davis, Grant W. Cannon, Lauren F. Pointer, Leah M. Haverhals, Roger K. Wolff, Ted R. Mikuls, Andreas M. Reimold, Gail S. Kerr, J. Steuart Richards, Dannette S. Johnson, Robert Valuck, Allan Prochazka, Liron Caplan

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Objective. C677T and A1298C polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with increased cardiovascular (CV) events in non-rheumatoid arthritis (RA) populations. We investigated potential associations of MTHFR polymorphisms and use of methotrexate (MTX) with time-to-CV event in data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry. Methods. VARA participants were genotyped for MTHFR polymorphisms. Variables included demographic information, baseline comorbidities, RA duration, autoantibody status, and disease activity. Patients' comorbidities and outcome variables were defined using International Classification of Diseases-9 and Current Procedural Terminology codes. The combined CV event outcome included myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass graft surgery, and stroke. Cox proportional hazards regression was used to model the time-to-CV event. Results. Data were available for 1047 subjects. Post-enrollment CV events occurred in 97 patients (9.26%). Although there was a trend toward reduced risk of CV events, MTHFR polymorphisms were not significantly associated with time-to-CV event. Time-to-CV event was associated with prior stroke (HR 2.01, 95% CI 1.03-3.90), prior MI (HR 1.70, 95% CI 1.06-2.71), hyperlipidemia (HR 1.57, 95% CI 1.01-2.43), and increased modified Charlson-Deyo index (HR 1.23, 95% CI 1.13-1.34). MTX use (HR 0.66, 95% CI 0.44-0.99) and increasing education (HR 0.87, 95% CI 0.80-0.95) were associated with a lower risk for CV events. Conclusion. Although MTHFR polymorphisms were previously associated with CV events in non-RA populations, we found only a trend toward decreased association with CV events in RA. Traditional risk factors conferred substantial CV risk, while MTX use and increasing years of education were protective.

Original languageEnglish (US)
Pages (from-to)809-817
Number of pages9
JournalJournal of Rheumatology
Volume40
Issue number6
DOIs
StatePublished - Jun 2013

Fingerprint

Methylenetetrahydrofolate Reductase (NADPH2)
Veterans
Methotrexate
Rheumatoid Arthritis
Arthritis
Comorbidity
Stroke
Current Procedural Terminology
Myocardial Infarction
Education
International Classification of Diseases
Percutaneous Coronary Intervention
Hyperlipidemias
Coronary Artery Bypass
Autoantibodies
Population
Registries
Demography
Transplants
Enzymes

Keywords

  • Cardiovascular Diseases
  • Methotrexate
  • Methylenetetrahydrofolate Reductase
  • Rheumatoid Arthritis
  • Single-Nucleotide Polymorphism

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy

Cite this

Cardiovascular events are not associated with MTHFR polymorphisms, but are associated with methotrexate use and traditional risk factors in US veterans with rheumatoid arthritis. / Davis, Lisa A.; Cannon, Grant W.; Pointer, Lauren F.; Haverhals, Leah M.; Wolff, Roger K.; Mikuls, Ted R.; Reimold, Andreas M.; Kerr, Gail S.; Richards, J. Steuart; Johnson, Dannette S.; Valuck, Robert; Prochazka, Allan; Caplan, Liron.

In: Journal of Rheumatology, Vol. 40, No. 6, 06.2013, p. 809-817.

