title: B-vitamin levels and genetics of hyperhomocysteinemia are not associated with arterial stiffness.
abstract: OBJECTIVE
  Hyperhomocysteinemia is associated with arterial stiffness, but underlying pathophysiological mechanisms explaining this association are to be revealed. This study was aimed to explore two potential pathways concerning the one-carbon metabolism. A potential causal effect of homocysteine was explored using a genetic risk score reflecting an individual's risk of having a long-term elevated plasma homocysteine level and also associations with B-vitamin levels were investigated.
  
  
  RESULTS
  Baseline cross-sectional data of the B-PROOF study were used. In the cardiovascular subgroup (n = 567, 56% male, age 72.6 ± 5.6 yrs) pulse wave velocity (PWV) was determined using applanation tonometry. Plasma concentrations of vitamin B12, folate, methylmalonic acid (MMA) and holo transcobalamin (holoTC) were assessed and the genetic risk score was based on 13 SNPs being associated with elevated plasma homocysteine. Associations were examined using multivariable linear regression analysis. B-vitamin levels were not associated with PWV. The genetic risk score was also not associated with PWV. However, the homocysteine-gene interaction was significant (p < 0.001) in the association of the genetic risk score and PWV. Participants with the lowest genetic risk of having long-term elevated homocysteine levels, but with higher measured homocysteine levels, had the highest PWV levels.
  
  
  CONCLUSIONS
  Homocysteine is unlikely to be causally related to arterial stiffness, because there was no association with genetic variants causing hyperhomocysteinemia, whereas non-genetically determined hyperhomocysteinemia was associated with arterial stiffness. Moreover, the association between homocysteine and arterial stiffness was not mediated by B-vitamins. Possibly, high plasma homocysteine levels reflect an unidentified factor, that causes increased arterial stiffness.
authors.affiliation: Erasmus Medical Center, Department of Internal Medicine, Section of Geriatrics, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands. Electronic address: s.c.vandijk@erasmusmc.nl.
authors.forename: S C
authors.initials: SC
authors.lastname: van Dijk
authors.affiliation: Erasmus Medical Center, Department of Internal Medicine, Section of Geriatrics, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: A W
authors.initials: AW
authors.lastname: Enneman
authors.affiliation: Erasmus Medical Center, Department of Internal Medicine, Section of Geriatrics, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van Meurs
authors.affiliation: VU University Medical Center, EMGO Institute for Health and Care Research, Department of Epidemiology and Biostatistics, Amsterdam, the Netherlands.
authors.forename: K M A
authors.initials: KM
authors.lastname: Swart
authors.affiliation: Erasmus Medical Center, Department of Internal Medicine, Section of Geriatrics, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Ham
authors.affiliation: Wageningen University, Division of Human Nutrition, Wageningen, the Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: van Wijngaarden
authors.affiliation: Wageningen University, Division of Human Nutrition, Wageningen, the Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: Brouwer-Brolsma
authors.affiliation: Wageningen University, Division of Human Nutrition, Wageningen, the Netherlands.
authors.forename: N L
authors.initials: NL
authors.lastname: van der Zwaluw
authors.affiliation: VU University Medical Center, EMGO Institute for Health and Care Research, Department of Epidemiology and Biostatistics, Amsterdam, the Netherlands.
authors.forename: N M
authors.initials: NM
authors.lastname: van Schoor
authors.affiliation: Wageningen University, Division of Human Nutrition, Wageningen, the Netherlands.
authors.forename: R A M
authors.initials: RA
authors.lastname: Dhonukshe-Rutten
authors.affiliation: Wageningen University, Division of Human Nutrition, Wageningen, the Netherlands.
authors.forename: L C P G M
authors.initials: LC
authors.lastname: de Groot
authors.affiliation: VU University Medical Center, EMGO Institute for Health and Care Research, Department of Epidemiology and Biostatistics, Amsterdam, the Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Lips
authors.affiliation: Erasmus Medical Center, Department of Internal Medicine, Section of Geriatrics, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands; Netherlands Consortium of Healthy Ageing, Rotterdam, the Netherlands; Netherlands Consortium of Healthy Ageing, Leiden, the Netherlands.
authors.forename: A G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: VU University Medical Center, Department of Clinical Chemistry, Metabolic Unit, Amsterdam, the Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Blom
authors.affiliation: Wageningen University, Division of Human Nutrition, Wageningen, the Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Geleijnse
authors.affiliation: Wageningen University, Division of Human Nutrition, Wageningen, the Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Feskens
authors.affiliation: VU University Medical Center, Department of Internal Medicine, Amsterdam, the Netherlands.
authors.forename: R T
authors.initials: RT
authors.lastname: de Jongh
authors.affiliation: VU University Medical Center, Department of Internal Medicine, Amsterdam, the Netherlands; Institute for Cardiovascular Research ICaR-VU, Amsterdam, the Netherlands.
authors.forename: Y M
authors.initials: YM
authors.lastname: Smulders
authors.affiliation: Erasmus Medical Center, Department of Internal Medicine, Section of Geriatrics, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: van den Meiracker
authors.affiliation: Erasmus Medical Center, Department of Internal Medicine, Section of Geriatrics, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: F U S
authors.initials: FU
authors.lastname: Mattace-Raso
authors.affiliation: Erasmus Medical Center, Department of Internal Medicine, Section of Geriatrics, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands; Academic Medical Center, Department of Internal Medicine, Section of Geriatrics, Amsterdam, the Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: van der Velde
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure / Q000502:physiology; D015992:Body Mass Index; D003404:Creatinine / Q000097:blood; D003430:Cross-Sectional Studies; D004311:Double-Blind Method; D005260:Female; D005492:Folic Acid / Q000097:blood; D060005:Genotyping Techniques; D006710:Homocysteine / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood* / Q000235:genetics*; D016014:Linear Models; D008297:Male; D008764:Methylmalonic Acid / Q000097:blood; D015999:Multivariate Analysis; D063177:Pulse Wave Analysis; D012307:Risk Factors; D059289:Vascular Stiffness / Q000235:genetics* / Q000502:physiology; D014805:Vitamin B 12 / Q000097:blood; D014803:Vitamin B Complex / Q000097:blood*
chemical_list: D006710:Homocysteine; D014803:Vitamin B Complex; D008764:Methylmalonic Acid; D005492:Folic Acid; D003404:Creatinine; D014805:Vitamin B 12
keywords: Arterial stiffness; B-vitamin status; Genetics; Homocysteine; Pathophysiology