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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Rheumatology, University of Colorado School of Medicine, Denver, CO, USA. lisa.davis@ucdenver.edu
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Davis
authors.forename: Grant W
authors.initials: GW
authors.lastname: Cannon
authors.forename: Lauren F
authors.initials: LF
authors.lastname: Pointer
authors.forename: Leah M
authors.initials: LM
authors.lastname: Haverhals
authors.forename: Roger K
authors.initials: RK
authors.lastname: Wolff
authors.forename: Ted R
authors.initials: TR
authors.lastname: Mikuls
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Reimold
authors.forename: Gail S
authors.initials: GS
authors.lastname: Kerr
authors.forename: J Steuart
authors.initials: JS
authors.lastname: Richards
authors.forename: Dannette S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Robert
authors.initials: R
authors.lastname: Valuck
authors.forename: Allan
authors.initials: A
authors.lastname: Prochazka
authors.forename: Liron
authors.initials: L
authors.lastname: Caplan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012042:Registries; D012307:Risk Factors; D012720:Severity of Illness Index; D014728:Veterans
chemical_list: D018501:Antirheumatic Agents; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate
keywords: CARDIOVASCULAR DISEASES; METHOTREXATE; METHYLENETETRAHYDROFOLATE REDUCTASE; RHEUMATOID ARTHRITIS; SINGLE-NUCLEOTIDE POLYMORPHISM
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