Research output: Contribution to journalArticle

Davis, LA, Cannon, GW, Pointer, LF, Haverhals, LM, Wolff, RK, Mikuls, TR, Reimold, AM, Kerr, GS, Richards, JS, Johnson, DS, Valuck, R, Prochazka, A & Caplan, L 2013, 'Cardiovascular events are not associated with MTHFR polymorphisms, but are associated with methotrexate use and traditional risk factors in US veterans with rheumatoid arthritis', Journal of Rheumatology, vol. 40, no. 6, pp. 809-817. https://doi.org/10.3899/jrheum.121012
Davis, Lisa A. ; Cannon, Grant W. ; Pointer, Lauren F. ; Haverhals, Leah M. ; Wolff, Roger K. ; Mikuls, Ted R. ; Reimold, Andreas M. ; Kerr, Gail S. ; Richards, J. Steuart ; Johnson, Dannette S. ; Valuck, Robert ; Prochazka, Allan ; Caplan, Liron. / Cardiovascular events are not associated with MTHFR polymorphisms, but are associated with methotrexate use and traditional risk factors in US veterans with rheumatoid arthritis. In: Journal of Rheumatology. 2013 ; Vol. 40, No. 6. pp. 809-817.
@article{a8ef7d5f671a46118dfbc56642584075,
title = "Cardiovascular events are not associated with MTHFR polymorphisms, but are associated with methotrexate use and traditional risk factors in US veterans with rheumatoid arthritis",
abstract = "Objective. C677T and A1298C polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with increased cardiovascular (CV) events in non-rheumatoid arthritis (RA) populations. We investigated potential associations of MTHFR polymorphisms and use of methotrexate (MTX) with time-to-CV event in data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry. Methods. VARA participants were genotyped for MTHFR polymorphisms. Variables included demographic information, baseline comorbidities, RA duration, autoantibody status, and disease activity. Patients' comorbidities and outcome variables were defined using International Classification of Diseases-9 and Current Procedural Terminology codes. The combined CV event outcome included myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass graft surgery, and stroke. Cox proportional hazards regression was used to model the time-to-CV event. Results. Data were available for 1047 subjects. Post-enrollment CV events occurred in 97 patients (9.26{\%}). Although there was a trend toward reduced risk of CV events, MTHFR polymorphisms were not significantly associated with time-to-CV event. Time-to-CV event was associated with prior stroke (HR 2.01, 95{\%} CI 1.03-3.90), prior MI (HR 1.70, 95{\%} CI 1.06-2.71), hyperlipidemia (HR 1.57, 95{\%} CI 1.01-2.43), and increased modified Charlson-Deyo index (HR 1.23, 95{\%} CI 1.13-1.34). MTX use (HR 0.66, 95{\%} CI 0.44-0.99) and increasing education (HR 0.87, 95{\%} CI 0.80-0.95) were associated with a lower risk for CV events. Conclusion. Although MTHFR polymorphisms were previously associated with CV events in non-RA populations, we found only a trend toward decreased association with CV events in RA. Traditional risk factors conferred substantial CV risk, while MTX use and increasing years of education were protective.",
keywords = "Cardiovascular Diseases, Methotrexate, Methylenetetrahydrofolate Reductase, Rheumatoid Arthritis, Single-Nucleotide Polymorphism",
author = "Davis, {Lisa A.} and Cannon, {Grant W.} and Pointer, {Lauren F.} and Haverhals, {Leah M.} and Wolff, {Roger K.} and Mikuls, {Ted R.} and Reimold, {Andreas M.} and Kerr, {Gail S.} and Richards, {J. Steuart} and Johnson, {Dannette S.} and Robert Valuck and Allan Prochazka and Liron Caplan",
year = "2013",
month = "6",
doi = "10.3899/jrheum.121012",
language = "English (US)",
volume = "40",
pages = "809--817",
journal = "Journal of Rheumatology",
issn = "0315-162X",
publisher = "Journal of Rheumatology",
number = "6",

}

TY - JOUR

T1 - Cardiovascular events are not associated with MTHFR polymorphisms, but are associated with methotrexate use and traditional risk factors in US veterans with rheumatoid arthritis

AU - Davis, Lisa A.

AU - Cannon, Grant W.

AU - Pointer, Lauren F.

AU - Haverhals, Leah M.

AU - Wolff, Roger K.

AU - Mikuls, Ted R.

AU - Reimold, Andreas M.

AU - Kerr, Gail S.

AU - Richards, J. Steuart

AU - Johnson, Dannette S.

AU - Valuck, Robert

AU - Prochazka, Allan

AU - Caplan, Liron

PY - 2013/6

Y1 - 2013/6

N2 - Objective. C677T and A1298C polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with increased cardiovascular (CV) events in non-rheumatoid arthritis (RA) populations. We investigated potential associations of MTHFR polymorphisms and use of methotrexate (MTX) with time-to-CV event in data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry. Methods. VARA participants were genotyped for MTHFR polymorphisms. Variables included demographic information, baseline comorbidities, RA duration, autoantibody status, and disease activity. Patients' comorbidities and outcome variables were defined using International Classification of Diseases-9 and Current Procedural Terminology codes. The combined CV event outcome included myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass graft surgery, and stroke. Cox proportional hazards regression was used to model the time-to-CV event. Results. Data were available for 1047 subjects. Post-enrollment CV events occurred in 97 patients (9.26%). Although there was a trend toward reduced risk of CV events, MTHFR polymorphisms were not significantly associated with time-to-CV event. Time-to-CV event was associated with prior stroke (HR 2.01, 95% CI 1.03-3.90), prior MI (HR 1.70, 95% CI 1.06-2.71), hyperlipidemia (HR 1.57, 95% CI 1.01-2.43), and increased modified Charlson-Deyo index (HR 1.23, 95% CI 1.13-1.34). MTX use (HR 0.66, 95% CI 0.44-0.99) and increasing education (HR 0.87, 95% CI 0.80-0.95) were associated with a lower risk for CV events. Conclusion. Although MTHFR polymorphisms were previously associated with CV events in non-RA populations, we found only a trend toward decreased association with CV events in RA. Traditional risk factors conferred substantial CV risk, while MTX use and increasing years of education were protective.

AB - Objective. C677T and A1298C polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with increased cardiovascular (CV) events in non-rheumatoid arthritis (RA) populations. We investigated potential associations of MTHFR polymorphisms and use of methotrexate (MTX) with time-to-CV event in data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry. Methods. VARA participants were genotyped for MTHFR polymorphisms. Variables included demographic information, baseline comorbidities, RA duration, autoantibody status, and disease activity. Patients' comorbidities and outcome variables were defined using International Classification of Diseases-9 and Current Procedural Terminology codes. The combined CV event outcome included myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass graft surgery, and stroke. Cox proportional hazards regression was used to model the time-to-CV event. Results. Data were available for 1047 subjects. Post-enrollment CV events occurred in 97 patients (9.26%). Although there was a trend toward reduced risk of CV events, MTHFR polymorphisms were not significantly associated with time-to-CV event. Time-to-CV event was associated with prior stroke (HR 2.01, 95% CI 1.03-3.90), prior MI (HR 1.70, 95% CI 1.06-2.71), hyperlipidemia (HR 1.57, 95% CI 1.01-2.43), and increased modified Charlson-Deyo index (HR 1.23, 95% CI 1.13-1.34). MTX use (HR 0.66, 95% CI 0.44-0.99) and increasing education (HR 0.87, 95% CI 0.80-0.95) were associated with a lower risk for CV events. Conclusion. Although MTHFR polymorphisms were previously associated with CV events in non-RA populations, we found only a trend toward decreased association with CV events in RA. Traditional risk factors conferred substantial CV risk, while MTX use and increasing years of education were protective.

KW - Cardiovascular Diseases

KW - Methotrexate

KW - Methylenetetrahydrofolate Reductase

KW - Rheumatoid Arthritis

KW - Single-Nucleotide Polymorphism

UR - http://www.scopus.com/inward/record.url?scp=84878630329&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878630329&partnerID=8YFLogxK

U2 - 10.3899/jrheum.121012

DO - 10.3899/jrheum.121012

M3 - Article

VL - 40

SP - 809

EP - 817

JO - Journal of Rheumatology

JF - Journal of Rheumatology

SN - 0315-162X

IS - 6

ER -